Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11](OC)=[O:12])[CH2:4][CH2:3][C:2]21[O:18][CH2:17][CH2:16][O:15]2.CC(C[AlH]CC(C)C)C>C1COCC1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][OH:12])[CH2:4][CH2:3][C:2]21[O:15][CH2:16][CH2:17][O:18]2
Reactant: COC(=O)c1cccc2c1CC1(CC2)OCCO1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1cccc2c1CC1(CC2)OCCO1
Temperature: 25 °C

Procedure:
To a round bottom flask containing methyl 3′,4′-dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalene]-8′-carboxylate (19-2) (1.88 g, 7.57 mmol) was added anhydrous THF (15 ml). The reaction mixture was then cooled to 0 C (ice water bath) while stirring under N2. Then added DIBAL-H (24 mL, 24.00 mmol) dropwise over 10 minutes with stirring. Stirred at 0 C for 10 minutes, then permitted to warm to room temperature. Followed by LC/MS. Stirred overnight at room temperature, noticed there was still some starting material so cooled back to 0 C, then added additional DIBAL-H (19 mL, 19.00 mmol) & after 10 minutes warmed to room temperature. The reaction mixture was cooled to 0 C (ice water bath), then quenched by slow dropwise addition of saturated Rochelle's Salt (Na+/K+ Tartrate) (lots of bubbling so add slowly), then stirred for an hour to help break up/solubilize the emulsion; then suspended in EtOAc, filtered emulsion (gooey material, very little desired product by LC/MS); organics separated, then washed with saturated Rochelle's salt again then washed with saturated NH4Cl, then with saturated NaHCO3, then H2O, then brine; organics dried over sodium sulfate, filtered & concentrated. Purification by silica gel chromatography (30-100% EtOAc/Hex; 80 g ISCO); desired fractions concentrated to yield (3′,4′-dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalen]-8′-yl)methanol (19-3). HRMS [M+Na] calculated; 243.0992, observed; 243.0990.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][CH2:13][C:14]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.[OH-].[K+].C(O)C>O>[CH2:16]([C:14]1[C:13]([O:12][CH3:11])=[CH:4][C:3]2[C:2](=[CH:9][C:8]([Br:10])=[CH:7][CH:6]=2)[N:1]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COCC(=O)Cc1ccccc1
Reactant: Nc1cc(Br)ccc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc2ccc(Br)cc2nc1Cc1ccccc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 68.3 %

Procedure:
A mixture of 3.3 g of 2-amino−4-bromobenzaldehyde, 3.3 g of 1-methoxy-3-phenylacetone, an aqueous potassium hydroxide solution (10 g of potassium hydroxide was dissolved in 10 ml of water) and 20 ml of ethanol was heated under stirring at 100° C. for 4 hours in a sealed tube. After cooling as it was, the reaction solution was poured into water and the mixture was extracted with diethyl ether. The organic phase was washed with brine and the solvent was removed. The residue was crystallized from hexane/ethyl acetate, to give 3.7 g of the target compound.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:15]([O:17]C)=[O:16])[C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].Cl>C1COCC1.[OH-].[Na+]>[C:1]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[C:11]([CH3:12])([CH3:13])[CH3:14])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCCC(=O)N[C@H](C(=O)OC)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCCCCC(=O)N[C@H](C(=O)O)C(C)(C)C
Yield: 84.7 %

Procedure:
A solution of methyl N-hept-6-enoyl-3-methyl-L-valinate (1.40 g, 5.48 mmol) in THF (10 mL) and 1N NaOH (10 mL) was stirred at 22° C. for 2 h. The reaction mixture was acidified to pH 3 with 1 N HCl and extracted with EtOAc (3×150 mL). The combined EtOAc layers were washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to give the title product (1.12 g, 84%). LRMS (ESI) m/z 242.3 [(M+H)+; calcd for C13H24NO3: 242.2].
Reaction SMILES: ClC1C(C2(F)CNC2)=CC(C#N)=CC=1NC1N=C(N(C2CC2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)C2=NC=C(C#N)N2N=1.NC1C(Cl)=C(C2(F)CN([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])C2)C=C(C#N)C=1.ClC1N=C(N(C2CC2)CC2C=CC(OC)=CC=2)C2=NC=C(C#N)N2N=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:53]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54]
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2cc(C#N)cc(N)c2Cl)C1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C4(F)CNC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: C1COCCO1
Product: COc1ccc(CC(=O)OC(C)(C)C)cc1
Temperature: 100 °C

Procedure:
2-((2-chloro-5-cyano-3-(3-fluoroazetidin-3-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile A mixture of tert-butyl 3-(3-amino-2-chloro-5-cyanophenyl)-3-fluoroazetidine-1-carboxylate (21-D), (163 mg, 0.500 mmol), 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (186 mg, 0.525 mmol), DPPF (27.7 mg, 0.050 mmol), Cs2CO3 (326 mg, 1.001 mmol), XANTPHOS (29.0 mg, 0.050 mmol), and palladium(f1) acetate (33.7 mg, 0.150 mmol) in a microwave vial in dioxane (4.5 mL) was evacuated and backfilled with nitrogen for three times, and then was heated in an oil bath at 100° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, filtered through celite to remove insoluble material. The filtrate was washed with water, and brine. After drying with sodium sulfate, the solvents were removed and the product was purified by ISCO column (4 g) chromatography, eluting with hexane containing 0 to 35% EtOAc to afford 167 mg of the Boc-PMB-protected product which was dissolved in DCM (6 ml), added TFA (3 ml), and left stirring at room temperature for 30 min. Removal of the solvent. The crude was applied onto a cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with a mixture of 2 N solution of ammonia in methanol and DCM (1:1). Removal of the solvents left 2-((2-chloro-5-cyano-3-(3-fluoroazetidin-3-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (143 mg) as a solid which was used on next step as such.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.ClC1C=C2C(C(O[Si](C)(C)C)=NC(O[Si](C)(C)C)=N2)=CC=1.Cl[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[N:9]2[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCl
Reactant: O=c1[nH]c(=O)c2ccc(Cl)cc2[nH]1
Agent: C[Si](C)(C)Oc1nc(O[Si](C)(C)C)c2ccc(Cl)cc2n1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Reaction time: 29 h

Procedure:
7-Chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline (10 g) was treated as in Example 1 to give a concentrate containing 7-chloro-2,4-bis(trimethylsilyloxy)quinazoline. To this concentrate was added ethyl chloroacetate (20 ml), and the reaction was carried out at an internal temperature of 140˜150° C. for 29 hours. This reaction mixture was cooled to ≦70° C., and after addition of ethyl acetate (20 ml) , a solvent mixture of methanol (30 ml) and ethyl acetate (20 ml) was added dropwise over about 30 minutes. After completion of dropwise addition, the mixture was worked up as in Example 1 to provide ethyl 2-(7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl)acetate (13.60 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1O.[N+:12]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])#[C-:13]>>[CH:13]1[N:1]2[C:10]3[C:5]([N:4]=[CH:3][C:2]2=[C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[N:12]=1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: Oc1cnc2ccccc2n1
Reactant: [C-]#[N+]CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)c1ncn2c1cnc1ccccc12

Procedure:
M.p. 187°-190° C., from 2-quinoxalinol and tert-butyl isocyanoacetate. (Compound 4)
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[CH:22]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[CH:30]([NH:33][C:34]([C:36]1[CH:37]=[C:38]([NH:46][C:47](=O)[O:48]C2C=CC=CC=2)[CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)=[O:35])([CH3:32])[CH3:31].C(O)(C(F)(F)F)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[CH:30]([NH:33][C:34]([C:36]1[CH:37]=[C:38]([NH:46][C:47]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][C:14]4[C:15]5[CH2:16][CH2:17][NH:8][CH2:9][C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:27][CH:26]=3)[CH:22]=[CH:23]2)=[O:48])[CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=1)=[O:35])([CH3:32])[CH3:31]
Reactant: CC(C)NC(=O)c1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3[nH]ccc3c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cc(NC(=O)n2ccc3cc(Oc4ncnc5c4CCNC5)ccc32)cc(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
To a solution of 4-(1H-Indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (0.16 g, 0.437 mmol) in 4 mL of THF at 0° C., NaH (0.105 g, 2.62 mmol) is added. After stirring for 45 min a solution of phenyl 3-(isopropylcarbamoyl)-5-(trifluoromethyl)phenylcarbamate, Example 13-B, (0.224 g, 0.611 mmol) in 2 mL of THF and 1 mL of DMF is added dropwise. The resulting mixture is stirred for 4 h before being partitioned between EtOAc and cold H2O. The aq layer is extracted further with EtOAc and the combined organic layers are washed with saturated aqueous NaHCO3, brine and dried over Na2SO4. Following concentration the residue is separated by FCC (heptane/EtOAc). The resulting product (0.23 g, 0.360 mmol) is then treated with 70 mL of 50% TFA in DCM at rt for 1 h. After concentration the residue is separated by semi-prep HPLC (10-100% CAN/H2O with 0.1% NH4OH) to provide the title compound. MS (ESI) m/z 539.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.49 (br. S., 1 H), 8.54 (d, J=7.8 Hz, 1 H), 8.38-8.46 (m, 2 H), 8.25-8.32 (m, 2 H), 8.15 (d, J=3.8 Hz, 1 H), 7.98 (s, 1 H), 7.46 (d, J=2.3 Hz, 1 H), 7.13 (dd, J=9.0, 2.4 Hz, 1 H), 4.07-4.21 (m, J=13.9, 6.9, 6.7, 6.7 Hz, 2 H), 3.85 (s, 2 H), 3.07 (t, J=5.8 Hz, 2 H), 2.75 (t, J=5.7 Hz, 2 H), 1.20 (d, J=6.6 Hz, 6 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3=[CH:24][C:25]([CH2:26][OH:27])=[C:21]4[N:22]3[C:17](=[CH:18][CH:19]=[CH:20]4)[C:16]=2[CH2:28][CH3:29])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][N:31]([CH3:40])[C:32](=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Br>>[CH3:30][N:31]([CH3:40])[C:32](=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:27][CH2:26][C:25]1[CH:24]=[C:23]2[N:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=13)[C:16]([CH2:28][CH3:29])=[C:15]2[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: CN(C)C(=O)CCCCCBr
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(CO)c3cccc1n32
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(COCCCCCC(=O)N(C)C)c3cccc1n32
Yield: 31 %

Procedure:
2-(4-Benzyloxyphenyl)-1-ethyl-4-hydroxymethylpyrrolo[2,1,5-cd]indolizine was alkylated, using 6-bromohexanoic acid dimethylamide as the alkylating agent, by the general synthetic principle outlined in Example 5, to afford 6-[2-(4-benzyloxyphenyl)-1-ethylpyrrolo[2,1,5-cd]indolizin-4-ylmethoxy]hexanoic acid dimethylamide as a yellow oil in 31% yield. 1H-NMR (CDCl3, 300 MHz) δ: 1.37-1.50 (m, 5H); 160-1.71 (m, 4H); 2.28 (t, 2H); 2.91 (s, 3H); 2.93 (s, 3H); 3.24 (q, 2H); 3.56 (t, 2H); 5.01 (s, 2H); 5.17 (s, 2H); 7.15 (d, 2H); 7.32-7.54 (m, 6H); 7.63 (t, 1H); 7.73 (d, 2H); 7.90 (d, 1H); 7.99 (d, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:25]([C:32](Cl)=[O:33])=[CH:24]1>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:32]([C:25]3[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[S:23][CH:24]=3)=[O:33])[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:20])[CH3:21]
Reactant: O=C(Cl)c1csc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)c3csc4ccccc34)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 1-benzothiophene-3-carbonyl chloride: ESMS m/e: 464.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]=[CH:4][C:5]([F:8])([F:7])[F:6]>O=[Cr]O[Cr]=O>[F:1][C:2]([F:10])([F:9])/[CH:3]=[CH:4]\[C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)(F)C=CC(F)(F)F
Agent: O=[Cr]O[Cr]=O
Product: FC(F)(F)/C=C\C(F)(F)F

Procedure:
Hexafluoro-2-butene was passed over at a flow rate of 12 g/h over 20 cc of fluorinated chromia catalyst in a Monel tube reactor (0.5 inch×14 inch) at 250° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][CH:13]=[N:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:27]([OH:30])(=[O:29])[CH3:28]>>[C:27]([O:30][CH:13]([NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:23])([F:24])[F:25])[CH2:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][N:4]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)O
Reactant: O=C(N=CCc1ncc(C(F)(F)F)cc1Cl)c1ccccc1C(F)(F)F
Product: CC(=O)OC(Cc1ncc(C(F)(F)F)cc1Cl)NC(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 24 %

Procedure:
0.16 g of N-{2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethylidene}-2-(trifluoromethyl)benzamide (Int-6) were diluted in 2 mL of acetic acid. The reaction mixture was stirred for two days at room temperature and then heated to 90° C. for one day and left at room temperature for four days. After concentration in vacuo, the crude product was purified by chromatography on silica gel to yield 0.045 g (24%) of desired product 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-1-{[2-(trifluoromethyl)benzoyl]amino}ethyl acetate (Ia-112), [M+1]=455.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([Cl:10])=[CH:4][N:3]=1.[NH2:11][C:12]1[N:16]([CH3:17])[N:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=1.C(O)CCC.Cl>O1CCOCC1>[Cl:10][C:5]1[C:6]([NH:8][CH3:9])=[N:7][C:2]([NH:11][C:12]2[N:16]([CH3:17])[N:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1cc(N)n(C)n1
Reactant: CNc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: CNc1nc(Nc2cc(C(=O)OC)nn2C)ncc1Cl
Temperature: 130 °C
Yield: 64.6 %

Procedure:
To a 30 mL microwave vial was added 0.98 g of 2,5-dichloro-N-methylpyrimidin-4-amine, 0.78 g of methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate, 10 mL of 1-butanol and 0.13 mL of 4M hydrogen chloride in dioxane. The vial was capped and the reaction was heated in a microwave for 30 minutes at 130° C. As the reaction cooled, a precipitate fell out. Filter the precipitate and rinse with a small amount of n-butanol. Drying the cake yielded 0.964 g of methyl 5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole-3-carboxylate which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][SH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[CH2:20]([O:19][C:17]([CH2:16][S:11][CH2:10][C@@H:9]([C:12]([OH:14])=[O:13])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CS)C(=O)O
Reactant: O=C(CBr)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CSCC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-(tert-Butyloxycarbonyl)-L-cysteine (3.5 g, 15.8 mmol), benzyl 2-bromoacetate (3.7 g, 16.1 mmol) and triethylamine (1.8 g, 18.0 mmol) were dissolved in THF (100 ml). The mixture was stirred for 18 hours at room temperature then diluted with ethyl acetate (100 ml), washed with 0.3M KHSO4, sat NaHCO3, water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant: 95% chloroform, 4% methanol, 1% acetic acid) to give a colourless oil identified as S-(benzyloxyrarbonylmethyl)-N-(tert-butyloxycarbonyl)-L-cysteine (5.2 g, 14.1 mmol, 89%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1([CH2:20][CH:21]=[CH2:22])[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=[O:6])[CH3:3]>O1CCOCC1>[CH2:2]([O:4][C:5]([C:7]1([CH2:20][CH:21]=[CH2:22])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: C=CCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C=CCC1(C(=O)OCC)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of hydrochloric acid (12N, 4 mL) in dioxane (6 mL) is added to 4-allyl piperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester (2 g, 0.006 mol) and stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure and the residue is treated with aqueous solution of sodium bicarbonate to adjust the pH to 8-9. It is again concentrated under reduced pressure and the residue is treated with dichloromethane. After drying over sodium sulfate solvent is removed to get 4-allylpiperidine-4-carboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[F:11].[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC.C(OCC)(=O)C>C(Cl)Cl.CO>[Br:12][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:11])[CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(Cl)c(F)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(CBr)c1ccc(Cl)c(F)c1
Yield: 68.6 %

Procedure:
To a solution of 1-(4-chloro-3-fluorophenyl)ethanone (3.4 g, 19.7 mmol), prepared in the previous step, in methylene chloride:methanol (1:3) was added tetrabutylammonium tribromide (9.5 g, 19.7 mmol) in portions. The reaction was monitored by TLC (3:1 hexane:ethyl acetate) until the starting material was consumed. The reaction solution was concentrated in vacuo and the residue was partitioned between diethyl ether and water. The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 4.2 g of crude product. The crude product was purified on silica gel using 5% ethyl acetate:hexane to give 2-bromo-1-(4-chloro-3-fluoro-phenyl)-ethanone (3.4 g, 69%) as desired product, MS (ES) m/z 252 [M+H+].
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[CH2:6][NH:7][C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.CC(C)([O-])C.[K+].[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=1[CH2:40]Br>C1COCC1>[F:18][C:17]([F:19])([F:20])[C:15]1[CH:14]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:16]=1)[CH2:6][N:7]([CH2:40][C:31]1[CH:32]=[C:33]([C:36]([F:37])([F:39])[F:38])[CH:34]=[CH:35][C:30]=1[Br:29])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: FC(F)(F)c1ccc(Br)c(CBr)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (3.9 g, 12 mmol) in THF (50 mL) at room temperature was added potassium tert-butoxide (KOtBu) (13.2 ml of 1M solution, 13.2 mmol) followed by 1-bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene (4 g, 12.6 mmol). The mixture was stirred at room temperature for 16 hours. Additional KOtBu in THF (13.2 mL of 1M solution, 13.2 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (3×50 mL). The combined organic layers were washed with saturated NaCl (50 mL), dried (MgSO4) and concentrated. The residue was purified by flash chromatography (silica gel) (eluted with 3:1 hexane-ethyl acetate) to yield the title compound (4.72 g). 1H NMR (400 MHz, CDCl3) δ 4.2 (s, 3 H) 4.8 (s, 2 H) 4.9 (s, 2 H) 7.4 (dd, J=8.2, 1.7 Hz, 1 H) 7.5 (d, J=1.7 Hz, 1 H) 7.7 (m, 3 H) 7.8 (s, 1 H). MS (ES+) Calc: 561.02, Found: 561.7 (M+1).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15]2[N:20]=[N:19][C:18]([N:21]([CH2:29][C:30]3([C:34]4[C:39]([F:40])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH2:33][CH2:32][CH2:31]3)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=2)=[N:12][CH:11]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl-].[NH4+]>C1COCC1>[F:40][C:39]1[C:34]([C:30]2([CH2:29][N:21]([C:18]3[N:19]=[N:20][C:15]([C:13]4[S:14][C:10]([CH2:9][OH:8])=[CH:11][N:12]=4)=[CH:16][CH:17]=3)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:33][CH2:32][CH2:31]2)=[N:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CO[Si](C)(C)C(C)(C)C)s2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CO)s2)nn1
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
To a solution of t-butyl 6-(5-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (112.5 g, 0.19 mol) in THF (1000 mL) was added TBAF (105 mL, 0.29 mol, 75% w/w). The reaction was stirred for 30 min followed by the addition of ammonium chloride (200 mL). The organic layer was separated, washed with brine (300 mL×3), and concentrated (this wash was repeated once). Ethyl acetate was added to the oil, resulting in a white solid. Filtration of the solid afforded 44 g of t-butyl (1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(5-(hydroxymethyl)thiazol-2-yl)pyridazin-3-yl)carbamate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.S(C1C=CC(C)=CC=1)(O[CH2:20][CH2:21][F:22])(=O)=O>CN(C=O)C.C(OCC)(=O)C>[F:22][CH2:21][CH2:20][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: Nc1ccccc1
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FCCNc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
In a round bottom flask aniline (0.5 g, 5.4 mmol), 2,6-lutidine (0.58 g, 5.4 mmol) and 2-fluoroethyl tosylate (12; prepared according to Example 2(a)) (1.17 g, 5.4 mmol) were combined in DMF (2.5 mL) and stirred at 100° C. overnight. The reaction was allowed to cool and then diluted with ethyl acetate (50 mL). This was washed with water (3×20 mL) and the organics were dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (100 g, 0-100% B, 18 CV, 85 mL/min) to give 435 mg (60%) of (2-fluoro-ethyl)-phenyl-amine (24) as a yellow oil. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 3.41 (1H, t, J=3 Hz, NCH2CH2F), 3.50 (1H, t, J=3 Hz, NCH2CH2F), 3.93 (1H, s, br), 4.54 (1H, t, J=3 Hz, NCH2CH2F), 4.71 (1H, t, J=3 Hz, NCH2CH2F), 6.65-6.82 (3H, m, 2×NCCH, NCCHCHCH), 7.14-7.28 (2H, m, 2×NCCHCHCH).