Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Br[CH2:19][C:20]#[C:21][CH2:22][CH3:23].[In]>C1COCC1.O.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([C:21]([CH2:22][CH3:23])=[C:20]=[CH2:19])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: CCC#CCBr
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: [In]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=C=C(CC)C(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F

Procedure:
1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (2 g), 1-bromo-2-pentyne (1.1 ml) and indium (983 mg) were suspended in THF (15 mL) and H2O (45 mL) and stirred vigorously overnight. The reaction mixture was then diluted with water and ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine and dried over Na2SO4 to yield a crude material. The crude material was purified by column chromatography (SiO2; 5-30% ethyl acetate/hexanes) to yield the title compound as a peach-colored solid.
Reaction SMILES: [C:1]1([C:7]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)[Cl:16].[CH:18]([N:21]([CH:25](O)[CH3:26])[CH:22](C)[CH3:23])(C)[CH3:19]>>[ClH:16].[C:1]1([C:7]2([C:11]([O:13][CH2:19][CH2:18][N:21]([CH2:25][CH3:26])[CH2:22][CH3:23])=[O:12])[CH2:8][CH2:9][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)N(C(C)C)C(C)O
Reactant: O=C(O)C1(c2ccccc2)CCC1
Product: CCN(CC)CCOC(=O)C1(c2ccccc2)CCC1
Product: Cl
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
1-Phenylcyclobutanecarboxylic acid (1.9 mmol) was refluxed with SOCl2 (5 mL). After 0.5 h, the reaction mixture was evaporated and the residue dissolved in toluene. Diisopropylaminoethanol (3.8 mmol) was added and the mixture was heated at 80° C. for 1.5 h. The reaction mixture was filtered and chromatographed on silica gel using toluene-Et3N 95:5 as eluent. The yield was 1.3 g (73%); mp 137-139° C.; 1H NMR (D2O) δ 1.25 (t, 6H), 1.92-2.01 (m, 1H), 2.07-2.16 (m, 1H), 2.64 (m, 2H), 2.89 (m, 2H), 3.11 (q, 4H), 3.50 (t, 2H), 4.48 (t, 2H), 7.44 (m, 1H), 7.48 (m, 2H), 7.53 (m, 2H). Anal. (C17H25NO2.HCl) C, H, N.
Reaction SMILES: [NH:1]([N])C1C=CC=CC=1.NN.[Cl:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16](Cl)[C:15]([N+:22]([O-:24])=[O:23])=[CH:14][C:13]=1C(F)(F)F>>[Cl:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([C:15]([N+:22]([O-:24])=[O:23])=[CH:14][CH:13]=1)[NH2:1]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: [N]Nc1ccccc1
Agent: NN
Product: Nc1c([N+](=O)[O-])ccc(Cl)c1[N+](=O)[O-]

Procedure:
The 3-chloro starting materials for the preparation of the azido compounds of my invention are prepared by reacting the appropriate amine or appropriate hydrazine with 2,4-dichloro-3,5-dinitrobenzotrifluoride as described in U.S. Pat. No. 3,617,252. The amine or hydrazine is chosen to give the desired substitution pattern on the anilino nitrogen of the final product. The amine or hydrazine reacts preferentially with the chlorine atom between the two nitro groups of the 2,4-dichloro-3,5-dinitrobenzotrifluoride to give the 3-chloro-2,6-dinitroaniline starting material for use in preparing the compounds of my invention.
Reaction SMILES: [CH:1]1([CH:7]=[N:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClN1C(=O)CCC1=O.[NH4+].[Cl-].[CH3:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:20][C:21]1[N:25]([C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:8][OH:9])[N:24]=[N:23][N:22]=1
Reactant: ON=CC1CCCCC1
Reactant: Cc1nnn[nH]1
Agent: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nnnn1C(=NO)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.3 %

Procedure:
To a solution of cyclohexane carboxaldehyde oxime (35.6 g, 280 mmol) in DMF (300 ml) is added N-chlorosuccinimide (39.2 g, 294 mmol) portionwise, while maintaining the reaction temperature below 45° C. On complete addition, the mixture is stirred overnight at room temperature before adding a saturated aqueous NH4Cl solution (900 ml). The mixture is extracted with ethyl acetate. The organic layer is washed successively with water (500 ml) and brine (500 ml), dried (MgSO4), filtered and concentrated. The residue and 5-methyltetrazole (24.7 g, 294 mmol) are diluted in dichloromethane (400 ml) and triethyamine (50.8 ml, 364 mmol) is added dropwise at room temperature. After stirring overnight, the mixture in concentrated and the residue is taken up in ethyl acetate. The solution is washed successively with a saturated aqueous NH4Cl solution, water and brine, then dried (MgSO4), filtered and concentrated. Silica-gel chromatography of the residue affords 16.6 g of 5-methyl-1-(cyclohexylcarbohydroximoyl)-tetrazole [yield 28.3%; 1H-NMR (CDCl3) δppm: 1.1-1.5 (m, 4H), 1.62-1.98 (m, 6H), 2.55 (s, 3H), 2.8 (m, 1H), 9.3 (broad, 1H); HPLC/MS: m/z=210 (M+H)].
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][C@H:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[S:28][C:29]4[C:34]([N:35]=3)=[CH:33][CH:32]=[C:31]([C:36]3([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH2:38][CH2:37]3)[N:30]=4)=[CH:23][CH:22]=2)[CH2:17][C@H:16]1[C:45]([OH:47])=[O:46])=O)(C)(C)C>C(Cl)Cl>[C:39]1([C:36]2([C:31]3[N:30]=[C:29]4[S:28][C:27]([C:24]5[CH:25]=[CH:26][C:21]([O:20][C@H:18]6[CH2:19][NH:15][C@H:16]([C:45]([OH:47])=[O:46])[CH2:17]6)=[CH:22][CH:23]=5)=[N:35][C:34]4=[CH:33][CH:32]=3)[CH2:37][CH2:38]2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2)C[C@H]1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@@H]1C[C@@H](Oc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2,2-Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-(4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenoxy)pyrrolidine-2-carboxylic acid (130.0 mg, 0.233 mmol) in DCM (4.5 mL) and the resulting solution was stirred at 25° C. for 2 h. The reaction mixture was then concentrated in vacuo, and the residue was taken up in DMSO (2.0 mL) and purified by rpHPLC (10-100% CH3CN/H2O+0.1% TFA) to provide (2S,4R)-4-(4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenoxy)pyrrolidine-2-carboxylic acid as a white solid. MS (ESI) m/z: Calculated: 457.1; Observed: 458.1 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:9]1[C:10]([C:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:19]3[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:18]=3[N:17]=2)=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:47]([NH2:50])[C:48]#[CH:49]>CN(C=O)C.C(OCC)(=O)C.I[Cu].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>[NH2:50][CH2:47][C:48]#[C:49][C:12]1[N:11]=[C:10]([C:16]2[N:20]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[C:19]3[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:18]=3[N:17]=2)[C:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])=[N:14][CH:13]=1
Reactant: Cc1ccc2nc(-c3nc(Br)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n(C(=O)OC(C)(C)C)c2c1
Reactant: C#CCN
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2nc(-c3nc(C#CCN)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n(C(=O)OC(C)(C)C)c2c1

Procedure:
tert-Butyl 2-[3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazin-2-yl]-6-methyl-benzimidazole-1-carboxylate (1000 mg, 1.654 mmol), iodocopper (31.50 mg, 0.1654 mmol), Pd(PPh3)4 (191.1 mg, 0.1654 mmol), triethylamine (836.8 mg, 1.153 mL, 8.270 mmol) and prop-2-yn-1-amine (182.2 mg, 3.308 mmol) were stirred in DMF (5 mL) at ambient temperature for 2 hours. The reaction mixture was diluted with ethyl acetate the organic layer washed with water, brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography eluting with 25/75 ethyl acetate/petroleum ether to give the sub-title compound as an off-white solid which was used directly in the next step with out further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[C:6]2[OH:20].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>C(#N)C>[OH:20][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)[CH:4]=2)[N:9]=[C:8]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(CBr)ccc2n1
Solvent: CC#N
Product: CC(C)(C)C(=O)Nc1nc(O)c2cc(Cn3ccnc3)ccc2n1
Yield: 34.7 %

Procedure:
A solution of 13 parts of N-[6-(bromomethyl)-4-hydroxy-2-quinazolinyl]-2,2-dimethylpropanamide, 15.5 parts of 1H-imidazole and 80 parts of acetonitrile was stirred for 4 hours at reflux temperature. The reaction mixture was evaporated and the residue was extracted with ethyl acetate. The extract was washed with NaHCO3 (aq.), dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 98:2). The eluent of the desired fraction was evaporated, yielding 4.3 parts (34.7%) of N-[4-hydroxy-6-(1H-imidazol-1-ylmethyl)-2-quinazolinyl]-2,2-dimethylpropanamide (interm. 69).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:11]([O:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:40])[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][N:36]=[C:35](Cl)[N:34]=2)=[CH:29][CH:28]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C)C(=O)C>[C:11]([O:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:40])[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([NH:1][CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[N:34]=2)=[CH:29][CH:28]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ccnc(Cl)n2)cc1
Reactant: NCCCN1CCCCC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ccnc(NCCCN3CCCCC3)n2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
To a 24 mm×150 mm pyrex tube, charged with 3-aminopropylpiperidine (73 mg, 0.51 mmol), was added a solution of N-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-4-yl)benzamide (Method 52, 85 mg, 0.20 mmol) in N,N-dimethylacetamide (4.6 ml). The reaction mixture was then heated to 50° C. and stirred for 16 hours, before being evaporated to dryness. The resultant residue was purified by flash chromatography, on silica (10 g), eluting with methanol/dichloromethane (5-15%), to give the title compound (48 mg, 45%); Mass Spectrum: M+H+ 531.
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)CCCC1.[C:28]([CH:32]1[CH2:37][CH2:36][CH:35]([NH:38][CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29].C(OC(=O)CSC1SC(N)=NC=1)C>>[C:28]([C@H:32]1[CH2:37][CH2:36][C@H:35]([N:38]([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)[CH2:34][CH2:33]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: CC(C)(C)C1CCC(NC2CCCC2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(C)(C)[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via (4-tert-butyl-cyclohexyl)-cyclopentyl-amine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester to give the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:5][CH:4]=1.CS(Cl)(=O)=O.[CH2:29]([N:31](CC)CC)[CH3:30].C(N)C>C(Cl)Cl.CO.C(OCC)(=O)C>[CH2:29]([NH:31][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:5][CH:4]=1)[CH3:30]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reactant: CCN(CC)CC
Agent: CCN
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCNCc1ccc(-c2ccccc2CNC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Yield: 68.2 %

Procedure:
4-Hydroxymethyl-2'(t-butoxycarbonylaminomethyl)-1,1'-biphenyl (70 mg; 0.224 mmol) was dissolved in dry methylene chloride and stirred at 0° C. in an iced water bath and methanesulfonyl chloride (22 μl; 0.285 mmol) and triethylamine (39 μl; 0.280 mmol) added. The reaction mixture was stirred for 3 h at 0° C. and then 70% aqueous ethylamine (5 ml) added. The mixture was stirred for 5 h at room temperature vigorously, then partitioned between water and methylene chloride. The organic phase was separated and the aqueous layer extracted with methylene chloride (2×25 ml). The combined methylene chloride layers were dried over potassium carbonate powder, filtered and evaporated under reduced pressure to leave a thick viscous oil. The oil was subjected to a short column chromatography using a solvent gradient initially of ethyl acetate and hexanes (1:1 v/v) then neat ethyl acetate and finally with ethyl acetate and methanol (3:1 v/v). This afforded 52 mg (68%) of the desired product. FAB-MS:- calculated for C21H28N2O2 340.2 found 341.1 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.C(OC([NH:12][C@@H:13]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C@@H:14]([OH:19])[CH2:15][C:16]([OH:18])=[O:17])=O)(C)(C)C.[CH3:27]O>>[ClH:3].[NH2:12][C@@H:13]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C@@H:14]([OH:19])[CH2:15][C:16]([O:18][CH3:27])=[O:17]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CC(=O)O
Reactant: O=S(Cl)Cl
Product: COC(=O)C[C@H](O)[C@@H](N)CC1CCCCC1
Product: Cl
Reaction time: 0.17 h

Procedure:
2 ml of thionyl chloride were added, at -20° C., to 20 ml of methanol, and the resulting solution was stirred for 10 minutes. At the end of this time. 2.85 g (9.0 mmole) of N-(t-butoxycarbonyl)-(3S, 4S)-4-amino- 5-cyclohexyl-3-hydroxypentanoic acid were added to the solution, and the reaction mixture was stirred at room temperature for 14 hours. The solvent was then removed by distillation, and the residue was dried by azeotropic distillation with benzene 3 times, to afford methyl (3S, 4S)-4-amino-5-cyclohexyl-3-hydroxypentanoate hydrochloride. The whole of this hydrochloride was dissolved in 30 ml of dimethylformamide, and 2.71 g (9.9 mmole) of N-(t-butoxycarbonyl)-3-(4thiazolyl)-L-alanine, 1,97 g (10.9 mmole) of diethyl cyanophosphonate (95%) and 2.76 ml (19.9 mmole) of triethylamine were added to the solution. The reaction mixture was then stirred at room temperature for 3 hours, after which the solvent was removed by evaporation under reduced pressure and the residue was dissolved in ethyl acetate. The resulting organic solution was washed with a 5% w/v aqueous solution of sodium bicarbonate, with a 5% w/v aqueous solution of citric acid and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: a 50: 1 by volume mixture of methylene chloride and methanol), after which it was triturated with diethyl ether, to give 3.76 g of the title compound as white crystals, melting at 128°-130° C.
Reaction SMILES: [CH:1]([P:4](Cl)(Cl)=[O:5])([CH3:3])[CH3:2].[CH:8]([Mg]Br)=[CH2:9].[NH4+].[Cl-].[CH2:14]1COC[CH2:15]1>>[CH:14]([P:4](=[O:5])([CH:8]=[CH2:9])[CH:1]([CH3:3])[CH3:2])=[CH2:15]
Reactant: C1CCOC1
Reactant: C=C[Mg]Br
Reactant: CC(C)P(=O)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Product: C=CP(=O)(C=C)C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A 20 L four-necked round bottom flask fitted with an overhead stirrer and dropping funnel, flame dried and cooled in a stream of nitrogen, was charged with isopropyl phosphonic dichloride (350.0 g, 2173 mmol) in THF (5000 mL). The mixture was cool to −78° C. and vinyl magnesium bromide (5217 mL, 5217 mmol, 1M in THF) was added dropwise over 4 h. The reaction mixture was stirred at −78° C. for additional 30 minutes. After completion, the reaction mixture was poured into cold saturated aqueous NH4Cl (3.5 L) and extracted with dichloromethane (4×1000 L). The organic layers were combined, washed with brine (2×15000 mL), dried over sodium sulfate and concentrated in vacuo to give diethenyl(propan-2-yl)phosphane oxide (250 g, 80%) as light-brown oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C@@H:14]1[CH2:17][C@H:16]([OH:18])[CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.O>ClCCl>[CH2:6]([O:13][C@@H:14]1[CH2:17][C@H:16]([O:18][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O[C@H]1C[C@@H](OCc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1C[C@@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Methanesulfonyl chloride (0.44 ml, 5.7 mmol) was added dropwise to a stirred solution of cis-3-benzyloxy-1-hydroxycyclobutane (0.85 g, 4.77 mmol) and triethylamine (1.0 ml, 7.2 mmol) in dry dichloromethane (15 ml) at 0° C. under nitrogen. The white suspension was stirred at 0° C. for 1.5 h then poured into water (50 ml) and extracted with dichloromethane (2×30 ml). The extracts were dried (Na2 SO4), filtered and concentrated. The oil was filtered through a plug of silica gel, eluting with ethyl acetate, a yellow oil; 1H NMR (250 MHz, CDCl3) δ2.26-2.39 (2H, m), 2.77-2.91 (2H, m), 2.97 (3H, s), 3.74 (1H, qn, J=7 Hz), 4.42 (2H, s), 4.68 (1H, qn, J=7 Hz), 7.26-7.42 (5H, m).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([N:15](CC1C=CC(OC)=CC=1OC)[C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([NH:15][C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)c1
Reactant: COc1ccccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1-c1cccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
A vial was charged with 5-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (INTERMEDIATE D) (73.69 mg, 0.142 mmol), 2-methoxyphenylboronic acid (43.0 mg, 0.283 mmol), Pd(AmPhos)2Cl2 (5.01 mg, 7.08 μmol), potassium phosphate (90 mg, 0.425 mmol), 1,4-dioxane (708 μl), and water (236 μl). The vial was sealed and heated in a microwave reactor for 30 min at 100° C. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 2 h, the mixture was diluted with MeOH and filtered through diatomaceous earth with the aid of DCM. The filtrate was concentrated. The residue was purified twice by chromatography on silica gel (12-g columns, first with 0 to 5% MeOH/DCM, then with 2.5% MeOH/DCM), and the resulting material was dissolved in DCM and loaded onto a 1-g PE-AX ion exchange column (Biotage AB, Uppsala, Sweden). The column was flushed with 1:1 MeOH/DCM, then eluted with 10% HCl/MeOH (made by dissolving 1 mL on conc. HCl in 9 mL of MeOH). The acidic fraction was concentrated to give 5-(2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (41.62 mg, 0.105 mmol, 74.0% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=8.59-8.44 (m, 2H), 8.20 (d, J=8.2 Hz, 1H), 7.77-7.66 (m, 2H), 7.58 (d, J=8.9 Hz, 1H), 7.54-7.45 (m, 2H), 7.26-7.16 (m, 2H), 7.13-7.05 (m, 1H), 3.63 (s, 3H); m/z (ESI) 398.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C@@H:6]1[CH2:11][CH2:10][N:9](C(OCC)=O)[CH2:8][C@H:7]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C@@H:6]1[CH2:11][CH2:10][NH:9][CH2:8][C@H:7]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)N1CC[C@@H](Oc2cccc(Cl)c2)[C@H](c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cl
Product: Clc1cccc(O[C@@H]2CCNC[C@H]2c2ccccc2)c1

Procedure:
A mixture of 3.84 g of trans-4-(3-chlorophenoxy)-1-ethoxy-carbonyl-3-phenylpiperidine of Example 33, 55 ml of absolute ethanol, and 28 ml of 10% aqueous NaOH solution is refluxed for 18 hours under nitrogen. The ethanol is then removed in vacuo and the aqueous residue is extracted with ether. The combined ether extracts are washed with saturated aqueous NaCl solution, dried over anhydrous MgSO4, and concentrated in vacuo to an oil. This oil is dissolved in ether, filtered, and the filtrate treated with HCl-saturated ether solution until acidic to wet pH paper. The resulting precipitate is filtered, washed with ether and dried to afford a solid, m.p. 239°-241° C. Recrystallization from isopropanol affords crystals of trans-4-(3-chlorophenoxy)-3-phenylpiperidine hydrochloride, mp s 240°, 241.5°-243.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:9]=1.[NH2:30][C:31]1[C:32]([C:38](O)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][CH:36]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:30][C:31]1[C:32]([C:38]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[N:9]=2)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][CH:36]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: Cc1cc(-c2ccncc2N)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccncc2NC(=O)c2nc(Br)ccc2N)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Yield: 12 %

Procedure:
Method 27 was followed using 4-(3-aminopyridin-4-yl)-N,N-di-BOC-6-methylpyrimidin-2-amine (1.0 equiv.), 3-amino-6-bromopicolinic acid (1.0 equiv), EDC (1.0 equiv.), and HOAt (1.0 equiv.) in DMF yielding 3-amino-6-bromo-N-(4-(2-(di-BOC-amino)-6-methylpyrimidin-4-yl)pyridin-3-yl)picolinamide in 12% yield. LCMS (m/z): 602.2 (MH+); LC Rt=3.60 min.