Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCCOC.I[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:10][C:9]=1[NH2:19].[CH3:20][Si:21]([C:24]#[C:25][Si](C)(C)C)([CH3:23])[CH3:22].C([O-])([O-])=O.[Na+].[Na+]>CCCCCC.CCOC(C)=O.CO>[CH3:18][S:15]([CH2:14][C:12]1[CH:13]=[C:8]2[C:9](=[CH:10][CH:11]=1)[NH:19][C:24]([Si:21]([CH3:23])([CH3:22])[CH3:20])=[CH:25]2)(=[O:17])=[O:16]
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Reactant: CS(=O)(=O)Cc1ccc(N)c(I)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: C[Si](C)(C)c1cc2cc(CS(C)(=O)=O)ccc2[nH]1
Yield: 82.7 %

Procedure:
To a solution of 1,2-dimethoxyethane (DME, 70 mL) was added 2 -iodo-4-[(methylsulfonyl)methyl]benzenamine (1) (1.9 g, 0.0061 mol), bis(trimethylsilyl) acetylene (1.56 g, 0.00915 mol), tetrakistriphenylphosphine Pd(O) (0.705 g, 0.00061 mol) and saturated aqueous Na2CO3 (5 mL). The reaction was heated at reflux for 48 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc and washed with brine. The organic layer was dried over MgSO4, filtered and evaporated to give the crude product. Silica gel chromatography (20-100% EtOAc gradient in hexane followed by 5-10% MeOH gradient in EtOAc) of the concentrate afforded the product (2) (1.42 g, 83%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH:7]=1.Cl.[CH3:21][N:22](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:22][CH3:21])=[O:14])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1Sc1ccc(C(=O)O)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(Sc2cc(Cl)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product from step (ii) (0.23 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.22 g), 1-hydroxybenzotriazole (0.15 g), N,N-diisopropylethylamine (0.3 g) and methylamine (2M in THF, 0.78 ml) in DMF (10 ml) was stirred at RT overnight. Water was added and the mixture extracted with ethylacetate, the organics were dried and evaporated under reduced pressure, yield 0.24 g.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.[CH2:12]([NH2:15])[CH:13]=[CH2:14].[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH2:12]([NH:15][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([O:18][C:17]([F:16])([F:28])[F:29])=[CH:20][CH:21]=1)[CH:13]=[CH2:14]
Reactant: C=CCN
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C=CCNC(=O)c1ccc(OC(F)(F)F)cc1
Reaction time: 2.5 h
Yield: 96 %

Procedure:
To a solution of 1-hydroxybenzotriazole hydrate (5.4 g, 40 mmol), allyl amine (60 mmol), and 4-(trifluoromethoxy)benzoic acid (8.3 g, 40 mmol) in DMF (110 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (11.5 g, 60 mmol) at R.T. After the reaction mixture was stirred for 2.5 hrs, the solution was partitioned between 10% citric acid and ether. The organic layer was washed with sat. aqueous sodium bicarbonate, dried (sodium sulfate), filtered, and concentrated. The residue was purified by silica gel chromatography (20% ether/hexanes) to yield the title compound (colorless solid 96%). 1H NMR (400 MHz, CDCl3) δ7.85 (d, J=7.1 Hz, 2 H, Ar), 7.28 (d, J=5.9 Hz, 2 H, Ar), 6.31 (s, 1 H, NH), 5.94 (m, 1 H, CH2CHCH2), 5.25 (dd,J=8.6, 7.1 Hz, 2 H, NHCH2CH), 4.10 (m, 2 H, CHCH2);
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[N+:14]([O-])=O)[CH3:2].CC(O)=O>C(O)C.ClCCl.[Fe]>[CH2:1]([O:3][C:4]([C:5]1[NH:14][C:8]2[C:7]([CH:6]=1)=[CH:12][CH:11]=[C:10]([Cl:13])[CH:9]=2)=[O:18])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1

Procedure:
To crude 3-(4-chloro-2-nitro-phenyl)-2-oxo-propionic acid ethyl ester (151 mmol) in ethanol:glacial HOAc (1:1, v/v, 560 mL) at rt was added iron powder (74.4 g) and the reaction mixture was stirred at reflux for 4 h. The mixture was filtered and evaporated to give a residue which was redistributed in dichloromethane/1N HCl. The organic layer was washed with 1N HCl, NaHCO3, and brine and dried. Evaporation followed by crystallization (DCM) gave 6-Chloro-1H-indole-2-carboxylic acid ethyl ester as a pale yellow solid (16.8 g, 50% over 2 steps).
Reaction SMILES: ClC(Cl)(Cl)COC([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:9][CH2:8]1)=O>C(O)(=O)C.O1CCCC1.O.[Zn]>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[O:13][CH:10]1[CH2:11][CH2:12][NH:7][CH2:8][CH2:9]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC(Oc2ccc3ccccc3c2)CC1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: c1ccc2cc(OC3CCNCC3)ccc2c1

Procedure:
The resulting 1-(2,2,2-trichloroethoxycarbonyl)-4-(2-naphthalenyloxy)piperidine is dissolved in a mixture of 250 ml of acetic acid, 250 ml of tetrahydrofuran and 125 ml of water. 28.5 g (0.436 mole) of zinc dust is added in portions with stirring and the exothermic reaction allowed to proceed for 21/2 hours. The mixture is filtered and the solvents are removed in vacuo. The residue is partitioned between ether and aqueous sodium hydroxide and the organic phase washed with water and extracted with dilute aqueous hydrochloric acid. The acid extracts are washed with ether, made basic with sodium hydroxide and extracted into ether and toluene and the organic solution washed, dried over magnesium sulfate and concentrated in vacuo to yield 4-(2-naphthalenyloxy)piperidine, which is redissolved in ethanol/ether and treated with dry HCl, and the hydrochloride salt recrystallized from butanone/methanol. M.P. 229.5°-231.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:19])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24](C(=O)C)[CH2:23][CH2:22]2)[N:3]=1.FC(F)(F)C(O)=O.[CH3:37][S:38](N1CCC(N)CC1)(=[O:40])=[O:39]>>[NH2:1][C:2]1[C:7]([C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:19])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1cccc(OC)c1C(=O)c1cnc(NC2CCN(C(C)=O)CC2)nc1N
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(OC)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with 1-[4-[4-amino-5-(2,6-dimethoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl}-ethanone (Example 333) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,6-dimethoxy-phenyl)-methanone. MS (M+H)+, 436
Reaction SMILES: O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:22][O:23][C:24]1[CH:40]=[CH:39][C:27]([CH:28]=[C:29]2[C:34](=[O:35])[O:33][C:32]([CH3:37])([CH3:36])[O:31][C:30]2=[O:38])=[CH:26][CH:25]=1>O.ClCCl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C@H:28]([CH:29]2[C:34](=[O:35])[O:33][C:32]([CH3:37])([CH3:36])[O:31][C:30]2=[O:38])[C:21]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:39][CH:40]=1
Reactant: COc1ccc(C=C2C(=O)OC(C)(C)OC2=O)cc1
Reactant: C#Cc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: O
Solvent: ClCCl
Product: COc1ccc([C@@H](C#Cc2ccccc2)C2C(=O)OC(C)(C)OC2=O)cc1
Temperature: 0 °C
Yield: 27.4 %

Procedure:
A solution of copper (II) acetate monohydrate (10 mg, 0.050 mmol) in water (0.2 ml) was treated with sodium (L)-ascorbate (20 mg, 0.10 mmol), the mixture was stirred until the mixture was turned bright orange (3 min). Subsequently, (R,M)-3-{[4-(2-diphenylphosphanyl-7-methoxy-naphthalen-1-yl)-phthalazin-1-ylamino]-phenyl-methyl}-pentan-3-ol (1st diastereomer, 33.1 mg, 0.050 mmol) and phenylacetylene (0.275 ml, 2.5 mmol) were added, the resulting mixture was stirred for 10 min at 23° C., cooled to 0° C., stirred for 5 min and treated with 5-(4-methoxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (65.6 mg, 0.25 mmol). The reaction mixture was stirred vigorously at 0° C. for 64 hrs, diluted with dichloromethane (2 ml) and subjected directly to flash chromatography on silica gel (hexane/EtOAc 3:1→1:1) to give 25 mg of the pure title compound as a white solid. (yield: 27%)
Reaction SMILES: CO[C:3]1[CH:27]=[CH:26][C:25]2[C:9]3[N:10]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:11]4[NH:12][CH2:13][CH2:14][CH2:15][C:16]=4[C:17](=[O:18])[C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=1.[C:28](Cl)(=[O:30])[CH3:29].C(N(CC)CC)C>C(Cl)Cl>[C:28]([N:12]1[C:11]2[N:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]3[C:25]4[CH:26]=[CH:27][CH:3]=[CH:4][C:5]=4[CH2:6][CH2:7][C:8]=3[C:17](=[O:18])[C:16]=2[CH2:15][CH2:14][CH2:13]1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)CCc1c-2n(-c2ccccc2)c2c(c1=O)CCCN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCc2c1n(-c1ccccc1)c1c(c2=O)CCc2ccccc2-1

Procedure:
Treat 5,6,8,9,10,11-hexahydro-3-methoxy-12-phenyl-naphtho[1,2-b][1,8]naphthyridin-7(12H)-one (10 mmoles) with equimolar amounts of acetyl chloride and triethylamine dissolved in CH2Cl2 (10 ml) at 0°-25° C. for 3 days. Wash the resulting solution with aqueous NaHCO3 solution and with water, and dry the organic solution. Evaporate the CH2Cl2, and chromatograph the residue on silica gel. Elute the N-acetylated product with 2% MeOH in CHCl3, and crystallize it from isopropyl acetate/disopropyl ether to provide 11-acetyl-5,6,8,9,10,11-hexahydro-12-phenyl-naphtho[1,2-b][1,8]naphthyridin-7(12H)-one, m.p. 178.5°-182° C.
Reaction SMILES: C1C=CC(N/N=C2/C(S([O-])(=O)=O)=CC3C(C/2=O)=C(N)C(N=NC2C=CC([N+]([O-])=O)=CC=2)=C(S([O-])(=O)=O)C=3)=CC=1.[Na+].[Na+].[CH2:42]([NH-])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59]CCCC.CC(CC(C)(C)C)=C.C1(=O)OC(=O)C=C1>>[CH2:42]=[CH:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]
Reactant: CCCCCCCCCCCCCCCCCCCCCC[NH-]
Agent: C=C(C)CC(C)(C)C
Agent: Nc1c(N=Nc2ccc([N+](=O)[O-])cc2)c(S(=O)(=O)[O-])cc2c1C(=O)/C(=N\Nc1ccccc1)C(S(=O)(=O)[O-])=C2
Agent: O=C1C=CC(=O)O1
Product: C=CCCCCCCCCCCCCCCCC

Procedure:
The white resin dispersion obtained in Production Example 2 (32 g), 2.5 g of the nigrosine dispersion obtained in Example 1, and 0.02 g of a half docosanylamide of diisobutylene/maleic anhydride copolymer were diluted with 1 liter of Isopar G to prepare a liquid developer.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]3[C:13]([CH3:14])=[CH:12][S:11][C:10]=13)[NH:7][C:6]([C:15]([O:17]C)=[O:16])=[CH:5]2>[OH-].[Na+].CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]3[C:13]([CH3:14])=[CH:12][S:11][C:10]=13)[NH:7][C:6]([C:15]([OH:17])=[O:16])=[CH:5]2
Reactant: COC(=O)c1cc2cc(Br)c3scc(C)c3c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1csc2c(Br)cc3cc(C(=O)O)[nH]c3c12
Temperature: 25 °C
Yield: 100.3 %

Procedure:
2.5 g of (70) was hydrolyzed during 3 hours at reflux in a mixture of 25 ml 4 N NaOH and 100 ml MeOH/water 1+1. After cooling to room temperature and acidification with acetic acid the product precipitated. Filtration and drying gave 2.4 g of (71). M.p. 229°-41° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11](=[O:21])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH3:22][N:14]1[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11](=[O:21])[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:15]1=[O:16]
Reactant: CC(C)(C)OC(=O)NC1CC(=O)c2ccccc2NC1=O
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)C(NC(=O)OC(C)(C)C)CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
A solution of 3-tertbutyloxycarbonylamino-2,3,4,5-tetrahydro-2,5-dioxobenzo[b]azepine (5 g, 17.2 mmole) in DMF (50 mL) was treated with potassium carbonate (4.76 g, 34.4 mmole) and methyl iodide (4.88 g, 34.4 mmole). The reaction was stirred at ambient temperature for 4 hours. The mixture was diluted with ethyl acetate (300 ml) and saturated aqueous sodium hydrogen carbonate (500 ml). The organic layer was separated and the aqueous layer was extracted again with ethyl acetate (2×300 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was swished with warm ethyl ether (200 mL) and collected by filtration to give 4.1 g of the product. mp 205°-206° C.
Reaction SMILES: C(N(CC)CC)C.N1(C2C=CN=CC=2)CCCC1.[CH2:19]([C:21]([CH3:27])([CH2:25][CH3:26])[C:22](Cl)=[O:23])[CH3:20].[Si:28]([O:35][C@H:36]1[CH2:45][C@H:44]([OH:46])[C@H:43]2[C:38]([CH:39]=[CH:40][C@H:41]([CH3:64])[C@@H:42]2[CH2:47][CH2:48][C@H:49]2[O:54][C:53](=[O:55])[CH2:52][C@H:51]([O:56][Si:57]([C:60]([CH3:63])([CH3:62])[CH3:61])([CH3:59])[CH3:58])[CH2:50]2)=[CH:37]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C1C=CC=CC=1.C(OCC)(=O)C>[Si:28]([O:35][C@H:36]1[CH2:45][C@H:44]([O:46][C:22](=[O:23])[C:21]([CH2:25][CH3:26])([CH3:27])[CH2:19][CH3:20])[C@H:43]2[C:38]([CH:39]=[CH:40][C@H:41]([CH3:64])[C@@H:42]2[CH2:47][CH2:48][C@H:49]2[O:54][C:53](=[O:55])[CH2:52][C@H:51]([O:56][Si:57]([C:60]([CH3:63])([CH3:62])[CH3:61])([CH3:58])[CH3:59])[CH2:50]2)=[CH:37]1)([C:31]([CH3:32])([CH3:33])[CH3:34])([CH3:30])[CH3:29]
Reactant: CCC(C)(CC)C(=O)Cl
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Agent: c1cc(N2CCCC2)ccn1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC(C)(CC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 99.6 %

Procedure:
0.76 ml (5.4 mmol) of triethylamine, 807 mg (5.4 mmol) of 4-(1-pyrrolidinyl)pyridine and 674 mg (4.5 mmol) of 2-ethyl-2-methylbutyryl chloride were added to a solution of 500 mg (0.91 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]-ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] in 10 ml of benzene and the resulting mixture was heated under reflux for 5 hours. At the end of this time, the reaction mixture was diluted with 50 ml of ethyl acetate. The diluted mixture was then washed with 30 ml of water, 30 ml of a 10% w/v aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, in that order. The organic phase was then dried over anhydrous magnesium sulfate, after which this phase was filtered. The filtrate was concentrated by evaporation under reduced pressure and the concentrate was purified by flash column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the-eluent, to give 601 mg (100% yield) of the title compound.
Reaction SMILES: O=S(Cl)Cl.[Br:5][C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[CH3:17]O>O>[Br:5][C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:7]=1[C:8]([O:10][CH3:17])=[O:9]
Reactant: CO
Reactant: COc1ccc(C(=O)O)c(Br)c1
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(OC)cc1Br
Temperature: 79 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
SOCl2 (7.5 mL, 103.0 mmol) is added dropwise to a stirred 0° C. suspension of 2-bromo-4-methoxybenzoic acid (3) (6.5 g, 28.1 mmol) in methanol (12 mL). The mixture is next stirred at 79° C. for 18 h and then cooled to room temperature before removal of methanol and excess SOCl2 at reduced pressure. The residue is diluted with H2O (50 mL) and extracted with ethyl acetate (100 mL and 70 mL). The extract is washed (2 N NaOH and brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (14.3% to 16.7% ethyl acetate/hexane) to give 5.9 g (85%) of 4 as a colorless liquid. IR 2952, 1728, 1597, 1261 cm−1; 1H NMR (CDCl3) δ 3.83 (s, 3H, CH3O), 3.89 (s, 3H, CO2CH3), 6.86 (dd, J=7.2, 2.0 Hz, 1H, 5-PhH), 7.18 (d, J=2.0 Hz, 1H, 3-PhH), 7.85 ppm (d, J=7.2 Hz, 1H, 6-PhH).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]([OH:19])=O)=[CH:15][N:16]=2)[CH:13]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:24]#[N:25].CCN(C(C)C)C(C)C>ClCCl.ClCCCl.CN(C=O)C>[C:24]([C:23]1[CH:26]=[CH:27][C:28]([CH3:29])=[C:21]([NH:20][C:17]([C:14]2[N:12]3[CH:13]=[C:8]([F:7])[CH:9]=[CH:10][C:11]3=[N:16][CH:15]=2)=[O:19])[CH:22]=1)#[N:25]
Reactant: O=C(O)c1cnc2ccc(F)cn12
Reactant: Cc1ccc(C#N)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1ccc(C#N)cc1NC(=O)c1cnc2ccc(F)cn12
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Oxalyl chloride (10 mL, 110 mmol) was added dropwise to a stirred suspension of 6-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid (24b) (2 g, 11 mmol) and catalytic amounts of DMF in dichloromethane (20 mL). After 5 hours, the solvent was evaporated and the solid was suspended in dry DCE (20 mL) and added to a stirred solution of 3-amino-4-methylbenzonitrile (1.45 g, 11 mmol) and DIEA (6 mmol) in DCE (10 mL) at 0° C. After the addition, the reaction was heated at 60° C. for 5 hours. The mixture was subjected to standard aqueous work and silica purification to give N-(5-cyano-2-methylphenyl)-6-fluoroimidazo[1,2-a]pyridine-3-carboxamide (39) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 10.14 (s, 1H), 9.45 (dd, J=5.2, 2.0 Hz, 1H), 8.62 (s, 1H), 7.90-7.87 (m, 2H), 7.68-7.63 (m, 1H), 7.53 (d, J=8.0 Hz, 1H), 2.37 (s, 3H). MS m/z 295.1 (M+1)+.