Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][CH:13]=[C:14]([CH3:16])[N:15]=1)[C:5]([OH:7])=[O:6].C(O)(=O)C.[Br:21]Br.S(=O)(O)[O-].[Na+]>>[Br:21][C:13]1[S:12][C:11]([C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[CH3:1])=[N:15][C:14]=1[CH3:16]
Reactant: BrBr
Reactant: Cc1csc(-c2ccc(C(=O)O)cc2C)n1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)ccc1-c1nc(C)c(Br)s1
Yield: 87 %

Procedure:
3-Methyl-4-(4-methylthiazol-2-yl)benzoic acid (all recovered product from step A above) was dissolved in acetic acid (20 mL, 349 mmol), and bromine (1.774 mL, 34.4 mmol) was added. After sonicating for 5 minutes, LCMS showed complete conversion. Excess sodium bisulfite was added to the reaction solution until the red color disappeared. The suspension was filtered, and the filtrate was concentrated. The crude was purified on a silica gel column, eluting with 30% ethyl acetate, to give title compound as a white solid (6.2 g, 87% yield). LCMS (M+H)+: 313.9. 1H NMR (DMSO, 500 MHz): δ 7.90 (s, 1H), 7.85 (s, 2H), 2.56 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[CH:11]=[C:10]([NH:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[C:9]([CH3:25])=[CH:8][C:7]=2[C:6]([CH3:27])([CH3:26])[CH2:5][CH:4]=1)[CH3:2].[CH:28](=O)[CH3:29]>>[CH2:28]([N:13]([C:10]1[C:9]([CH3:25])=[CH:8][C:7]2[C:6]([CH3:27])([CH3:26])[CH2:5][CH:4]=[C:3]([CH2:1][CH3:2])[C:12]=2[CH:11]=1)[C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=1)[CH3:29]
Reactant: CC=O
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CC=C3CC)cc1
Product: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C)(C)CC=C3CC)cc1
Yield: 44.4 %

Procedure:
Following General Procedure D, ethyl 4-[(8-ethyl-3,5,5-trimethyl-5,6-dihydronaphthalen-2-yl)amino]benzoate (Compound 16, 0.25 g, 0.69 mmol) was reacted with acetaldehyde (0.8 mL, 13.8 mmol) to give 0.12 g (43%) of the title compound as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([CH3:15])[C:4]=1[C:5]([O:7][CH3:8])=[O:6].C1C(=O)N([Br:23])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:15][C:9]1[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)cc(OC)cc1OC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)cc(OC)cc1OC
Yield: 82.1 %

Procedure:
Dissolve compound 3 (10 g, 0.0476 mol) in 50 ml carbon tetrachloride, heat to reflux under nitrogen protection, add portion wise a mixture of NBS (8.5 g, 0.0476 mol) and BPO (0.11 g, 0.476 mmol), after finishing the addition, reflux to react for 1 h. Then stop the reaction, cool and filter the mixture, spin-dry filtrate to obtain a pale yellow solid, re-crystallize from ethanol to obtain 11.3 g white solid (82%). 1H-NMR (400M, CDCl3) δ (ppm): 3.85 (s, 3H), 3.93 (s, 3H), 3.96 (s, 3H), 4.66 (s, 2H), 6.47 (s, 1H), 6.74 (s, 1H).
Reaction SMILES: [CH3:1][SH:2].BrBr.[CH3:5][C:6]([CH3:14])([CH:12]=[CH2:13])[C:7]([O:9]CC)=[O:8]>C(Cl)(Cl)(Cl)Cl>[CH3:5][C:6]([CH3:14])([CH:12]=[CH:13][S:2][CH3:1])[C:7]([OH:9])=[O:8]
Reactant: CS
Reactant: C=CC(C)(C)C(=O)OCC
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CSC=CC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
A solution of methanethiol (8 g) in CCl4 was stirred and treated dropwise at -25° C. with bromine (26.6 g). Ethyl 2,2-dimethyl-3-butenoate (23 g) was then added dropwise at that temperature over two hours. Following the addition, the solution was allowed to warm to room temperature, then concentrated in vacuo. NMR showed near complete conversion to the 4-bromo-3-methylthio ester (38 g). The residual oil was then heated one hour on a steam bath to effect conversion to the thermodynamically favored 3-bromo-4-methylthio ester. This material was then dissolved in 50 mL of DMF and treated with 26 g of DBU. The solution was heated briefly on a steam bath, then was allowed to cool and worked up by pouring into water, extracting with 2×200 mL of ether, drying and concentrating. The residual oil (24.75 g) was hydrolyzed by stirring overnight in a solution of 50 mL of ethanol, 15 mL of water and 7.8 g of sodium hydroxide. Acidification with 1N HCl and extraction into ether followed by drying and concentration furnished a solid which was recrystallized from ether/hexane to give 13.5 g of 2,2-dimethyl-4-methylthio-3-butenoic acid, m.p. 49°-51° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([CH2:14][C:15]([OH:17])=O)[CH2:10][C:11](O)=[O:12].[NH4+:18].[OH-]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[CH2:14][C:15](=[O:17])[NH:18][C:11](=[O:12])[CH2:10]1
Reactant: O=C(O)CC(CC(=O)O)c1c(Cl)cccc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1CC(c2c(Cl)cccc2Cl)CC(=O)N1
Temperature: 190 °C

Procedure:
14.5 g (52 mmol) of 3-(2,6-dichloro-phenyl)-pentanedioic acid were dissolved in 140 mL of conc. NH4OH solution. All the volatiles were removed in vacuo and the resulting solid was heated to 190° C. for 6 h. The crude reaction mixture was taken up in CH2Cl2, the organic phase was washed with 0.1 M Na2CO3 solution, dried and evaporated to dryness. The resulting crude solid was triturate with Et2O, filtered and dried, yielding 9.37 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:21](O)=O)[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([NH2:35])[CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[C:21]1[NH:34][C:31]2[CH:32]=[CH:33][C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:29][C:30]=2[N:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCOCc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CCCOCc1ccccc1)c1nc2cc(C(C)(C)C)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 4 Steps 1 and 2 using 5-(benzyloxy)-N-(tert-butoxycarbonyl)-L-norvaline and 4-tert-butyl-1,2-diaminobenzene. The crude product was purified by silica gel column chromatography eluting with 30-40% EtOAc in petroleum ether (430 mg, 52%).
Reaction SMILES: O[CH2:2][C:3]1[C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([OH:17])[CH:13]=3)[C:8]3([C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19](=[O:26])[O:18]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[OH:27].[F:28][C:29]([F:52])([F:51])[C:30]([NH:32][C@@H:33]([CH3:50])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)(=[O:43])=[O:42])=[CH:37][CH:36]=1)=[O:31].[I-].[Na+].N1C(C)=CC=CC=1C>CN(C)C=O>[OH:27][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3([C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19](=[O:26])[O:18]3)[C:9]3[C:14]([O:15][C:16]=2[C:3]=1[CH2:2][N:47]1[CH2:48][CH2:49][N:44]([S:41]([C:38]2[CH:37]=[CH:36][C:35]([CH2:34][C@@H:33]([NH:32][C:30](=[O:31])[C:29]([F:52])([F:51])[F:28])[CH3:50])=[CH:40][CH:39]=2)(=[O:42])=[O:43])[CH2:45][CH2:46]1)=[CH:13][C:12]([OH:17])=[CH:11][CH:10]=3
Reactant: C[C@@H](Cc1ccc(S(=O)(=O)N2CCNCC2)cc1)NC(=O)C(F)(F)F
Reactant: O=C1OC2(c3ccc(O)cc3Oc3c2ccc(O)c3CO)c2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: C[C@@H](Cc1ccc(S(=O)(=O)N2CCN(Cc3c(O)ccc4c3Oc3cc(O)ccc3C43OC(=O)c4ccccc43)CC2)cc1)NC(=O)C(F)(F)F
Temperature: 120 °C
Yield: 35 %

Procedure:
A mixture of 61 mg (0.160 mmol) of rac-4'-(hydroxymethyl)-3',6'-dihydroxyspiro[isobenzofuran-1(3H), 9'-[9H]xanthen]-3-one (2), 125 mg (0.33 mmole) of (S)-2,2,2-trifluoro-N-[1-methyl-2-[4-(1-piperazinylsulfonyl)phenyl]ethyl]acetamide (17), 150 mg (1.0 mmol) of sodium iodide and 600 μL (5.15 mmol) of 2,6 lutidine in 4.5 mL of anhydrous dimethylformamide was heated at 120° C. for 2 hours. The reaction mixture was concentrated and 20 mL of a 1:1 mixture of methanol:THF was added. Inorganic salt was filtered off and the filtrate was concentrated. The residue was purified by thin layer chromatography using 50% chloroform in ethyl acetate to yield 41 mg of (S)-N-[2-[4-[[4-[(3',6'-dihydroxy-3-oxospiro[isobenzo-furan-1(3H),9'-[9H]xanthen]-4'-yl)methyl]-1-piperazinyl]-sulfonyl]phenyl]-1-methylethyl]-2,2,2-trifluoroacetamide (1:1 epimers) (18) (0.056 mmol, 35%) as an orange red powder. NMR, IR and MS data confirmed the compound identity.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.C[N:14](C)[CH:15]=[CH:16][C:17]#N.N>O.C(O)CC>[NH2:14][C:15]1[N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[N:11]=[CH:17][CH:16]=1
Reactant: CN(C)C=CC#N
Reactant: NNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: N
Solvent: CCCO
Solvent: O
Product: Nc1ccnn1-c1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
7.65 g (50 mmol) of 4-nitrophenylhydrazine was suspended in 70 mL of water and 10 mL of n-propanol and the suspension was heated to about 50° C. At this temperature, 5 g (50 mmol) of concentrated hydrochloric acid and 4.81 g (50 mmol) of 3-dimethylaminoacrylonitrile were then added. After an additional 15 minutes, 3.8 mL (50 mmol) of a 25% ammonia solution was added dropwise within 15 minutes. The reaction mixture was then allowed to agitate at about 50° C. until the 3-dimethylaminoacrylonitrile had completely reacted (about 1 hour) after which the resulting dark-brown suspension was cooled in an ice bath. The precipitate was filtered off, washed 3 times with small portions of cold water and then dried. Yield of crude product: 9.4 g (46 mmol. 92% of the theoretical).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].CN(C)[CH:14]=[CH:15][C:16]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)=O>C(O)(=O)C>[S:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:16]1[N:3]2[CH:4]=[N:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[N:1]=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1[nH]cnc1N
Reactant: CN(C)C=CC(=O)c1cccs1
Solvent: CC(=O)O
Product: CCOC(=O)c1ncn2c(-c3cccs3)ccnc12

Procedure:
A mixture of 1.55 g. (0.01 mols) of ethyl 4-amino-5-imidazolecarboxylate and 1.81 g. (0.01 mols) of 3-dimethylamino-1-(2-thienyl)-2-propen-1-one (prepared as described in Example 1, Part A) in 25 ml. of glacial acetic acid can be refluxed for 16 hours, then cooled and evaporated to dryness in vacuo. The residue can be dissolved in dichloromethane and passed through a short column of hydrous magnesium silicate. The effluent can be refluxed on a steam bath with a slow constant addition of n-hexane. At the first appearance of crystallization, heating should be curtailed and the solution allowed to cool. The precipitated material can be collected by filtration to produce ethyl 4-(2-thienyl)imidazo[1,5-a]pyrimidine-8carboxylate.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N+:12]([O-])=O)=[O:5])[CH2:3][CH2:2]1.[H][H]>>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(c1ccccc1[N+](=O)[O-])C1CC1
Reactant: [H][H]
Product: Nc1ccccc1C(=O)C1CC1

Procedure:
Beneficially, the o-nitrophenyl cyclopropyl ketone may be reduced in the presence of hydrogen and a catalyst to give o-aminophenyl cyclopropyl ketone. The reaction is shown in Flow Diagram II. ##STR2##
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].[Cl:7][S:8]([N:11]=C=O)(=[O:10])=[O:9]>C1C=CC=CC=1>[C:1]([NH:11][S:8]([Cl:7])(=[O:10])=[O:9])(=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCCC(=O)O
Solvent: c1ccccc1
Product: CCCC(=O)NS(=O)(=O)Cl
Yield: 99.7 %

Procedure:
n-Butanoic acid (0.881 g, 10 mmol) was added slowly dropwise to chlorosulfonyl isocyanate (1.42 g, 10 mmol), with ice/water bath cooling as required to maintain gentle gas evolution. After the addition was complete, the residue was taken up in benzene (10 mL) and the mixture concentrated in vacuo to provide the title compound (1.85 g, quantitative) as a crystalline, hygroscopic solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.CN(C)C=O.[H-].[Na+].Cl[CH2:25][C:26]1[N:27]=[C:28]([CH:31]=[CH:32][C:33]2[CH:43]=[CH:42][C:36]3[O:37][C:38]([F:41])([F:40])[O:39][C:35]=3[CH:34]=2)[O:29][CH:30]=1>O>[F:41][C:38]1([F:40])[O:37][C:36]2[CH:42]=[CH:43][C:33]([CH:32]=[CH:31][C:28]3[O:29][CH:30]=[C:26]([CH2:25][O:16][C:13]4[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]5[CH:5]=[CH:4][N:3]=[N:2]5)=[CH:15][CH:14]=4)[N:27]=3)=[CH:34][C:35]=2[O:39]1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: FC1(F)Oc2ccc(C=Cc3nc(CCl)co3)cc2O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC1(F)Oc2ccc(C=Cc3nc(COc4ccc(CCCCn5ccnn5)cc4)co3)cc2O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.4 %

Procedure:
To a solution of 0.217 g (1.00 mmol) 4-(4-[1,2,3]Triazol-1-yl-butyl)-phenol in 4 ml N,N-dimethyl formamide 40 mg (1.00 mmol) of NaH (60% dispersion in mineral oil) were added and the mixture stirred for 15 min at room temperature. Subsequently 0.3 g (1.00 mmol) 4-chloromethyl-2-[2-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-vinyl]-oxazole were added and stirring continued for 12 h. 20 ml of water were added, the resulting precipitate collected, washed with water (2×), methanol/water (1:1), ether (3×) and dried in vacuo yielding 0.42 g (87%) 1-[4-(4-{2-[2-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-1H-[1,2,3]triazole as white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([C:14]1[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=1)([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:20][N:17]1[CH2:16][C:15]2[C:4]3[C:3](=[CH:2][CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=3)[C:11]([CH3:13])([CH3:12])[C:14]=2[CH:19]=[CH:18]1
Reactant: CN1CC=C(C(C)(C)c2ccc([N+](=O)[O-])cc2Br)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1C=CC2=C(C1)c1cc([N+](=O)[O-])ccc1C2(C)C
Temperature: 80 °C

Procedure:
4-[1-(2-Bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-1,2,3,6-tetrahydro-pyridine (9 g), Pd(OAc)2 (900 mg), and DIEA (15 mL) was dissolved in DMF (300 mL), and heated to 80° C. overnight. Solvents were removed in vacuo. The residue was partitioned between CH2Cl2/NaHCO3(sat, aq.). The CH2Cl2 layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified via flash chromatography on silica to give the desired compound. (MS: M+H=257)
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[N:28]=[C:29]=[O:30]>O1CCCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[NH:28][C:29]([NH:13][C:12]1[CH:14]=[CH:15][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)=[O:30]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)OC1(C)C
Reaction time: 1 h

Procedure:
To an ambient solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.0 g, 9.13 mmol) in tetrahydrofuran (30 mL) was added 2-fluoro-5-trifluoromethylphenyl isocyanate (1.32 mL, 9.13 mmol). After 1 h, the mixture was concentrated under reduced pressure to afford the title compound as a white solid. MS (ESI) m/z 425 [M+H]+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([CH2:10]O)=[N:5]2.S(Cl)([Cl:14])=O>>[Cl:14][CH2:10][C:6]1[CH:7]=[CH:8][C:9]2[N:4]([CH:3]=[CH:2][N:1]=2)[N:5]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2nccn2n1
Product: ClCc1ccc2nccn2n1
Yield: 69 %

Procedure:
Thionyl chloride (10 ml) was added to imidazo[1,2-b]pyridazin-6-ylmethanol (1.5 g, 9.0 mmol) at 20° C. under an atmosphere of nitrogen at RT. The reaction mixture was stirred at reflux for 3 h (the reaction was monitored by TLC) upon which the volatiles were removed under reduced pressure. The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 15% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 6-(chloromethyl) imidazo[1,2-b]pyridazine (1.2 g, 69%) as an off-white solid. 1H NMR, 200 MHz, DMSO-d6: δ 8.35 (s, 1H), 8.3 (d, 1H), 7.85 (s, 1H), 7.35 (d, 1H), 4.95 (s, 2H). MS: [M+H]+: m/z=149.9.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=O.[C:10](OC(=O)C)(=[O:12])C>C(O)=O>[CH:10]([NH:1][C@@H:2]1[C:7](=[O:8])[O:9][C:4](=[O:6])[CH2:3]1)=[O:12]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Solvent: O=CO
Product: O=CN[C@H]1CC(=O)OC1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
13.3 g (0.1 mole) of L-aspartic acid was added to the mixture of 6.0 g of formic acid and 20.6 g of acetic anhydride, and the mixture was stirred for 4 hours at 50° C. After cooling the reaction mixture to 20° C., the crystal of N-formyl-L-aspartic anhydride precipitated was isolated by filtration, and washed with 30 ml of ethylether. After drying, 10.8 g (0.075 moles) of N-formyl-L-aspartic anhydride were obtained. The crystal thus obtained was admixed with 75 ml of acetic acid to form a slurry, to which 700 ml of toluene containing 16.4 g (0.07 moles) of D-valine-N-(S)-ethylbenzylamide was added over a period of 40 minutes while stirring at 15° C., and the mixture was stirred for further 1 hour at 60° C. Quantitative analysis using HPLC indicated that 0.044 moles of N-formyl-α-L-aspartyl-D-valine-N-(S)-ethylbenzylamide (yield of 62.9% based on D-valine-N-(S)-ethylbenzylamide) were produced in the reaction mixture. 1000 ml of 0.5N hydrochloric acid was added to the reaction mixture, which was then heated under reflux for 20 minutes. The toluene layer was subjected to layer separation to isolate the aqueous layer, which was cooled to 40° C. and then adjusted to pH 5 with 15% sodium carbonate. After stirring for 5 hours at 10° C., the crystal precipitated was isolated by filtration and dried to obtain 11.65 g (0.0333 moles) of α-L-aspartyl-D-valine-N-(S)-ethylbenzylamide. Yield: 47.6% based on D-valine-N-(S)-ethylbenzylamide.
Reaction SMILES: C(OC([N:8]1[CH:16]2[CH2:17][O:18][CH2:19][CH:9]1[C:10]1[CH:11]=[N:12][O:13][C:14]=1[CH:15]2[F:20])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:20][CH:15]1[CH:16]2[NH:8][CH:9]([CH2:19][O:18][CH2:17]2)[C:10]2[CH:11]=[N:12][O:13][C:14]1=2
Reactant: CC(C)(C)OC(=O)N1C2COCC1C(F)c1oncc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC1c2oncc2C2COCC1N2
Yield: 145.1 %

Procedure:
A solution of 7-Fluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene-12-carboxylic acid tert-butyl ester (150 mg) in TFA/DCM (5 mL, 1:2) was stirred at room temperature for 1 h. The solvent was removed in vacuo to give 7-fluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene 106a (141 mg) as yellow oil, crude yield: 100%. MS: calc'd (MH+) 185, measured (MH+) 185.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@H:8]2[F:20])[C:5](=[O:21])[CH2:4][S:3]1.[Cl:22][C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([CH:37]=O)=[CH:34][CH:35]=3)[CH:30]=[N:29]2)=[C:25]([C:41]([F:44])([F:43])[F:42])[CH:24]=1>>[Cl:22][C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33](/[CH:37]=[C:4]4/[C:5](=[O:21])[N:6]([C@@H:7]5[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][C@H:8]5[F:20])[C:2](=[O:1])[S:3]/4)=[CH:34][CH:35]=3)[CH:30]=[N:29]2)=[C:25]([C:41]([F:42])([F:44])[F:43])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N2C(=O)CSC2=O)[C@H](F)C1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Product: CC(C)(C)OC(=O)N1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@H](F)C1

Procedure:
1,1-Dimethylethyl trans-4-{(5Z)-5-[(1-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}-1H-indazol-5-yl)methylidene]-2,4-dioxo-1,3-thiazolidin-3-yl}-3-fluoropiperidine-1-carboxylate was prepared either from 1,1-dimethylethyl trans-4-(2,4-dioxo-1,3-thiazolidin-3-yl)-3-fluoropiperidine-1-carboxylate (from Example 273) and [4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 1) following General Procedure F1, or as described in Example 273, Preparation 2.
Reaction SMILES: [Na+].[CH:2]1([CH2:8][S:9]([O-:12])(=O)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O=P(Cl)(Cl)[Cl:15]>>[CH:2]1([CH2:8][S:9]([Cl:15])(=[O:12])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=S(=O)([O-])CC1CCCCC1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Product: O=S(=O)(Cl)CC1CCCCC1
Temperature: 100 °C

Procedure:
To the compound of Example 12 (4.0 g, 20 mmole) was added POCl3 (15 mL) and the mixture heated at 100° C. for 48 hours. Upon cooling to room temperature the mixture was poured onto crushed ice and then the aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic extracts were then washed with saturated aqueous sodium bicarbonate (2×50 mL), brine and then dried over MgSO4, filtered and the solvent was evaporated under vacuum to provide 3.46 g of the title compound as a light yellow oil. Thin layer chromatography analysis of the title compound showed a single spot with Rf =0.53 (silica, 4:1 hexanes/ethyl acetate).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[N:19]=[CH:18][C:17]3[C:16]4[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13][C:12]=4[S:11][C:10]=3[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH:54]4[CH2:57][O:56][CH2:55]4)[CH2:50][C@@H:49]3[CH3:58])=[CH:44][N:43]=2)[C:27]1=[O:59]>>[CH3:20][C:14]1([CH3:21])[CH2:13][C:12]2[S:11][C:10]3[C:9](=[O:22])[N:8]([C:4]4[C:3]([CH:23]=[O:24])=[C:2]([C:30]5[CH:29]=[C:28]([NH:41][C:42]6[CH:47]=[CH:46][C:45]([N:48]7[CH2:53][CH2:52][N:51]([CH:54]8[CH2:55][O:56][CH2:57]8)[CH2:50][C@@H:49]7[CH3:58])=[CH:44][N:43]=6)[C:27](=[O:59])[N:26]([CH3:25])[CH:31]=5)[CH:7]=[CH:6][N:5]=4)[N:19]=[CH:18][C:17]=3[C:16]=2[CH2:15]1
Reactant: CC1(C)Cc2sc3c(=O)n(-c4nccc(Cl)c4C=O)ncc3c2C1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5c6c(sc5c4=O)CC(C)(C)C6)c3C=O)cn(C)c2=O)nc1

Procedure:
Following the procedure for preparation in Example 191k, and starting with 282i (216 mg, 0.60 mmol), and (5)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 191j (482 mg, 0.90 mmol), 282j was obtained as a yellow solid (407 mg, 48%). MS-ESI: [M+H]+ 678.8
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8]P(=O)(OCC)OCC)[CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.CC(C)([O-])C.[K+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6](/[CH:8]=[CH:20]/[C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[F:17])[N:7]=1
Reactant: CCOP(=O)(Cc1cccc(Br)n1)OCC
Reactant: O=Cc1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccccc1/C=C/c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of diethyl (6-bromopyridin-2-yl)methylphosphonate (320 mg, 1.039 mmol) in tetrahydrofuran (9.4 mL) was added 2-fluorobenzaldehyde (129 mg, 1.04 mmol). The resulting solution was cooled to 0° C., and treated with potassium tert-butoxide (1M in tetrahydrofuran, 1.1 mL, 1.1 mmol). After 15 min at 0° C., the reaction was quenched by addition of saturated ammonium chloride and concentrated. The resulting residue was dissolved in ether, washed with water, then brine, dried over magnesium sulfate, and concentrated to give an oil which solidified upon standing. The solid was triturated with hexane to afford 215 mg (78%). 1H NMR (CDCl3) δ: 7.78 (d, J=16.2 Hz, 1H), 7.64 (td, J=7.6, 1.5 Hz, 1H), 7.50-7.58 (m, 1H), 7.37 (t, J=7.8 Hz, 2H), 7.29-7.34 (m, 1H), 7.15-7.26 (m, 2H), 7.12 (dd, J=10.5, 8.7 Hz, 1H). 13C NMR (CDCl3) δ: 161.1, 157.0, 142.3, 138.9, 130.1, 129.0, 128.4, 127.2, 126.5, 124.4, 124.2, 120.8, 116.1 19F NMR (CDCl3) δ: −116.28 (br. s., 1F). Mass spec.: 278.0 (MH)+.