Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Br[C:13]1[S:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][C:13]3[S:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=3)=[N:3][C:4]=2[CH:10]=1
Reactant: Cc1ccc2nc(S)[nH]c2c1
Reactant: O=Cc1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2[nH]c(Sc3ccc(C=O)s3)nc2c1
Temperature: 110 °C
Yield: 47.4 %

Procedure:
a mixture of 0.82 g of 2-mercapto-5-methyl-benzimidazole (5 mmoles), 0.6 ml of 5-bromo-2-thiophenecarboxaldehyde (5 mmoles) and 1.4 g of potassium carbonate in 10 ml of DMF is heated at 110° C. for 2 hours. The mixture is cooled down to room temperature, then poured into 200 ml of water and extracted twice with 50 ml of ethyl acetate. The combined organic extracts are washed with brine, dried over MgSO4 and concentrated. The crude product is purified on silica gel using DCM/MeOH as eluent to give 0.65 g of 5-(5-methyl-1H-benzimidazol-2-ylsulfanyl)-thiophene-2-carbaldehyde. (Yield=47%). Analytical LC/MS method A: ([M+H]+): 275). RT: 3.42 min (gradient 5 to 85% acetonitrile in 7 min).
Reaction SMILES: [CH2:1]([C:3]1[S:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=1)[CH3:2].[Cl:12][S:13](O)(=[O:15])=[O:14].P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([C:3]1[S:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]=1[S:13]([Cl:12])(=[O:15])=[O:14])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCc1cc2cccnc2s1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1sc2ncccc2c1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.3 %

Procedure:
To a solution of 2-ethylthieno[2,3-b]pyridine (0.43 g, 2.6 mmoles) in CH2Cl2 (10 ml) at -78° C. was added chlorosulfonic acid (0.9 ml, 13 mmoles). The reaction was warmed to ambient temperature over a 1 hr. period, then stirred an additional 20 hrs., followed by the addition of phosphorus oxychloride (1.7 ml, 18 mmoles) and phosphorus pentachloride (0.82 g, 4.0 mmoles). One hour later the reaction mixture was added to ice (100 ml) and extracted with EtOAc (75 ml), then washed with sat. NaHCO3 (200 ml). The organic phase was dried (MgSO4), filtered and concentrated to collect a brown oil. Flash chromatography (10% EtOAc/hexanes) provided 0.39 g (56%) of the title compound as a light yellow oil.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([NH2:21])=[CH:16][C:15]=1[CH3:22].O>O1CCOCC1>[Br:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([N:21]=[C:5]=[O:11])=[CH:16][C:15]=1[CH3:22]
Reactant: Cc1cc(N)cc(C)c1Br
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(N=C=O)cc(C)c1Br
Temperature: 100 °C
Reaction time: 15 h
Yield: 117.6 %

Procedure:
Triphosgene (2.23 g, 7.52 mmol) was added to a solution of 4-bromo-3,5-dimethyl-phenylamine (4.3 g, 21.49 mmol) in dioxane (71 ml). After stirring at 100° C. for 15 hours, water was added to the reaction solution. After extraction with ethyl acetate, the organic phase was sequentially washed with water and saturated brine and concentrated under reduced pressure to give 2-bromo-5-isocyanato-1,3-dimethylbenzene (2.0 g, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:17][CH:16]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH:19]=4)[CH2:14][CH2:13]3)[C:6]=2[CH:27]=1.[CH3:28][CH2:29][CH2:30]CCC.C(Br)C=C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:13][CH:14]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]([CH2:30][CH:29]=[CH2:28])[CH:19]=4)[CH2:16][CH2:17]3)[C:6]=2[CH:27]=1
Reactant: CCCCCC
Reactant: Clc1ccc2scc(CCN3CC=C(c4c[nH]c5ccccc45)CC3)c2c1
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCn1cc(C2=CCN(CCc3csc4ccc(Cl)cc34)CC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole (392 mg, 1 mmol) (obtained from example 32, step 2) in dry THF (50 ml) was slowly added to a stirred suspension of hexane and was washed with 60% sodium hydride (44 mg) at 0° C. After the addition, the reaction mixture was stirred for 30 min and allyl bromide (183 mg, 1.5 mmol) was added. The reaction mixture was stirred for 4 hrs and quenched carefully with ice cold water. The reaction mixture was extracted with chloroform; washed well with water; dried over anhydrous MgSO4; filtered and concentrated. The residue obtained was purified by silica-gel column chromatography by eluting it with 50% ethyl acetate:hexane. Yellow semi-solid. Yield: 156 mg (36%); 432 (M+H); 1H NMR: δ 7.90(1H, s, NH), 7.78(3H,m), 7.26(6H, m), 6.21(1H, s), 5.99(1H, m), 5.13(2H, m), 4.71(2H, m), 3.40(2H, s), 3.15(2H, m), 2.92(4H, m), 2.68(2H, s).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[NH2:17].Cl.N1C=C[CH:22]=[CH:21][CH:20]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=[C:20]1[CH2:21][CH3:22]
Reactant: c1ccncc1
Reactant: Nc1cnc2ccccc2c1NCCCCCl
Agent: Cl
Product: CCc1nc2cnc3ccccc3c2n1CCCCCl
Yield: 734.5 %

Procedure:
Using the general method of Example 1 Part D, N4-(4-chlorobutyl)quinoline-3,4-diamine (˜35.75 mmol) was cyclized using triethyl orthopropioniate (7.56 g, 42.9 mmol) in the presence of pyridine hydrochloride (0.41 g). The crude product was purified by chromatography (silica gel eluting with 95/5 dichloromethane/methanol) to provide 7.5 g of 1-(4chlorobutyl)-2-ethyl-1H-imidazo[4,5-c]quinoline as a white powder.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li]CCCC.[C:19]([S:23]([N:25]=[CH:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[O:24])([CH3:22])([CH3:21])[CH3:20].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:26]([NH:25][S:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:24])[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: Ic1ccccc1-c1ccccc1
Reactant: COC(=O)CCCC=NS(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCCC(NS(=O)C(C)(C)C)c1ccccc1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of commercially available 2-iodo-1,1′-biphenyl (617 mg; 2.20 mmol) in anh. THF (5 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (1.50 ml; 2.40 mmol). The resulting solution was further stirred at −78° C. for 10 min. A solution of methyl 5-((tert-butylsulfinyl)imino)pentanoate (514 mg; 2.20 mmol) in anh. THF (2 ml) was added to the cooled reaction mixture, and stirring at −78° C. was continued for 10 min., and then at −20° C. for 2 h. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (15 ml), Et2O (30 ml) and water (15 ml). The separated organic layer was then washed with brine (15 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=7/3) afforded methyl 5-([1,1′-biphenyl]-2-yl)-5-(1,1-dimethylethylsulfinamido)pentanoate as a yellow oil. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 387.83 g/mol.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([C:21]([N:23]([CH2:42][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][CH3:59])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:22])[CH:3]=1.[N:60]1C=CC=CC=1.Cl[S:67]([C:70]1[CH:71]=[C:72]([C:76](=[O:78])[CH3:77])[CH:73]=[CH:74][CH:75]=1)(=[O:69])=[O:68]>C1COCC1>[C:76]([C:72]1[CH:71]=[C:70]([S:67]([NH:60][C:3]2[C:4]([C:21]([N:23]([CH2:42][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][CH3:59])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:22])=[C:5]([O:12][C:13](=[O:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]3[C:7]([CH:2]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)(=[O:69])=[O:68])[CH:75]=[CH:74][CH:73]=1)(=[O:78])[CH3:77]
Reactant: CC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: c1ccncc1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cc(N)c2ccccc2c1OC(=O)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1c(NS(=O)(=O)c2cccc(C(C)=O)c2)cc2ccccc2c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A solution of 4-amino-1-benzoyloxy-N,N-dioctadecyl-2-naphthamide (15.7 mmol), and 2 ml of pyridine in 110 ml of THF was cooled to 0° to 5° C. and 3.42 g of m-chlorosulfonylacetophenone was added all at once. The solution was allowed to warm to room temperature and stirred overnight. The THF was removed under reducing pressure and the resulting solid was reslurried in water, dried and then recrystallized from heptane to give 9.32 g (58 percent) of a tan solid, melting point 91° to 93° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(N(CC)C(C)C)(C)C.[C:23](Cl)(=[O:25])[CH3:24].CO.ClCCl>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][C:23](=[O:25])[CH3:24])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cc(N)ccc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(NC(C)=O)ccc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Alternately, combine methyl 2-methoxy-5-aminobenzoate (1.5 g, 8.3 mmol) and dichloromethane (25 mL). Cool in an ice bath. Add N,N-diisopropylethylamine (3.2 mL, 18.2 mmol), and acetyl chloride (0.62 mL, 9.7 mmol). Warm to ambient temperature. After 4 hours, dilute the reaction mixture with dichloromethane and extract three times with half saturated aqueous ammonium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 3% methanol/dichloromethane/0.1% concentrated aqueous ammonia to give methyl 2-methoxy-5-acetamidobenzoate: mp; 132-134° C. Elemental Analysis calculated for C11H13NO4: C, 59.19; H, 5.87. Found C, 59.04; H, 5.86.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:40]=[N:39][C:34]3=[N:35][CH:36]=[CH:37][N:38]=[C:33]3[CH:32]=2)O1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:40]=[N:39][C:34]4=[N:35][CH:36]=[CH:37][N:38]=[C:33]4[CH:32]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: CC1(C)OB(c2cnc3nccnc3c2)OC1(C)C
Product: COc1cc(CCc2cnc3[nH]c(-c4cnc5nccnc5c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrido[2,3-b]pyrazine (from Combi-Blocks). LCMS calculated for C23H21N6O2(M+H)+: m/z=413.2. Found 413.2.
Reaction SMILES: C1(C)C=CC=CC=1.CN(C)C.[CH3:12][O:13][CH:14]([CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:15][S:16]([CH2:19][CH2:20]OS(C)(=O)=O)(=[O:18])=[O:17]>CCCCCC>[CH:19]([S:16]([CH2:15][CH:14]([O:13][CH3:12])[CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])(=[O:18])=[O:17])=[CH2:20]
Reactant: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CCOS(C)(=O)=O)OC
Agent: CN(C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C=CS(=O)(=O)CC(COCCCCCCCCCCCCCCCCCC)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.3 %

Procedure:
Into 10 ml of toluene containing 2 g of trimethylamine is dissolved 1.0 g of 2-mesyloxyethyl 2-methoxy-3-octadecyloxypropyl sulfone and the solution is stirred at room temperature for 6 hours. Then 30 ml of hexane is added to the mixture and precipitates are removed by filtration. The filtrate is concentrated to give 0.6 g of the captioned compound as colorless crystals (m.p.47°-49° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:20][O:21][C:22](=[O:28])[C@H:23]([C@@H:25]([CH3:27])[OH:26])[NH2:24]>C(Cl)(Cl)Cl.CO>[CH3:20][O:21][C:22](=[O:28])[C@H:23]([C@@H:25]([CH3:27])[OH:26])[NH:24][C:16](=[O:18])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)[C@@H](C)O

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and L-threonine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.1 in 95:5 CHCl3/MeOH) and the product was purified by silica gel chromatography using 95:5 CHCl3/MeOH as the eluent.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:16]=1[C:17](OCC)=[O:18]>>[CH2:22]([C:14]1[S:13][C:12]2[N:11]=[C:2]3[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[CH:6][N:7]3[C:17](=[O:18])[C:16]=2[CH:15]=1)[CH2:23][CH2:24][CH3:25]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CCCCc1cc(C(=O)OCC)c(N)s1
Product: CCCCc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Yield: 15.8 %

Procedure:
From 6.2 g (0.040 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) and 9.0 g (0.040 mol) of 2-amino-5-butyl-3-thiophenecarboxylic acid, ethyl ester and heating in a wax bath at 180°-195° C. for one hundred forty-five minutes and then at 185°-200° C. for ninety minutes, following the procedure of Example 22 there is obtained 1.9 g of 2-butyl-4-oxo-4H-pyrido-[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 266°-267° C. after recrystallization from glacial acetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[O:10][CH:11]([CH3:17])[C:12]([O:14]CC)=[O:13])([O-:3])=[O:2].[OH-].[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[O:10][CH:11]([CH3:17])[C:12]([OH:14])=[O:13])([O-:3])=[O:2]
Reactant: CCOC(=O)C(C)Oc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(Oc1cccc(Oc2ccccc2[N+](=O)[O-])c1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
In 100 ml of ethanol was dissolved 6.7 g of ethyl 2-[3-(2-nitrophenoxy)phenoxy]propionate followed by addition of a solution of 1.6 g of sodium hydroxide in 10 ml of water, and the mixture was stirred at room temperature for 1 hour. The ethanol was then distilled off and the residue was diluted with water, acidified with hydrochloric acid and extracted with chloroform. The chloroform layer was dried and concentrated to give 6.2 g of the title compound as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][C:18](=[O:23])[CH2:19]2>O1CCCC1>[CH3:14][N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][C:18]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)([OH:23])[CH2:19]2
Reactant: Cc1ccc(Br)cc1
Reactant: CN1C2CCC1CC(=O)C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)CC3CCC(C2)N3C)cc1

Procedure:
The title compound was prepared from 4-bromotoluene (13.9 g, 81.4 mmol), n-butyllithium in hexanes (31.2 mL, 2.5 M; 78 mmol) and 8-methyl-8-azabicyclo[3.2.1]-octan-3-one (5 g, 35.9 mmol) in anhydrous tetrahydrofuran (40 mL). Yield 3.5 g (42%) as a white solid, m.p. 247-249° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([O:13][CH2:14][CH3:15])[CH:12]=1>C(Cl)Cl.[Cl-].[Na+].O>[Br:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([Cl:3])=[N:9][CH:8]=1
Reactant: CCOc1cncc(Br)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOc1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
As shown in step 2-iv of Scheme 2, phosphorous oxychloride (48.02 g, 403.6 mmol) was added to 3-bromo-5-ethoxypyridine, 1-oxide (4.4 g, 20.18 mmol) in 700 mL of DCM at RT. The reaction mixture was stirred at RT overnight. After the addition of brine, the organics were partitioned, dried over MgSO4, filtered, and the filtrate concentrated under reduced pressure. The product was purified by filtering the concentrate through a pad of silica gel and eluting the pad with ethyl acetate. The volatiles were removed under reduced pressure to provide 5-bromo-2-chloro-3-ethoxypyridine (Compound 2003, 4.3 g, 85.6%): 1H NMR (CDCl3) δ 8.1 (s, 1H), 7.32 (s, 1H), 4.15 (q, 2H), 1.6 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][Si:12]([C:10]#[C:11][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 4-bromobenzaldehyde (10.00 g, 54.08 mmol) and triphenylphosphine (0.500 g, 1.91 mmol) in anhydrous triethylamine (80 mL) under argon were added ethynyltrimethylsilane (6.00 g, 61.09 mmol) and palladium (II) acetate (0.100 g, 0.445 mmol). The final mixture was heated to reflux for 2 hours, and was then cooled to room temperature and filtered. The filtrate was concentrated under vacuum to a thick oil, which was purified by column chromatography (dichloromethane/petroleum ether 1:4) and recrystallized from cold cyclohexane to give 10.5 g (96.1% yield) of 4-(trimethylsilylethynyl)benzaldehyde [MS m/e 187.2 (M+); 1H-NMR (CDCl3) δ ppm: 0.27 (s, 9H, SiMe3), 7.60 (d, 2H, ArH, J=8.1 Hz), 7.82 (d, 2H, ArH, J=8.1 Hz), 10.00 (s, 1H, CHO)]. This compound (8.00 g, 39.59 mmol) was treated with K2CO3 (0.500 g) in methanol (50 mL) at 25° C. for 2 hours under Argon. The solvent was removed under vacuum, and the residue was dissolved in dichloromethane (100 mL). This solution was washed once with a saturated aqueous NaHCO3 solution, and once with water, was then dried over anhydrous Na2SO4, and the solvent was evaporated under vacuum. The yellow residue was purified by column chromatography using dichloromethane/petroleum ether 1:4, and then recrystallized from cold cyclohexane to give 4.40 g (85.5% yield) of the title compound; MS (EI) m/e 130.0; (M+). 1H-NMR (CDCl3) δ ppm: 3.30 (s, 1H, CH), 7.64 (d, 2H, ArH, J=8.1 Hz), 7.84 (d, 2H, ArH, J=8.1 Hz), 10.02 (s, 1H, CHO).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([CH:11]=[N:12][OH:13])[C:5]=1[F:14].[Cl:16]N1C(=O)CCC1=O.O.CCOC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([C:11]([Cl:16])=[N:12][OH:13])[C:5]=1[F:14]
Reactant: COC(=O)c1c(Cl)ccc(C=NO)c1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Cl)ccc(C(Cl)=NO)c1F
Temperature: 50 °C

Procedure:
To a solution of methyl-6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate (553 mg, 2388 μmol) in DMF (5.3 ml) at 0° C. was added N-chlorosuccinimide (351 mg, 2626 μmol). The mixture was heated to 50° C. for 10 min after which time LCMS analysis indicated the reaction was complete. The mixture was cooled to RT, water was added followed by EtOAc, the layers were separated, and the aqueous was extracted with EtOAc (3×). The combined organic layers were washed with brine (2×), dried over MgSO4, filtered and concentrated to yield the title compound as a yellow viscous oil, which solidified under reduced pressure.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].Cl.[CH3:16][S:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([S:17][CH3:16])=[CH:19][CH:20]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1ccncc1
Reactant: CSc1ccc(CN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CSc1ccc(CN=C(NC#N)c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.40 g, 2.1 mmol) was dissolved in methanol (15 ml), and 4-methylthiobenzylamine hydrochloride (0.60 g, 3.2 mmol) and triethylamine (0.43 g, 4.2 mmol) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was then concentrated under reduced pressure. The residual concentrate was extracted with ethyl acetate (50 ml×3). The ethyl acetate layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was crystallized from methanol-diethyl ether to give the title compound (0.29 g, 1.0 mmol, yield: 49%) as colorless crystals.
Reaction SMILES: BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CCCCP(=O)O[CH2:34][C:35]([CH3:52])([CH3:51])[CH2:36][N:37]4[CH:41]=[C:40]([B:42]5[O:46][C:45]([CH3:48])([CH3:47])[C:44]([CH3:50])([CH3:49])[O:43]5)[CH:39]=[N:38]4)=CC=3OC)N=2)=CC=1.[Br:58][C:59]1[N:64]=[C:63]([C:65](=[O:68])[NH:66][CH3:67])[C:62]([NH:69][C:70]2[C:75]([C:76]([F:79])([F:78])[F:77])=[CH:74][N:73]=[C:72]([NH:80][C:81]3[CH:92]=[CH:91][C:84]([CH2:85][CH2:86][CH2:87][PH:88](=[O:90])[OH:89])=[CH:83][C:82]=3[O:93][CH3:94])[N:71]=2)=[CH:61][CH:60]=1>>[Br:58][C:59]1[N:64]=[C:63]([C:65](=[O:68])[NH:66][CH3:67])[C:62]([NH:69][C:70]2[C:75]([C:76]([F:79])([F:77])[F:78])=[CH:74][N:73]=[C:72]([NH:80][C:81]3[CH:92]=[CH:91][C:84]([CH2:85][CH2:86][CH2:87][PH:88](=[O:89])[O:90][CH2:34][C:35]([CH3:52])([CH3:51])[CH2:36][N:37]4[CH:41]=[C:40]([B:42]5[O:46][C:45]([CH3:48])([CH3:47])[C:44]([CH3:50])([CH3:49])[O:43]5)[CH:39]=[N:38]4)=[CH:83][C:82]=3[O:93][CH3:94])[N:71]=2)=[CH:61][CH:60]=1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCCC[PH](=O)OCC(C)(C)Cn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC[PH](=O)OCC(C)(C)Cn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F

Procedure:
Prepared analogously to Compound 74A replacing Compound 74B with (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)ethylphosphinic acid (Compound 67B). MS (ESI): m/z 865.86/867.92 [M+H]+. UPLC: tR=1.61 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:9]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[CH:8][S:7][CH:6]=1.C([O-])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[K+]>C(O)C1C=CC=CC=1>[CH2:1]([O:2][C:3](=[O:19])[CH2:4][C:5]1[C:9]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[CH:8][S:7][CH:6]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [O-]Cc1ccccc1
Reactant: COC(=O)Cc1cscc1Nc1c(Cl)cccc1Cl
Agent: [K+]
Solvent: OCc1ccccc1
Product: O=C(Cc1cscc1Nc1c(Cl)cccc1Cl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
316 mg (1 mmole) of 4-(2,6-dichloroanilino)-3-thiophenacetic acid methyl ester are introduced into a solution of 10 mg of potassium benzyl alcoholate in 20 ml of benzyl alcohol. The mixture is stirred at room temperature for 2 hours, excess alcohol is distilled off in vacuo and 4-(2,6-dichloroanilino)-3-thiophenacetic acid benzyl ester is obtained as the residue.