Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C([Li])CCC.C(=O)=O.CC(C)=O.[CH3:19][C:20](C)([CH3:24])[C:21](Cl)=O.Cl>C1COCC1.CCCCCC.C(Cl)Cl>[CH3:19][C:20]([CH3:24])([CH3:21])[C:4](=[O:6])[CH2:3][C:1]#[N:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: N#CCC(=O)O
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)C(=O)CC#N
Temperature: -70 °C
Yield: 89.9 %

Procedure:
Cyanoacetic acid (8.5 g) was dissolved in dry THF (300 ml), placed under an inert atmosphere and the solution cooled using a dry ice-acetone bath. Butyllithium (80 ml of a 2.5M solution in hexane) was added dropwise over 1 hour. During the addition the internal reaction temperature was maintained below -65° C. The reaction mixture was stirred in the dry ice-acetone bath for 1 hour and then the bath was removed and the reaction stirred for an additional hour, during which time the internal temperature rose to -45° C. The resultant reaction mixture was cooled to -70° C. and trimethylacetyl chloride (6.0 g) in THF (50 ml) added dropwise over 30 minutes while keeping the temperature of the reaction mixture below -65° C. The reaction mixture was allowed to stir in a dry ice-acetone bath for 1 hour and then allowed to warm to room temperature overnight. The resultant mixture was acidified by the addition of 2N HCl (200 ml) and diluted with CH2Cl2 (500 ml). The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and, after removal of the drying agent by filtration, the solvents were removed. The residue was dissolved in ether (200 ml) and the etheral solution extracted with 2N NaOH (twice with 50 ml portions). To the combined aqueous extracts was added conc. HCl to adjust the solution to pH 1. The resulting mixture was extracted with ether. The combined extracts were dried (MgSO4) and, after removal of the drying agent by filtration, the solvents were removed to afford 5.6 g of 4,4-dimethyl-3-oxopentanonitrile as an orange oil which slowly solidified; m.p. 60° C.
Reaction SMILES: C[N:2]([CH3:13])[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH3:11].[OH:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22]C#N)[CH2:16]1>>[OH:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22][C:13]2[NH:2][C:3](=[O:12])[C:4]3[C:5]([CH:11]=2)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=3)[CH2:16]1
Reactant: N#CCCN1CCCC(O)C1
Reactant: Cc1cccc(C(=O)N(C)C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCN3CCCC(O)C3)cc12
Yield: 6.6 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-dimethyl-2,3-dimethylbenzamide (5.1101 g) and 3-(3-hydroxypiperidin-1-yl)propionitrile (2.2 g), 3-[2-(3-hydroxypiperidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (269.6 mg) was obtained.
Reaction SMILES: [F:1][CH:2]([F:49])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:43]=[CH:44][CH:45]=[C:46]([O:47][CH3:48])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:49][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36][N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)[CH:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)[N:9]=2)[C:6]2[CH:43]=[CH:44][CH:45]=[C:46]([O:47][CH3:48])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCOCC2)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCOCC2)C2CCNCC2)n1
Yield: 75 %

Procedure:
Reaction of tert-butyl 4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(4-morpholinyl)propyl]amino}-1-piperidinecarboxylate with TFA in CH2Cl2 gave 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-N-(4-piperidinyl)-1,3,5-triazin-2-amine (75% yield over two steps): 1H NMR (DMSO-d6) (rotamers) δ 7.94 (t, J=7.6 Hz, 1H), 7.73 and 7.70 (2t, JHF=53.1, 53.0 Hz, 1H), 7.42-7.36 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 4.63-4.55 and 4.50-4.42 (2m, 1H), 3.98 (s, 3H), 3.80-3.77 (m, 4H), 3.70 (br, 4H), 3.59-3.47 (m, 6H), 3.08-3.03 (m, 2H), 2.60-2.53 (m, 2H), 2.36-2.33 (m, 6H), 1.85-1.59 (m, 6H).
Reaction SMILES: Cl.[CH2:2]([N:4]([C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[F:31])[N:19]=[CH:20][C:13]=12)[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:3].Br[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:2]([N:4]([C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[F:31])[N:19]=[CH:20][C:13]=12)[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:10][CH2:11]1)[CH3:3]
Reactant: CCN(CC1CCNCC1)c1ncnc2c1cnn2-c1ccc(S(C)(=O)=O)cc1F
Reactant: Brc1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC1CCN(c2ccccn2)CC1)c1ncnc2c1cnn2-c1ccc(S(C)(=O)=O)cc1F
Temperature: 165 °C
Yield: 15.3 %

Procedure:
A mixture of ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-piperidin-4-ylmethyl-amine hydrochloride salt (30 mg, 0.064 mmol), 2-bromopyridine (0.62 μL, 0.64 mmol), and triethylamine (26 μL, 0.19 mmol) in DMF (1.0 mL) was heated under microwave irradiation for 30 minutes at 165° C. The crude mixture was purified by HPLC to provide compound A126 as a white solid (5 mg, 15%). Exact mass calculated for C25H28FN7O2S 509.2, found 510.5 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:21]([O-])=O)=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=3[O-:19])[C:6]=2[CH:20]=1.[C:24](O)(=[O:26])C>O.[C].[Pd]>[CH3:11][C:9]1([CH3:12])[O:10][C:5]2=[CH:4][C:3]3[NH:21][C:24](=[O:26])[NH:1][C:2]=3[CH:20]=[C:6]2[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=2[O-:19])[CH2:8]1
Reactant: CC(=O)O
Reactant: CC1(C)CN(c2cccc[n+]2[O-])c2cc(N)c([N+](=O)[O-])cc2O1
Agent: [Pd]
Solvent: O
Product: CC1(C)CN(c2cccc[n+]2[O-])c2cc3[nH]c(=O)[nH]c3cc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 632 mg 2-(6-amino-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-4-yl)pyridine 1 -oxide in 10 ml acetic acid, was added 50 mg of 10% palladium carbon, and catalytic hydrogenation was performed. The reaction mixture was filtered by the use of Celite, the solvent was distilled off from the filtrate under reduced pressure, the residue was dissolved in 10 ml tetrahydrofuran, 5 ml tetrahydrofuran solution containing 324 mg carbonyldiimidazole was added under ice cooling, and the mixture was stirred overnight at room temperature. The precipitate which separated out was filtered off, the solvent was distilled off from the filtrate under reduced pressure, the residue thus obtained was dissolved in water, the aqueous solution was washed with chloroform and allowed to stand at room temperature for one hour, and the crystals which separated out were collected by filtration, thus giving 130 mg of 2-(7,8-dihydro-6,6-dimethyl-2-oxo-6H-[1,4]oxazino[2,3-f]benzimidazolin-8-yl)pyridine 1-oxide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[CH3:17][NH:18][C@@H:19]([CH3:22])[CH2:20][OH:21]>C(#N)C.CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([N:18]([CH3:17])[C@@H:19]([CH3:22])[CH2:20][OH:21])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CN[C@@H](C)CO
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](CO)N(C)c1cc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4,6-trichloropyrimidine (5.42 mL, 47.1 mmol) and triethylamine (19.7 mL, 141 mmol) in acetonitrile (40 mL) was slowly added (S)-2-(methylamino)propan-1-ol (6.30 g, 70.7 mmol) in N,N-dimethylformamide (DMF) (3.00 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, filtered, dried over anhydrous Na2SO4, concentrated. Purification via flash chromatography column (petroleum ether/ethyl acetate=10/1) afforded the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:3]=1.[Br:15]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[N:3]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(-c2cccc(Cl)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(-c2ccc(CBr)cc2)n1
Temperature: 25 °C
Yield: 275 %

Procedure:
The mixture (4.02 g) obtained in Example 36-1 in a carbon tetrachloride solution (45 ml) was added with N-bromosuccinimide (1.31 g) and 2,2′-azobisisobutyronitrile (0.121 g) and the whole was refluxed for 30 minutes. After that, the solution was cooled to room temperature and a solid component was separated by filtration. The organic layer was washed with a 1 mol/l sodium hydroxide aqueous solution and a saturated saline solution in the stated order, and dried with anhydrous magnesium sulfate. The solvent was distilled off and dried under reduced pressure, thereby obtaining a mixture (5.72 g) containing the subject compound.
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([C:10]1[CH:25]=[C:24]2[C:13]([CH2:14][C:15]3[CH:19]=[CH:18][N:17]([CH2:20][C@H:21](O)[CH3:22])[C:16]=32)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.[N-:33]=[N+:34]=[N-:35].[Na+]>ClCCl.CN(C)C=O.O>[N:33]([C@@H:21]([CH3:22])[CH2:20][N:17]1[CH:18]=[CH:19][C:15]2[CH2:14][C:13]3[C:24]([C:16]1=2)=[CH:25][C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:11][CH:12]=3)=[N+:34]=[N-:35]
Reactant: C[C@@H](O)Cn1ccc2c1-c1cc(C(C)(C)C)ccc1C2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H](Cn1ccc2c1-c1cc(C(C)(C)C)ccc1C2)N=[N+]=[N-]
Yield: 39.5 %

Procedure:
1.1 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 1.9 g of (R)-1-(7-tert-butyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 3.9 ml of triethylamine in 55 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 150 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 0.83 g of sodium azide and the reaction mixture was heated to 60° for 16 hours while stirring. After cooling the solution was poured into 120 ml of water and extracted twice with 120 ml of ethyl acetate each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 0.82 g (44%) of (S)-1-(2-azido-propyl)-7-tert-butyl-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as a light brown oil.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][CH:6]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=2)[N:8]=1)[NH2:2].[C:19]([O-])([O-])(OCC)[CH3:20]>>[CH3:19][C:20]1[N:4]2[N:5]=[CH:6][C:7]([C:9]3[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=3)=[N:8][C:3]2=[N:1][N:2]=1
Reactant: NNc1nncc(-c2cccc(C(F)(F)F)c2)n1
Reactant: CCOC(C)([O-])[O-]
Product: Cc1nnc2nc(-c3cccc(C(F)(F)F)c3)cnn12

Procedure:
A mixture of 5.1 g. of 3-hydrazino-5-(α,α,α-trifluoro-m-tolyl)-1,2,4-triazine and 60 ml. of ethyl orthoacetate is refluxed for 2.5 hours, cooled and the solid is collected by filtration and washed with hexane and ethanol, giving the desired product as yellow plates, m.p. 230°-233° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:28][C:29]([OH:31])=[O:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]([OH:31])=[O:30])=[CH:4][CH:3]=1
Reactant: O=C(O)CBr
Reactant: COc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1ccccc1C1CCN(C(=O)c2cn(CC(=O)O)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) bromo-acetic acid gave the title compound.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].N1CCCCC1.[ClH:33]>ClCCl.C(O)C>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[ClH:33]
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
Fmoc-L-Ile-AE (19 mg; 0.0314 mmol) was treated with piperidine (0.05 ml; 0.502 mmol) in dichloromethane (2 ml) for 1 hr. The solvent and piperidine were removed under vacuum. The residue was suspended in n-hexane and centrifuged. Once the supernatant solvent was removed, the solid obtained was treated with HCl in ethanol (2 ml). Solvent evaporation gave L-Ile-AE×HCl (10 mg; 77%).
Reaction SMILES: O[C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11]([OH:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[N:9]1([O:19][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=[N:8]1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)c1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(On1nnc2ccccc21)c1ccccc1
Reaction time: 5 h

Procedure:
Hydroxybenzotriazole resin (0.107 g, 0.196 mmol) was treated with benzoic acid (0.12 g, 0.982 mmol, 5 eq), DIC (0.152 mL, 0.982 mmol, 5 eq) and DMAP (0.024 g, 0.196 mmol, 1 eq) in DMF-CH2Cl2 (1:1) and shaken for 5 h. The mixture was filtered and the resin was washed with DMF (10×5 mL) and CH2Cl2 (10×5 mL) to give resin-supported benzoic acid benzotriazol-1-yl ester. To a suspension of the resin-ester (0.196 mmol, 1.5 eq) in CH2Cl2 (2 mL) were added i-Pr2NEt (0.033 mL, 0.196 mmol, 1.5 eq) and 2-amino-2-methyl-pentan-3-one (0.03 g, 0.131 mmol, 1 eq). The mixture was agitated for 16 h and filtered. The filtrate was shaken with a weakly basic ion exchange resin Amberlite IRA-95 (1 g, 4.7 mmol g−1, 25 eq) for 16 h to remove benzoic acid present in the solution and filtered. The filtrate was eluted through a short column of silica gel (hexane/ethyl acetate 50:50) to remove the unreacted amine. The organic solvent was evaporated to leave N-(1,1-dimethyl-2-oxo-butyl)-benzamide (0.03 g, 87%) as a white solid. 1H NMR (200 MHz, CDCl3) δ (ppm): 1.14 (t, J=7.2 Hz, 3H), 1.57 (s, 6H), 2.63 (q, J=7 Hz, 2H), 7.21 (bs, 1H), 7.38-7.56 (aromatic H's, 3H), 7.79 (dd, J=8, 1.8 Hz, 2H). MS (ESI, positive ion): m/z 220.2 (M+1)+.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[O:14][CH3:15].[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH3:32])=[C:24]1B1OC(C)(C)C(C)(C)O1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH3:32])=[C:24]1[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[O:14][CH3:15])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)n(C(=O)OC(C)(C)C)c2ccccc12
Reactant: COc1nnc(-c2ccncc2)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1nnc(-c2ccncc2)cc1-c1c(C)c2ccccc2n1C(=O)OC(C)(C)C

Procedure:
Argon is passed for 30 min through a suspension of 333 mg 4-Iodo-3-methoxy-6-pyridin-4-yl-pyridazine, 380 mg 3-Methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indole-1-carb-oxylic acid tert-butyl ester, 294 mg potassium carbonate, and 111.6 mg triphenylphosphine in 4.8 ml DME and 2.4 ml water. 24 mg palladium (II) acetate is added and the mixture stirred under reflux for 3 h. The product is isolated by extraction with ethyl acetate and purified by chromatography on silica gel yielding 52.1 mg 2-(3-Methoxy-6-pyridin-4-yl-pyridazin-4-yl)-3-methyl-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+]([O-])=O)=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([Br:20])=[C:17]([Cl:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH3:24][S-:25].[Na+].C(O)(=O)C>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:25][CH3:24])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([Br:20])=[C:17]([Cl:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(Br)c(Cl)c2)c([N+](=O)[O-])s1
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(Br)c(Cl)c2)c(SC)s1
Yield: 22.9 %

Procedure:
The procedure described in Example 27: step a was followed using 4-(6-Bromo-5-chloro-pyridine-3-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (63 mg, 0.14 mmol, Example 123: step b) and sodium thiomethoxide (0.5 M in EtOH, 0.18 mmol, 360 μL). The reaction was quenched with acetic acid (10 uL, 0.18 mol) followed by concentration in vacuo. The residue was then dissolved into EtOAc and washed with saturated NaHCO3 and brine solutions. The organic layers were dried (Na2SO4) and removal of the solvents in vacuo was followed by purification by preparative SiO2 TLC (30% EtOAc in hexanes) that yielded the title compound (14.2 mg, 23%) as a yellow solid. ESI-MS (m/z): Calcd. for C12H9BrClNO4S3: 441.9 (M+1) found: 442.0.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH:14]([P:16]([CH2:21][CH2:22][CH2:23][CH3:24])(=[O:20])[O:17]CC)[OH:15])=O)C1C=CC=CC=1.O.C(O)C.[ClH:29]>>[ClH:29].[NH2:11][CH2:12][CH2:13][CH:14]([P:16]([CH2:21][CH2:22][CH2:23][CH3:24])(=[O:17])[OH:20])[OH:15]
Reactant: CCCCP(=O)(OCC)C(O)CCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCCP(=O)(O)C(O)CCN
Temperature: 25 °C

Procedure:
A suspension of 1.3 g of ethyl 3-(N-benzyloxycarbonylamino)-1-hydroxy-propyl(n-butyl)phosphinate in 10 ml of concentrated aqueous hydrochloric acid is heated to reflux for 20 hours. The clear solution is cooled to room temperature and washed with 1×50 ml of dichloromethane and 1×50 ml of ether. Evaporation of the aqueous layer affords a solid which is co-evaporated with 5×50 ml of water and 5×50 ml of absolute ethanol. Drying of the solid and crystallisation from ethanol affords 3-amino-1-hydroxy-propyl(n-butyl)phosphinic acid hydrochloride, m.p. 147-150°. Dissolution of the hydrochloride salt in ethanol and treatment with propylene oxide affords, after filtration and drying, 3-amino-1-hydroxy-propyl(n-butyl)phosphinic acid, m.p. 123-125°.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]2[CH:11]=[CH:12][CH:13]=[C:6]12)=[O:4].[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]2[C:11]([C:19](=[O:20])[C:18]3[CH:22]=[CH:23][C:15]([F:14])=[CH:16][CH:17]=3)=[CH:12][CH:13]=[C:6]12)=[O:4]
Reactant: COC(=O)C1CCCn2cccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: Cc1ccccc1C
Product: COC(=O)C1CCCn2c(C(=O)c3ccc(F)cc3)ccc21

Procedure:
A solution of methyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate (2.0 g., 0.01 moles) in dry xylene (30 ml.) containing 4-fluorobenzoyl chloride (4.5 g., 0.028 moles) is heated at reflux temperature in a nitrogen atmosphere for 20 hours. The solvent is removed in vacuo and the residue is purified by t.l.c. on silica gel using hexane-ethyl acetate (3:1) as the developing solvent. Removal of the solvent gives methyl-3-p-fluorobenzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate which, when crystallized from acetone-hexane exhibits a m.p. of 78°-79° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][CH2:15][OH:16])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:16][CH2:15][CH2:14][CH:13]([NH:17][C:18]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:24])[C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NC(CCO)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCOS(C)(=O)=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
Methanesulfonyl chloride (0.097 mL, 1.25 mmol) was added dropwise to tert-butyl 1-(4-chlorophenyl)-3-hydroxypropylcarbamate (Intermediate 30) (0.326 g, 1.14 mmol) and triethylamine (0.191 mL, 1.37 mmol) in DCM (15 mL) at 22° C. The resulting solution was stirred at 22° C. for 2 hours. The mixture was concentrated and the residue was purified by flash silica chromatography, elution gradient 20 to 40% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 3-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propyl methanesulfonate (0.366 g, 88%) as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11](O)[C:10]=1[N+:20]([O-:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(Cl)([Cl:31])=O)C=CC=CC=1.CCCCCC>C(OCC)C>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([Cl:31])[C:10]=1[N+:20]([O-:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)cc(C(F)(F)F)nc1O
Solvent: CCCCCC
Solvent: CCOCC
Product: O=[N+]([O-])c1c(NCc2ccccc2)cc(C(F)(F)F)nc1Cl
Temperature: 100 °C
Yield: 92 %

Procedure:
4-Benzylamino-3-nitro-6-trifluoromethyl-pyridin-2-ol (61.7 gm 197 mmol) was added to phenylphosphonic dichloride (180 mL) and heated to 100° C. in an oil bath, under N2 overnight. The starting material dissolved on heating to give a light yellow solution. Quenched the cooled reaction mixture on to ice water (600 gm of ice+100 mL water) to give a pale yellow solid. Filtered off and washed the solid well with water. The solid was dissolved in ethyl acetate (600 mL) and washed with aqueous sodium hydrogen carbonate solution (10% w/v) until there was no further effervescence and the pH of the aqueous washings were basic. The organic layer was dried over sodium sulphate, filtered and evaporated to give a dirty yellow solid. The solid was dissolved in diethyl ether and to this was added n-hexane until the solution was cloudy, within a few minutes a thick flocculent solid had formed, filtered off, washed with n-hexane and dried to give benzyl-(2-chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl)-amine (60.59 gm 92% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C@@H:11]([O:13]C1CCCCO1)[CH3:12])=[CH2:10].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:10])[C@@H:11]([OH:13])[CH3:12]
Reactant: C=C(c1ccc(F)cc1F)[C@H](C)OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C=C(c1ccc(F)cc1F)[C@H](C)O
Temperature: 60 °C

Procedure:
A mixture of crude 5a and pyridinium-p-toluenesulfonate (70 g, 0.278mole) in ethanol (250 ml) is heated at 60° C. for 9 hours. The reaction mixture is concentrated in vacuo and co-evaporated with toluene. The residue is diluted with toluene and the resulting solid is removed by filtration. The filtrate is evaporated under reduced pressure to give the crude 6a as light brown oil.