Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)[CH:3]=1.[C:13]([O:17][C:18](=[O:26])[NH:19][C:20]1[S:21][CH:22]=[C:23]([CH3:25])[N:24]=1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:26])[NH:19][C:20]1[S:21][C:22]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3([C:11]#[N:12])[CH2:10][CH2:9]3)[CH:3]=2)=[C:23]([CH3:25])[N:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: N#CC1(c2cc(Br)ccn2)CC1
Reactant: Cc1csc(NC(=O)OC(C)(C)C)n1
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C2(C#N)CC2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
The title compound is prepared in analogy to the procedure described in Step 1.3, but using 1-(4-bromo-pyridin-2-yl)-cyclopropanecarbonitrile (Step 18.3) and (4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (Step 18.4). The reaction mixture is stirred for 2 h at 100° C., quenched by dilution with EtOAc/H2O, and extracted with EtOAc. The crude product is purified by silica gel column chromatography (Hex/EtOAc, 1:1) to afford 122 mg of the title compound as a white solid: ESI-MS: 357.1 [M+H]+; tR=4.86 min (System 1); TLC: Rf=0.29 (Hex/EtOAc, 1:1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([CH2:14][C:15]2[C:23]([I:24])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([F:26])=[N:9][C:10]=2[NH2:25].[CH:27]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28]1.C(N(CC)CC)C>CN(C=O)C>[NH2:25][C:10]1[N:9]=[C:8]([F:26])[N:7]=[C:6]2[C:11]=1[N:12]=[C:13]([CH2:14][C:15]1[C:23]([I:24])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=1)[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][S:30]([CH:27]1[CH2:29][CH2:28]1)(=[O:32])=[O:31]
Reactant: NCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(F)nc2c1nc(Cc1cc3c(cc1I)OCO3)n2CCCNS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of 9-(3-aminopropyl)-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine (100 mg, 0.21 mmol) in DMF (3 mL) was added cyclopropanesulfonyl chloride (89 mg, 0.32 mmol) and triethylamine (90 uL, 0.96 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed and purified by flash chromatography to yield WS72 as a white solid (82 mg, 67%). 1H NMR (600 MHz, CDCl3/MeOH-d4): δ 7.32 (s, 1H), 6.79 (s, 1H), 6.02 (s, 2H), 4.27 (s, 2H), 4.22 (t, J=7.3 Hz, 2H), 3.18 (t, J=6.4 Hz, 2H), 2.45-2.50 (m, 1H), 2.00-2.06 (m, 2H), 1.12-1.17 (m, 2H), 0.99-1.04 (m, 2H); 13C NMR (150 MHz, CDCl3/MeOH-d4): δ 159.0 (d, J=209.8 Hz), 156.9 (d, J=19.7 Hz), 152.4 (d, J=18.5 Hz), 151.2 (d, J=2.3 Hz), 149.3, 148.4, 131.4, 119.0, 116.3 (d, J=3.6 Hz), 110.4, 102.4, 88.7, 40.7, 40.1, 39.3, 30.2, 29.9, 5.3; HRMS (ESI) m/z [M+H]+ calcd, for C19H21FIN6O4S, 575.0374. found 575.0390.
Reaction SMILES: C12(COC3C(I)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[C:24]12([CH2:34][O:35][C:36]3[C:44]([Br:45])=[CH:43][C:39]([C:40](O)=[O:41])=[C:38]([F:46])[CH:37]=3)[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2.N1(S(N)(=O)=O)CCC1.[CH3:55][S:56]([NH2:59])(=[O:58])=[O:57]>>[C:24]12([CH2:34][O:35][C:36]3[C:44]([Br:45])=[CH:43][C:39]([C:40]([NH:59][S:56]([CH3:55])(=[O:58])=[O:57])=[O:41])=[C:38]([F:46])[CH:37]=3)[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2
Reactant: O=C(O)c1cc(Br)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: CS(N)(=O)=O
Agent: NS(=O)(=O)N1CCC1
Agent: O=C(O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: CS(=O)(=O)NC(=O)c1cc(Br)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 299 Step 2 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with 4-(adamantan-1-ylmethoxy)-5-bromo-2-fluorobenzoic acid and to replace azetidine-1-sulfonamide with methanesulfonamide, the title compound was obtained as a colorless solid (1.00 g, 49%): 1H NMR (300 MHz, DMSO-d6) δ 12.10 (br s, 1H), 7.90 (d, J=7.3 Hz, 1H), 7.17 (d, J=12.4 Hz, 1H), 3.71 (s, 2H), 3.35 (s, 3H), 1.98 (br s, 3H), 1.78-1.56 (m, 12H); MS (ES−) m/z 458.2, 460.1 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].[CH2:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:12]#[CH:13].CCN(CC)CC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CC#N>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13]#[C:12][CH2:11][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(Br)s1
Reactant: C#CCNS(C)(=O)=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCNS(C)(=O)=O)s1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
To a solution of 5-bromo-thiophene-2-carboxylic acid methyl ester (1.66 g, 8.0 mmol), N-prop-2-ynyl-methanesulfonamide (1.09 g, 8.2 mmol), Et3N (1.7 mL, 12.1 mmol), and CH3CN (30 mL) was added Pd(PPh3)4 (462 mg, 0.4 mmol) followed by CuI (76 mg, 0.4 mmol). The reaction was heated at reflux for 24 h and was cooled to room temperature. The volatiles were removed in vacuo and the residue was purified via flash chromatography (20% EtOAc in hexanes to 33% EtOAc in hexanes) to yield 5-(3-methanesulfonylamino-prop-1-ynyl)-thiophene-2-carboxylic acid methyl ester as a pale yellow solid (1.1 g). 1H NMR (300 MHz, CDCl3) δ 7.64 (d, 1H), 7.14 (d, 1H), 4.60 (m, 1H), 4.22 (d, 2H), 3.88 (s, 3H), 3.10 (s, 3H); MS 274 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>ClCCl>[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:35])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]4)=[CH:4][CH:3]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Temperature: 25 °C
Reaction time: 9 h

Procedure:
The compound of example 223 (0.230 g, 0.00153 mol) was dissolved in 5 mL dichloromethane and to this reaction mixture, 4-fluorophenyl isocyanate (0.102 g, 0.000744 mol) was added and stirred at room temperature for 8-10 h. The reaction mixture was concentrated and purified by column chromatography (silicagel, 30-40% ethyl acetate in petroleum ether to obtain the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[CH:27]=[CH:26][C:20]2[O:21][C:22]([F:25])([F:24])[O:23][C:19]=2[CH:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:27]3[CH:17]=[CH:18][C:19]4[O:23][C:22]([F:24])([F:25])[O:21][C:20]=4[CH:26]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2ccc3c(c2)OC(F)(F)O3)CCN1c1cnccc1C1CC1
Yield: 59.4 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.492 mmol) was reacted with 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (128.4 mg, 0.541 mmol), 1,4-dioxane (5 mL), copper iodide (9.3 mg, 0.049 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (5.6 mg, 0.049 mmol) and potassium phosphate (313.6 mg, 1.447 mmol) to afford the crude product. Purification by column chromatography on silica gel (2.0% methanol in CHCl3) afforded 105 mg of the product (60% yield).
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][CH2:18][CH:17]=[CH:16][O:15]1)([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.[OH-:20].[Na+].OO>C1COCC1.C([O-])(O)=O.[Na+]>[CH:1]([C@@H:14]1[O:15][CH2:16][C@@H:17]([OH:20])[CH2:18][CH2:19]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: C1=COC(C(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: O[C@H]1CC[C@H](C(c2ccccc2)c2ccccc2)OC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Into a solution of 0.5M 9-BBN-THF complex (24 ml, 12 mmol) in dry THF (20 ml) was added in a drop wise manner 2-diphenyl-3,4-dihydro-2H-pyran 10 (1 g, 4 mmol) dissolved in dry THF (10 ml). The mixture was kept under stirring at room temperature. After the completion of initial addition reaction, the intermediate reaction mixture was oxidized with 5.3 ml 3N sodium hydroxide and 3 ml of 30% hydrogen peroxide. The reaction was continued at 55° C. for 1 hr to insure the completion of oxidation. After the mixture was diluted with sat. aqueous NaHCO3, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×40 ml). The combined extract was dried over anhydrous Na2SO4. The solvent was removed in vacuo and the crude product was purified by flash chromatography (Hexane/Ethyl Acetate 7:3) to furnish trans-6-diphenyltetrahydropyran-3-ol 11 (1 g, 93.5%) as a liquid.
Reaction SMILES: [OH-:1].[CH2:2]([N+:9]([CH3:12])([CH3:11])[CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:13](=[O:15])=[O:14]>CO>[C:13](=[O:1])([OH:15])[O-:14].[CH2:2]([N+:9]([CH3:12])([CH3:11])[CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: O=C=O
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CO
Product: O=C([O-])O

Procedure:
As described for C-13, a solution of benzyltrimethylammonium hydroxide (Triton B) in methanol was reacted with gaseous CO2, to obtain a clear solution of 0.986 meq/g.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19](O)=O>>[CH2:1]([N:8]1[C:9](=[O:18])[C:10]2[C:11](=[CH:12][C:13]([Br:16])=[CH:14][CH:15]=2)[N:17]=[CH:19]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Br)ccc1C(=O)NCc1ccccc1
Reactant: O=CO
Product: O=c1c2ccc(Br)cc2ncn1Cc1ccccc1

Procedure:
10 ml of formic acid was added to 18.5 g of N-benzyl-2-amino-4-bromobenzamide, and was heated under reflux for 2 hours. After distilling out excess reagent under reduced pressure, saturated sodium bicarbonate aqueous solution was added, and extracted with ethyl acetate. Ethyl acetated layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by silicagel column chromatography (hexane/ethyl acetate=7/3), to obtain 821 mg of the above compound as a colorless solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[CH:26])[CH2:20][CH2:19][C:18]4([O:24][CH2:23][CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:28]1[CH:33]=[CH:32][C:31](O)=[C:30]([N+:35]([O-:37])=[O:36])[CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>N1CCCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:33]4[CH:32]=[CH:31][C:30]([N+:35]([O-:37])=[O:36])=[CH:29][CH:28]=4)[CH2:20][CH2:19][C:18]4([O:21][CH2:22][CH2:23][O:24]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC2(CC1)OCCO2
Reactant: O=[N+]([O-])c1cc(I)ccc1O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCNCC1
Product: COc1ccc(C2(C#Cc3ccc([N+](=O)[O-])cc3)CCC3(CC2)OCCO3)cc1OC1CCCC1
Temperature: 80 °C

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.15 g, 0.42 mmol) and 4-iodonitrophenol (0.11 g, 0.42 mmol) in piperidine (2 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium(0) (0.02 g, 4%), copper(I) iodide (0.005 g, 6%) and a small crystal of triphenylphosphine. After heating at 80° C. for 0.5 h, water and 1N hydrochloric acid were added. The mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(4-nitrophenylethynyl)cyclohexane as a red-orange wax. mp 58°-59° C. 1H-NMR (400 MHz, CDCl3) δ 8.18 (d, J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 7.16 (d, J=2.5 Hz, 1H), 7.12 (dd, J=8.4, 2.5 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 4.80 (m, 1H), 4.01 (s, 4H), 3.85 (s, 3H), 1.8-2.3 (m, 14H), 1.6 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:51][CH:52]1[CH2:54][NH:53]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:25]([N:53]3[CH2:54][CH:52]3[CH3:51])=[O:26])[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:22]=[N:21][C:20]([CH3:23])=[N:19][CH:18]=3)=[O:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC1CN1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3cnc(C)nc3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(C(=O)N3CC3C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-((2-methylpyrimidin-5-yl)methylcarbamoyl)-biphenyl-3-carboxylic acid (11 mg, 0.030 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (12 mg, 0.061 mmol), 1-hydroxybenzotriazole hydrate (4.7 mg, 0.030 mmol), CH2Cl2 (2 mL) were added 2-methyl-aziridine (3.5 mg, 0.061 mmol) and N,N-diisopropylethylamine (11 μL, 0.061 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-70% MeCN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14].[NH2:17][C:18]1[CH:25]=[C:24](F)[C:21]([C:22]#[N:23])=[CH:20][N:19]=1>C1COCC1>[NH2:17][C:18]1[CH:25]=[C:24]([O:14][CH2:13][C:12]([F:16])([F:15])[F:11])[C:21]([C:22]#[N:23])=[CH:20][N:19]=1
Reactant: OCC(F)(F)F
Reactant: N#Cc1cnc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cnc(N)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of KHMDS in THF (1 M, 16.1 ml, 16.04 mmol) was added drop wise to a solution of 2,2,2-trifluoroethanol (0.53 ml, 7.29 mmol) in THF (40 ml) at room temperature. After 2 min a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 1.0 g, 7.29 mmol) in THF (10 ml) was added and the reaction mixture stirred for 2 h at room temperature. The reaction mixture was partitioned between saturated aqueous NH4Cl and EtOAc, extracted with EtOAc (2×), the combined organic layers were dried over Na2SO4 and evaporated. The residue was triturated with Et2O and heptane to give the title compound. (UPLC-MS 7) tR 0.70; ESI-MS 218.1 [M+H]+.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[Br:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[Br:14][C:15]1[N:16]=[CH:17][N:18]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[O:12][CH3:13])[CH:19]=1
Reactant: Brc1c[nH]cn1
Reactant: COC(=O)c1ccc(F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cnc(Br)c2)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 16.1 %

Procedure:
A mixture of methyl 4-fluoro-3-methoxybenzoate (2.13 g), 4-bromo-1H-imidazole (3.74 g) and potassium carbonate (4.80 g) in DMF (20 mL) was stirred at 100° C. overnight, and allowed to cool to room temperature, and ethyl acetate and water were added. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.580 g).
Reaction SMILES: [C:1]([N:5]1[C:29](=[O:30])[C:28]2[N:13]3[CH2:14][CH2:15][C:16]4[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:21]=4[C:12]3=[CH:11][C:10]=2[CH2:9][O:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:31]N1C(=O)CCC1=O.O>CN(C=O)C.[O-]S([O-])(=S)=O.[Na+].[Na+]>[C:1]([N:5]1[C:29](=[O:30])[C:28]2[N:13]3[CH2:14][CH2:15][C:16]4[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:20][C:21]=4[C:12]3=[C:11]([Br:31])[C:10]=2[CH2:9][O:8][CH2:7][CH2:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc2c(cc1OC(C)C)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC(C)C)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of 180 mg of 18c in 2 ml of DMF was added 85 mg of N-bromosuccinimide. The mixture was stirred for ½ hr at RT. 3 ml of water was added and two drops of sat. aq. Na2S2O3 and the mixture was stirred for ½ hr. The precipitate was filtered and washed with water, dried and then triturated with diisopropyl ether, to provide 175 mg of 18d as white crystalline material. Mp 160-162° C.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:21](=[O:22])[N:10]2[CH2:11][C@@H:12]([O:19][CH3:20])[CH2:13][CH2:14][C@@H:15]([NH:16][CH2:17][CH3:18])[C:9]2=[N:8][C:7]=1[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:24])(=[O:4])=[O:3].[CH3:34][N:35]([CH3:41])[C:36](=[O:40])[C:37](O)=[O:38].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CS(Cl)(=O)=O>C(Cl)Cl.O.C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:21](=[O:22])[N:10]2[CH2:11][C@@H:12]([O:19][CH3:20])[CH2:13][CH2:14][C@@H:15]([N:16]([C:37](=[O:38])[C:36]([N:35]([CH3:41])[CH3:34])=[O:40])[CH2:17][CH3:18])[C:9]2=[N:8][C:7]=1[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:24])(=[O:3])=[O:4]
Reactant: CN(C)C(=O)C(=O)O
Reactant: CCN[C@@H]1CC[C@H](OC)Cn2c1nc(C(=O)NCc1ccc(F)cc1)c(OS(C)(=O)=O)c2=O
Agent: CS(=O)(=O)Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CC#N
Solvent: O
Product: CCN(C(=O)C(=O)N(C)C)[C@@H]1CC[C@H](OC)Cn2c1nc(C(=O)NCc1ccc(F)cc1)c(OS(C)(=O)=O)c2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the (7S,10R)-10-(ethylamino)-2-{[(4-fluorobenzyl)amino]carbonyl}-7-methoxy-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-3-yl methanesulfonate (4.8 g, 9.99 mmol) in DCM (100 mL) at room temperature was added TEA (8.35 mL, 59.9 mmol), N,N-dimethyloxamic acid (2.34 g, 19.98 mmol), EDC (5.74 g, 30 mmol), and HOAt (4.62 g, 30 mmol). The resulting mixture was stirred at room temperature overnight, then diluted with H2O and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. To a solution of crude material (8 g, 15.89 mmol) in ACN (159 mL) at 0° C. was added TEA (6.64 mL, 47.7 mmol) and MsCl (3.64 g, 31.8 mmol) dropwise. The reaction mixture was stirred at 0° C. for 20 min, then diluted with water and extracted with EtOAc (3×). The combined organic extracts were concentrated in vacuo and the residue was purified by flash column chromatography eluted with 0 to 7% MeOH in DCM to provide (7S,10R)-10-[[(dimethylamino)(oxo)acetyl](ethyl)amino]-2-{([(4-fluorobenzyl)amino]carbonyl}-7-methoxy-4-oxo-4,6,7,8,9,10-hexahydropyrimido [1,2-a]azepin-3-yl methanesulfonate, LC-MS: 582.5 (M+1).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].C(CC(O)=O)C1C=CC=CC=1.[CH2:16]([O:23][C:24](=[O:29])[CH2:25][C:26]([CH3:28])=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.C(O)(=O)C>[CH2:16]([O:23][C:24](=[O:29])[CH2:25][C:26]([CH:28]=[N:1][OH:3])=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=N[O-]
Reactant: CC(=O)CC(=O)OCc1ccccc1
Agent: O=C(O)CCc1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(C=NO)CC(=O)OCc1ccccc1

Procedure:
450 g of Sodium nitrite in 600 ml of water are added dropwise, at 0° over 3 hrs. to a solution of 1000 ml acetoacetic acid benzylester (benzylacetate) in 1000 ml of glacial acetic acid and the mixture stirred for 18 hrs. at room temperature. After the addition of 3000 ml of water the mixture is extracted three times with 1500 ml portions of dichloromethane. The combined extracts are washed twice with 500 ml portions of water. Potassium carbonate is added with thorough stirring until the aqueous phase is neutral. The organic phase is separated, dried with magnesium sulphate and the solvent removed in vacuum. The residue is taken up in 5000 ml of di-isopropyl ether, the insoluble material filtered off and the solution again evaporated to dryness. Trituration with petroleum ether and filtration yields the title product
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8](N(OC)C)=[O:9])[S:4][N:3]=1.I[Mg][C:16]1[CH:20]=[CH:19][S:18][CH:17]=1.Cl>O1CCCC1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[O:9])[S:4][N:3]=1
Reactant: CON(C)C(=O)c1snc(Cl)c1Cl
Reactant: I[Mg]c1ccsc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(c1ccsc1)c1snc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 65 %

Procedure:
To a solution of 3,4-dichloro-N-methoxy-N-methyl-1,2-thiazole-5-carboxamide (3.80 g, 15.7 mmol) in tetrahydrofuran (130 mL) at −5° C. was added dropwise a solution of iodo(3-thienyl)magnesium in tetrahydrofuran (0.3 M, 158 mL, 47.4 mmol). After stirring at room temperature for 72 h, the reaction was worked-up by the addition of aq. HCl (1 M) until pH<7. After removal of the tetrahydrofuran in vacuo, the aqueous phase was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The residue was purified on silica gel to afford (3,4-dichloro-1,2-thiazol-5-yl)(3-thienyl)methanone [3.00 g, yield 65%; HPLC/MS: m/z=264 (M+H); log P(HCOOH)=3.31].
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][O:30][C:31]([C:33]1[N:34]([CH3:39])[N:35]=[C:36]([NH2:38])[CH:37]=1)=[O:32]>>[CH3:29][O:30][C:31]([C:33]1[N:34]([CH3:39])[N:35]=[C:36]([NH:38][C:8](=[O:9])[CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:26])([F:27])[F:28])[CH:13]=[N:12]2)[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:37]=1)=[O:32]
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2C(F)(F)F)cc1=O
Reactant: COC(=O)c1cc(N)nn1C
Product: COC(=O)c1cc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C(F)(F)F)cc2=O)nn1C
Yield: 17 %

Procedure:
Using the method described in Example 11, 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 21) and 5-amino-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (Intermediate 8) afforded 5-{3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionylamino}-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester as a white solid (22.1 mg, 17%); ES+-HRMS m/e calcd for C25H26N5O5F3 [M+H+] 534.1959 found 534.1959. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.09 (m, 1H), 1.23-1.75 (m, 8H), 1.95 (m, 1H), 2.23 (m, 1H), 3.82 (s, 3H), 4.01 (s, 3H), 5.46 (dd, J=4.5, J=10.4 Hz, 1H), 5.93 (d, J=2.9 Hz, 1H), 6.95 (s, 1H), 7.53-7.60 (m, 2H), 7.83 (t, J=7.8 Hz, 1H), 7.90 (d, J=7.8 Hz, 1H), 8.19 (d, J=2.9 Hz, 1H), 11.06 (s, 1H).