Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][CH2:8][C@@H:7]3C[C@H](N(CC4CC4)CC4CC4)C[C:5]=1[C:6]=23)(=O)C.C([N:27]([CH2:30]C)CC)C.ClC(Cl)(Cl)C[O:35]C(Cl)=O>C(Cl)Cl.ClCl>[C:30]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:12][CH:11]=2)[CH2:7][CH2:8]1)(=[O:35])[NH2:27]
Reactant: CC(=O)c1ccc2c3c1C[C@@H](N(CC1CC1)CC1CC1)C[C@H]3CN2
Reactant: CCN(CC)CC
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: ClCl
Solvent: ClCCl
Product: NC(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 248.2 %

Procedure:
To a solution of (-)(2aR,4S)-6-acetyl-4-[di-(cyclopropylmethyl)amino]-1,2,2a,3,4,5-hexahydrobenz[cd]indole (2.5 g, 7.7 mmol) and triethylamine (1.1 ml, 8 mmol) in 90 ml CH2Cl2 was added dropwise a solution of 2,2,2-trichloroethylchloroformate (1.7 g, 8 mmol) in 10 ml CH2 Cl2. The reaction mixture was stirred at room temperature for one hour and then extracted with water and 1N HCl. The organic solution was washed with a saturated NaHCO3 solution, and a saturated brine solution, dried over MgSO4 and then concentrated to dryness in vacuo to give 3.1 g of the 1-carbamylindoline.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[C:5]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])#N.Cl.C1C[O:18]CC1>>[NH2:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[C:5](=[O:18])[CH2:1][CH3:2]
Reactant: C1CCOC1
Reactant: CC[Mg]Cl
Reactant: N#Cc1ccccc1N
Agent: Cl
Product: CCC(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
A 2.0N solution of ethylmagnesium chloride in THF (100 ml) was cooled to 0° C. under nitrogen atmosphere, and thereto was added dropwise a solution of 2-cyanoaniline (7.90 g) in THF (65 ml) over a period of 50 minutes. The mixture was stirred at room temperature for 20 minutes, and refluxed for 3 hours. The reaction solution was cooled to 0° C., and thereto was added a 4N aqueous hydrochloric acid solution (80 ml) over a period of 40 minutes, and the mixture was further refluxed for 3 hours. The solvent in the reaction solution was evaporated under reduced pressure, and the resultant was added to a saturated aqueous sodium hydrogen carbonate solution for neutralization. The mixture was extracted three times with ethyl acetate, and the extract was washed with a saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=8/1) to give 1-(2-aminophenyl)-1-propanone (6.78 g, 68%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[CH2:5][CH2:6][C:7](O)=[O:8].[CH2:12]([C@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C@H:19]1[CH2:23][N:22]([C:7](=[O:8])[CH2:6][CH2:5][C:4]([N:3]([CH3:11])[CH3:2])=[O:10])[C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: CN(C)C(=O)CCC(=O)O
Agent: Cl
Product: CN(C)C(=O)CCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 20 %

Procedure:
Proceeding as in Example 1, but substituting 4-(dimethylamino)-4-oxobutanoic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 89, (2S,4R)-4-benzyl-1-(4-(dimethylamino)-4-oxobutanoyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (6.2 mg, 20%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.68 (s, 1H), 7.57 (m, 2H), 7.27 (m, 2H), 7.23-7.15 (m, 7H), 6.93 (m, 2H), 4.43 (m, 1H), 3.68 (m, 1H), 3.27 (m, 1H), 2.94 (s, 3H), 2.78 (s, 3H), 2.67-2.58 (m, 4H), 2.44 (m, 3H), 1.91 (m, 2H). MS (EI) for C30H32FN3O4. found 518.6 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=3)[N:8]=[C:9]2O)=[CH:4][C:3]=1[O:23][CH3:24].O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:23][CH3:24])=[C:2]([F:1])[CH:11]=2)[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2cc(-c3ccc(OC(C)C)cc3)nc(O)c2cc1F
Product: COc1cc2cc(-c3ccc(OC(C)C)cc3)nc(Cl)c2cc1F
Yield: 94.6 %

Procedure:
A solution of 7-fluoro-3-(4-isopropoxyphenyl)-6-methoxyisoquinolin-1-ol (1.8 g, 5.50 mmol) in POCl3 (7.69 ml, 82 mmol) was refluxed for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 50% DCM in hexanes. The product fractions were collected and the solvent removed under vacuum to give 1-chloro-7-fluoro-3-(4-isopropoxyphenyl)-6-methoxyisoquinoline (1.8 g, 95% yield). MS: MS m/z 346.1 (M++1).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[F:5][C:6]([F:13])([F:12])[C:7](OCC)=[O:8]>CO>[CH2:1]([NH:4][C:7](=[O:8])[C:6]([F:13])([F:12])[F:5])[C:2]#[CH:3]
Reactant: CCOC(=O)C(F)(F)F
Reactant: C#CCN
Solvent: CO
Product: C#CCNC(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 24 h
Yield: 95.9 %

Procedure:
This compound has been prepared using a literature method (K. A. Cruickshank, D. L. Stockwell (1988) Tetrahedron Lett. 29, 5221). Propargylamine (90.9 mmol, 5 g, 6.227 mL) was added to methanol (90 mL) and the solution cooled to 0° C. Ethyl trifluoroacetate (1.3 equiv., 118.2 mmol, 16.8 g, 14.1 mL) was added and the mixture stirred at room temperature for 24 h. The solvent was evaporated, the residue diluted with 90 mL chloroform and washed with aqueous NaHCO3 solution (2×75 mL) and water (1×75 mL). The organic layer was evaporated and the orange residue distilled in vacuum to give N-propargyltrifluoroacetamide (13.171 g, 96%) as a colorless liquid which solidifies at -20° C. bp: 41° C./1.5 mm (bp ref.: 51° C./2.5 mm), mp: 31-33° C. 1H-NMR (CDCl3): 2.34 (m, 1H, CH), 4.15 (dd, 2H, CH2), 7.80 (br s, H, NH). 1H-NMR ref. (CDCl3): 2.34 (t, 1H), 4.16 (dd, 2H), 7.00 (br s, 1H). 13C-NMR (CDCl3): 29.4 (CH2), 72.4 (CH), 77.0 (C), 109.859, 113.673, 117.470, 121.276 (CF3, J=286.37 Hz), 156.748, 157.249, 157.750, 158.250 (CO, J=37.77 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[O:10][CH2:11][C@H:12]2[N:16]([C:17]([O:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]=[N:32][C:33]4[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=4[Cl:42])=[CH:27][CH:26]=3)=[O:18])[CH2:15][C@H:14]([OH:43])[CH2:13]2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH:67]([N:70]([CH:78]([CH3:80])[CH3:79])[P:71](Cl)[O:72][CH2:73][CH2:74][C:75]#[N:76])([CH3:69])[CH3:68].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:50]2[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[O:10][CH2:11][C@@H:12]2[CH2:13][C@@H:14]([O:43][P:71]([N:70]([CH:78]([CH3:80])[CH3:79])[CH:67]([CH3:68])[CH3:69])[O:72][CH2:73][CH2:74][C:75]#[N:76])[CH2:15][N:16]2[C:17]([O:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([N:31]=[N:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=3[Cl:42])=[CH:29][CH:30]=2)=[O:18])=[CH:5][CH:4]=1
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Reactant: COc1ccc(C(OC[C@@H]2C[C@@H](O)CN2C(=O)OCCNCCc2ccc(N=Nc3ccc([N+](=O)[O-])cc3Cl)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1ccc(C(OC[C@@H]2C[C@@H](OP(OCCC#N)N(C(C)C)C(C)C)CN2C(=O)OCCNCCc2ccc(N=Nc3ccc([N+](=O)[O-])cc3Cl)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of 4a (12.63 g, 15.91 mmol) dissolved in 440 ml of anhydrous methylene chloride, containing 8.0 ml of N,N-diisopropylethylamine, was added 5.94 ml of 2-cyanoethyl diisopropylchlorophosphoramidite. The solution was stirred 30 min under argon at room temperature. The reaction mixture was treated with 10 ml of methanol and poured into 400 ml of 5% sodium bicarbonate solution. The organic phase was dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting with a gradient of 40-20% hexane in ethyl acetate (2% triethylamine). The pure product fractions were evaporated affording an amorphous solid: 14.75 g (93% yield). 31P NMR (DMSO-d6) δ 146.93 (singlet). Anal. Calcd for C52H61ClN7O9+1.0H2O: C, 61.68; H, 6.27; N, 9.68. Found: C, 61.44; H, 6.47; N, 9.35.
Reaction SMILES: [NH2:1][CH:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[OH:4].[C:29]1([C:40](O)=[O:41])[CH:30]=[CH:31][CH:32]=[C:33]2[CH2:39][CH2:38][CH2:37][CH:36]=[CH:35][C:34]=12.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)[CH:2]([NH:1][C:40]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[CH2:39][CH2:38][CH2:37][CH:36]=[CH:35][C:34]=12)=[O:41])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (206 mg, 0.53 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (100 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153 mg, 0.80 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (268 mg, 90%).
Reaction SMILES: [CH3:1][C:2]([OH:30])([CH3:29])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[O:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=1.Br[C:32]1[C:36]2=[N:37][CH:38]=[CH:39][CH:40]=[C:35]2[N:34]([CH:41]([CH3:43])[CH3:42])[N:33]=1.C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>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.O>[CH3:29][C:2]([OH:30])([CH3:1])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:32]2[C:36]3=[N:37][CH:38]=[CH:39][CH:40]=[C:35]3[N:34]([CH:41]([CH3:43])[CH3:42])[N:33]=2)=[CH:16][CH:15]=1
Reactant: CC(C)n1nc(Br)c2ncccc21
Reactant: CC(C)(O)Cn1c(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CC(C)n1nc(-c2ccc(Oc3nc4ccccc4n3CC(C)(C)O)cc2)c2ncccc21
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
A mixture of 2-methyl-1-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol (237 mg), 3-bromo-1-(1-methylethyl)-1H-pyrazolo[4,3-b]pyridine (139 mg), Cs2CO3 (378 mg), Pd(PPh3)4 (20.1 mg), DME (5 mL), and water (1 mL) was stirred at 140° C. for 30 min under microwave irradiation. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) and recrystallized from AcOEt/hexane to give the title compound (175 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2cc(-c3ccc(Br)cc3)sc2c1
Agent: BrB(Br)Br
Product: Oc1ccc2cc(-c3ccc(Br)cc3)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
To a stirred solution of 2-(4-bromo-phenyl)-6-methoxy-benzo[b]thiophene (80 mg, 0.25 mmol) was added BBr3 (0.5 mL of 1 M in DCM, 0.5 mmol) at 0° C. The mixture was stirred for 3 hours at ambient temperature. DCM was removed under vacuum, and the residue was dissolved in ethyl acetate (30 mL) The organic layer was washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was treated with hexane to give the product (67 mg, 88%). m/z 303.0, 305.0 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:43]=[CH:44][CH:45]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:29][C@@H:28]([C:30]3[CH:41]=[CH:40][C:33]4[O:34][C:35]([CH3:39])([CH3:38])[O:36][CH2:37][C:32]=4[CH:31]=3)[O:27][C:26]2=[O:42])[CH:9]=1)=[O:6].[C:46]1([S:52](Cl)(=[O:54])=[O:53])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:38][C:35]1([CH3:39])[O:34][C:33]2[CH:40]=[CH:41][C:30]([C@H:28]3[O:27][C:26](=[O:42])[N:25]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][C:10]4[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]5[CH:43]=[CH:44][CH:45]=[C:2]([NH:1][S:52]([C:46]6[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=6)(=[O:54])=[O:53])[CH:3]=5)[CH:13]=[CH:12][CH:11]=4)[CH2:29]3)=[CH:31][C:32]=2[CH2:37][O:36]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)c5cccc(N)c5)c4)C(=O)O3)ccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)c5cccc(NS(=O)(=O)c6ccccc6)c5)c4)C(=O)O3)ccc2O1
Reaction time: 2 h

Procedure:
3-Amino-N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]benzamide (200 mg) in pyridine (5 ml) under nitrogen was treated with benzenesulfonyl chloride (0.045 ml) and the mixture was stirred at 20° for 2 h. Sat. sodium bicarbonate solution (30 ml) was added and the mixture was extracted with dichloromethane (2×20 ml). The combined extracts were dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel. Elution with EtOAc-dichloromethane (1:1) gave the title compound (155 mg). LCMS RT=3.72 min, ES+ve 758 (MH)+.
Reaction SMILES: Cl[Si](C)(C)C.Br[C:7]1[N:15]2[C:10]([C:11]([NH2:16])=[N:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1.CC([Mg]Cl)C.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].[O:35]1CCCC1>ClCCl>[NH2:16][C:11]1[C:10]2=[CH:9][CH:8]=[C:7]([C:32]3([OH:35])[CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28])[CH2:30][CH2:31]3)[N:15]2[N:14]=[CH:13][N:12]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCCCC1
Reactant: Nc1ncnn2c(Br)ccc12
Agent: CC(C)[Mg]Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc3c(N)ncnn23)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
Chlorotrimethylsilane (89 mL, 0.70 mol) was added drop wise to a stirred solution of 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine in tetrahydrofuran (1.6 L, anhydrous) and stirring was continued for 3 h. The solution was cooled to 0° C. and 2-propyl magnesium chloride solution (2M in THF, 740 mL, 1.48 mol) was slowly added. The reaction was warmed to 25° C. and stirring continued for 2 h, then cooled back down to −5° C. and a solution of N-tert-butoxycarbonyl piperidine (91.0 g, 0.68 mol) in THF (1 L) was added drop wise. The reaction was continued for 18 h at 25° C., then the mixture was, poured into vigorously-stirred ice water (8 L). The aqueous mixture was extracted with ethyl acetate (3×3 L) and the combined organic portions were dried over magnesium sulfate. Filtration and concentration in vacuo gave a dark-orange oil which was dissolved in a minimal volume of dichloromethane and crystallization induced. After cooling (−10° C.) the mixture for several hours, the crystalline product was collected by suction filtration, washed with diethyl ether and dried to give a colorless solid (61 g, 52%). Purification of the filtrate by silica gel chromatography (5% methanol/dichloromethane) yielded additional product (37 g, 32%). 1H-NMR (DMSO-d6) δ 7.77 (s, 1H), 7.69 (br s, 2H), 6.80 (d, 1H), 6.55 (d, 1H), 5.74 (s, 1H), 3.77 (m, 2H), 3.15 (br m, 2H), 2.48 (m, 2H), 1.70 (d, 2H), 1.40 (s, 9H). ES-MS m/z=334.1 [M+H]+, RT (min) 2.15.
Reaction SMILES: COS([O-])(=O)=O.[CH3:7][C:8]1[CH:9]=[N+:10](OC)[CH:11]=[CH:12][CH:13]=1.[C-:16]#[N:17]>>[CH3:7][C:8]1[C:9]([C:16]#[N:17])=[N:10][CH:11]=[CH:12][CH:13]=1.[C:16]([C:13]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)#[N:17]
Reactant: [C-]#N
Reactant: CO[n+]1cccc(C)c1
Agent: COS(=O)(=O)[O-]
Product: Cc1cccnc1C#N
Product: N#Cc1ccncc1

Procedure:
It has been reported by Fife et al , Heterocycles 22:1121-4(1984) that 3-methyl-1-methoxypyridinium methylsulfate reacted with cyanide ion to give 3-methyl-2-cyanopyridine and "high percentages" of the 4-cyanopyridine isomer. In Table 1 on page 1122, Fife et al. reported that the 4 cyano compound was obtained in 69% yield and 3-methyl2-cyanopyridine was obtained in 24% yield.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=[O:3])[CH3:2].[CH3:26]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][C@H:8]([N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:26])[CH2:9][O:10][Si:11]([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:12])[CH3:13])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)OCCC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 105.6 %

Procedure:
To a solution of (S)-4-(tert-butoxycarbonylamino)-5-(tert-butyldimethylsilyloxy)pentyl acetate (48.2 g, 0.124 mol) and MeI (23.2 mL, 0.372 mol) in DMF (500 mL) was added sodium hydride (60%, 9.9 g, 0.248 mol) at 0° C. The resulting mixture was stirred at 0° C. for 2½ h and LC-MS indicated the reaction was completed. The reaction was quenched with saturated NH4Cl solution and diluted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give (S)-4-(tert-butoxycarbonyl(methyl)amino)-5-(tert-butyldimethylsilyloxy)pentyl acetate (51 g, crude). LRMS (M+H+-Boc) m/z 290.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.[NH2:32][CH2:33][C:34]1[C:35]([OH:42])=[N:36][C:37]([CH3:41])=[CH:38][C:39]=1[CH3:40]>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:32][CH2:33][C:34]1[C:35]([OH:42])=[N:36][C:37]([CH3:41])=[CH:38][C:39]=1[CH3:40])=[O:6]
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1ccccc1)c1ccc(C(=O)O)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3)cc2Cl)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 87.6 %

Procedure:
To a solution of 2-chloro-4-(1-phenoxyethyl)benzoic acid (262 mg, 1.0 mmol), 1-hydroxybenzotriozole (202 mg, 1.5 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288 mg, 1.5 mmol) triethylamine (0.4 mL) in dichloromethane (15 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1.0 mmol). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give 2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenoxyethyl)benzamide as a white solid (360 mg, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:5]([OH:7])=[O:6].[C:18]([O:21][CH2:22][C:23](Cl)=O)(=[O:20])[CH3:19]>O1CCOCC1>[C:18]([O:21][CH2:22][C:23]1[N:11]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1)(=[O:20])[CH3:19]
Reactant: Nc1cc(C(=O)O)ccc1NC1CCOCC1
Reactant: CC(=O)OCC(=O)Cl
Solvent: C1COCCO1
Product: CC(=O)OCc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 92.6 %

Procedure:
A 4-neck flask (1 L) equipped with a reflux condenser was charged with 3-amino-4-((tetrahydropyran-4-yl)amino)benzoic acid (14.53 g, 45.65 mmol) and anhydrous 1,4-dioxane (226 mL) and this was refluxed. Acetoxyacetyl chloride (12.57 g, 92.07 mmol) in 1,4-dioxane solution (100 mL) was added dropwise to this over approx. 15 minutes. This was stirred under these conditions for 13 hours. This was allowed to cool to room temperature, and after the precipitated crystals were filtered off, they were washed with distilled water, and dried under reduced pressure with heating to yield the title compound (13.46 g, 92.6% yield) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[C:18](=[S:20])=[S:19]>CS(C)=O.O>[OH:15][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][C:9]([C:18]([SH:20])=[S:19])=[CH:8][C:7]=1[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: S=C=S
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(C(=S)S)cc(C(C)(C)C)c1O
Reaction time: 2 h

Procedure:
The compound 4-hydroxy-3,5-di-tert.-butyl dithiobenzoic acid was prepared by dissolving 2,6 -di-tert.-butyl phenol (20.6 g) in dimethylsulfoxide (60 cm3). To this well stirred solution under a nitrogen blanket was added KOH (5.6 g) dissolved in a minimum amount of water. After the addition was completed carbon disulfide (7.6 g) was added while maintaining the temperature between 20°-25° C. The mixture was maintained at this temperature for 1 hour, then at 60° C. for 2 hours, cooled and poured into water (250 cm.3). After acidification (10% HCl), extraction into diethyl ether and drying over Na2SO4 the product was isolated by rotoevaporation.