Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([C:9]([OH:11])=[O:10])[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=O>C(OC(=O)C)(=O)C>[C@@H:2]12[C:6](=[O:8])[O:11][C:9](=[O:10])[C@@H:1]1[CH2:5][CH2:4][CH2:3]2
Reactant: O=C(O)[C@@H]1CCC[C@H]1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)[C@@H]2CCC[C@H]12
Temperature: 165 °C

Procedure:
To the trans-cyclopentane-1,2-dicarboxylic acid (1.16 g, 7.33 mmol) at room temperature, was added Acetic anhydride (10 mL, ex). The reaction mixture was refluxed at about 165° C. for 14 hrs. Workup consisted of concentration in vacuo and co-evaporation with toluene three times. The crude product (1.0 g, ~100%, with a little impurity of Acetic anhydride) was given as a brown oily solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C@@H:16]2[C@H:19]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18](=[O:31])[NH:17]2)[N:11]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C@@H:16]2[C@H:19]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18](=[O:31])[NH:17]2)[N:11]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(N[C@@H]1C(=O)N[C@@H]1Cn1ncc(CO)n1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
To a solution of benzyl ((2R,3S)-2-((4-(((tert-butyldimethylsilyl)oxy)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)carbamate (10.8 g, 24.4 mmol) in THF (100 mL) was added TBAF (1 M in THF, 26.6 mL, 26.6 mmol) slowly over a period of 15 min. After stirring at rt for 1.5 h, the reaction mixture was concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 1-5%) to afford the title compound (6.8 g, 85%) as a pale yellow solid. LCMS: m/z=330.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](O)=[O:19])[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:24].[CH3:25][O:26][CH2:27][CH2:28][NH2:29].ON1C2C=CC=CC=2N=N1.CCN=C=NCCC[N+](C)(C)C.[I-]>ClC(Cl)C.CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([NH:29][CH2:28][CH2:27][O:26][CH3:25])=[O:19])[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: Cc1cc(-c2cc(-c3cccc(C(=O)O)c3)[nH]c(=O)n2)ccc1O
Reactant: COCCN
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: COCCNC(=O)c1cccc(-c2cc(-c3ccc(O)c(C)c3)nc(=O)[nH]2)c1
Yield: 35.6 %

Procedure:
To a solution of 3-(6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl)benzoic acid (16.9 mg, 48 umol) and 2-methoxyethanamine (3.0 mg, 40 umol) in dichloroethane (1.25 mL) and N,N-dimethylformamide (0.79 mL) was added 1-hydroxybenzotriazole (6.8 mg, 50 umol) followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (17.8 mg, 60 umol). The resultant mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo. Purification of the residue by HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) followed by concentration in vacuo gave the title compound 3-[6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl]-N-[2-(methyloxy)ethyl]benzamide (5.4 mg, 36%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[CH3:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: COC(=O)c1cncc(Br)c1
Reactant: Cc1ccc(B(O)O)cc1C
Product: COC(=O)c1cncc(-c2ccc(C)c(C)c2)c1

Procedure:
11.0 g (50.1 mmol) of methyl 5-bromonicotinate and 7.7 g (50.1 mmol) of 3,4-dimethylphenylboronic acid were reacted according to the General Method 1A. Yield: 4.0 g (31% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[CH2:16][CH3:17]>CC(C)=O.[I-].[K+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1
Reactant: CCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc(Br)cc1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
A mixture of 4-bromophenol (8.65 g), potassium iodide (83 mg), potassium carbonate (6.9 g) and propyl bromide (6.15 g) was heated under reflux in acetone (100 ml) for 48 hours. The reaction was cooled to ambient temperature, filtered and the acetone removed in vacuo to give an amber oil. This was purified by gradient elution with 20% ethyl acetate/isohexane through a silica gel Mega Bond Elut column to give 1-bromo-4-propoxybenzene (9.4 g) as a clear oil, mass spectrum (+ve CI): 214 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.O[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([O:8][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CC(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Yield: 57.6 %

Procedure:
1-Methylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (0.71 g, 58%) was prepared as a light yellow solid from 2-bromo-5-hydroxypyridine (0.60 g, 3.45 mmol), 1-methylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate (prepared as in Example 9, Step 1, 0.71 g, 3.45 mmol) and Ph3P (0.92 g, 3.45 mmol) in THF (18 mL) followed by diisopropyl azodicarboxylate (0.75 g, 94%, 3.45 mmol) in THF (6 mL) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CDCl3): δ 8.04 (bs, 1H), 7.36 (d, 1H, J=8.8 Hz), 7.15-7.05 (m, 1H), 4.91 (septet, 1H, J=6.2 Hz), 4.30-4.10 (m, 2H), 3.82 (d, 2H, J=6.1 Hz), 2.85-2.70 (m, 2H), 2.05-1.90 (m, 1H), 1.90-1.75 (m, 2H), 1.35-1.15 (m, 8H); LRMS (ESI), m/z 357/359 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[N+:17]([O-])=O.[H][H]>[Pd]>[NH2:17][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:8]=1[N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[CH3:1])[C:12]([OH:14])=[O:13]
Reactant: [H][H]
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC1CCCCN1c1ccc(C(=O)O)cc1N
Yield: 100 %

Procedure:
A methanolic solution of 4-(2-methylpiperidin-1-yl)-3-nitrobenzoic acid obtained in step 1 (500 mg; 1.89 mmol; 0.01 M) was pumped through an H-Cube (1 mL/min) fitted with a 10 mol % Pd/C catalyst cartridge (30×4 mm) and heated to 25° C. with the full hydrogen option enabled. Solvent was evaporated under vacuum to give the title compound as a pinkish oil (443 mg, 99%). 1H NMR (DMSO-d6, 300 MHz) δ 12.39 (bs, 1H), 7.28 (d, J=1.86 Hz, 1H), 7.14 (dd, J=8.1, 2.1 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 5.01 (bs, 1H), 3.07-3.03 (m, 1H), 2.91-2.88 (m, 1H), 2.43-2.35 (m, 1H), 1.79-1.70 (m, 2H), 1.62-1.61 (m, 2H), 1.41-1.31 (m, 2H), 0.79 (d, J=6 Hz, 3H). HPLC (Method A) Rt 1.66 min (Purity: 99.2%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH3:37][O:38][CH2:39][CH:40]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:25]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][NH:22][C:5]2[N:4]=[C:3]([CH2:2][NH:1][CH2:40][CH2:39][O:38][CH3:37])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: COCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCNCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC)[C@@H](O)[C@H]3O)c2n1
Yield: 36.2 %

Procedure:
The title compound was prepared by a similar method to example 5 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (320 mg, 0.63 mmol) (example 1), 2-methoxyacetaldehyde (53 mg, 0.63 mmol) and sodium triacetoxyborohydride (210 mg, 0.95 mmol) in tetrahydrofuran (22 ml). The product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (92:8:0.4) to give the title compound (125 mg) as a foam. MS: 548 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:9][N:10]=2)[CH:7]=1.[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:3]2[C:2]([C:34]3[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][C:35]=3[Cl:37])=[CH:7][N:6]3[C:8]([CH2:11][C:12]4[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)=[CH:24][CH:25]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(Br)cn12
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)cn12
Yield: 50 %

Procedure:
The title compound (5.5 mg, 50%) as a white powder was prepared from 6-bromo-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (9.5 mg, 0.020 mmol), 2,4-dichlorophenylboronic acid (7.5 mg, 0.039 mmol, K2CO3 (8.2 mg, 0.059 mmol) and Pd(PPh3)4 (2.8 mg, 0.002 mmol) in 1,4-dioxane (0.28 mL) and H2O (0.09 mL) by the procedures analogous to those described for 7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((6-(trifluoromethylpyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (Example 56E). LC/MS (method B): retention time=2.04 min, [M+H]+=547.2.
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[N:13]=[C:12]([C:14]([O:16]C)=O)[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][C:19]#[N:20]>>[CH:1]1([CH2:6][O:7][C:8]2[N:13]=[C:12]([C:14](=[O:16])[CH2:18][C:19]#[N:20])[CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC#N
Reactant: COC(=O)c1cccc(OCC2CCCC2)n1
Product: N#CCC(=O)c1cccc(OCC2CCCC2)n1

Procedure:
CH3CN addition to methyl 6-(cyclopentylmethoxy)picolinate following the method described in Example 6 gave 3-(6-(cyclopentylmethoxy)pyridin-2-yl)-3-oxopropanenitrile as a yellow oil which was used in the next step without further purification. Yield (1.22 g, quant.).
Reaction SMILES: [NH:1]([C:3]([CH:5]1[CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6]1)=[O:4])[NH2:2].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]1[C:38](O)=[O:39])=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.S([O-])(O)(=O)=O.[K+]>CN(C=O)C.O.CCOC(C)=O>[CH2:12]([O:11][C:9]([N:7]1[CH2:8][CH:5]([C:3]([NH:1][NH:2][C:38]([CH:27]2[CH:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:29][CH2:30][CH2:31][N:26]2[C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])=[O:39])=[O:4])[CH2:6]1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccccc2)C1C(=O)O
Reactant: NNC(=O)C1CN(C(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(c2ccccc2)C1C(=O)NNC(=O)C1CN(C(=O)OCc2ccccc2)C1
Reaction time: 48 h
Yield: 31 %

Procedure:
To a solution of benzyl 3-(hydrazinocarbonyl)azetidine-1-carboxylate (350 mg, 1.40 mmol) in DMF (10 ml) were added 1-(tert-butoxycarbonyl)-3-phenylpiperidine-2-carboxylic acid (1A.5, 427 mg, 1.40 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (322 mg, 1.68 mmol), and 1-hydroxy-7-azabenzotriazole (95.3 mg, 0.700 mmol). The reaction was allowed to stir for 48 h, and then poured onto 10% potassium hydrogen sulfate and diluted with water (10 ml) and EtOAc (30 ml). The organic portion was isolated, washed with 3M lithium chloride (2×) and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified via flash chromatography (silica, 0-50% EtOAc/hexanes) to yield tert-butyl 2-{[2-({1-[(benzyloxy)carbonyl]azetidin-3-yl}carbonyl)hydrazino]carbonyl}-3-phenylpiperidine-1-carboxylate (31%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:16][CH:17]2[CH2:22][CH2:21][N:20](CC3C=CC=CC=3)[CH2:19][CH2:18]2)=[CH:2]1.C(Cl)(=O)OCC>CC1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:16][CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[CH:2]1
Reactant: c1ccc(CN2CCC(Cc3nc4ccccc4n3Cc3ccoc3)CC2)cc1
Agent: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)nc(CC1CCNCC1)n2Cc1ccoc1
Reaction time: 2 h
Yield: 49.8 %

Procedure:
To a stirred mixture of 72 parts of 1-(3-furanylmethyl)-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazole and 324 parts of methylbenzene were added dropwise 25.5 parts of ethyl carbonochloridate at reflux. Upon completion, stirring was continued for 2 hours at reflux temperature. After cooling, the mixture was washed twice with a sodium hydroxide solution 5%, once with water, dried, filtered and evaporated. This residue, together with 560 parts of 2-propanol, 69.9 parts of potassium hydroxide and 6 parts of water, was stirred and refluxed for 22 hours. The whole was cooled and evaporated. The residue was taken up in water. The product was extracted three times with dichloromethane. The combined extracts were washed twice with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and ammonium hydroxide (90:10:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2-propanone. The product was filtered off and dried, yielding 28.0 parts (49.8%) of 1-(3-furanylmethyl)-2-(4-piperidinylmethyl)-1H-benzimidazole; mp. 180° C. (73).
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9]C(=O)OCC2C=CC=CC=2)[CH2:7][CH2:6][S:5][C@H:4]2[CH2:20][CH2:21][CH2:22][CH2:23][N:3]12.I[Si](C)(C)C>C(Cl)Cl>[NH2:9][C@H:8]1[CH2:7][CH2:6][S:5][C@H:4]2[CH2:20][CH2:21][CH2:22][CH2:23][N:3]2[C:2]1=[O:1]
Reactant: O=C(N[C@H]1CCS[C@H]2CCCCN2C1=O)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: N[C@H]1CCS[C@H]2CCCCN2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of benzyl (4S,10aS)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (103 mg, 0.308 mmol) in DCM (2 mL) stirred at rt was added iodotrimethylsilane (0.054 mL, 0.40 mmol) dropwise. After addition, the resulting yellowish solution was stirred at rt under argon for 1 hr. Additional TMSI (0.054 mL, 0.40 mmol) was added. The yellowish reaction mixture stirred for an additional 1 hr. The reaction was quenched by addition of a drop of 1 N aqueous HCl and then diluted with EtOAc. The organic layer extracted with aqueous 1 N HCl (2×2.5 mL). The combined HCl extracts were washed with EtOAc and basified with 1 N aqueous NaOH solution to pH 9-10. The aqueous solution was extracted with DCM (3×10 mL). The combined DCM extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to give (4S,10aS)-4-aminohexahydro-2H-pyrido[2,1-b][1,3]thiazepin-5(7H)-one (50.8 mg, 0.254 mmol, 82% yield) as a colorless oil. Anal. Calcd. for C9H16N2OS m/z 200.3. found: 201.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 5.33 (t, J=3.8 Hz, 1H), 4.37-4.24 (m, 1H), 4.07 (dd, J=10.0, 4.5 Hz, 1H), 3.06-2.87 (m, 2H), 2.63 (ddd, J=14.5, 7.5, 3.2 Hz, 1H), 2.27-2.15 (m, 1H), 2.03-1.92 (m, 2H), 1.92-1.77 (m, 3H), 1.76-1.41 (m, 4H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:25])[CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17].[H-].[Na+]>>[CH3:11][N:12]([CH3:25])[CH2:13][CH2:14][N:15]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:17])=[O:18]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN(C)CCNS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCN(c1ccc([N+](=O)[O-])cc1)S(=O)(=O)c1ccccc1

Procedure:
Prepared from 1-fluoro-4-nitro-benzene, N-(2-dimethylamino-ethyl)-benzenesulphonamide and sodium hydride as base
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:3].C([O-])([O-])=O.[K+].[K+].Cl[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26]>CN(C=O)C>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[CH:9][N:10]=1
Reactant: CN(C)Cc1ccc(O)cn1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(Oc2ccncc2[N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 6-((dimethylamino)methyl)pyridin-3-ol in DMF (5 mL) was added, K2CO3 (834.8 mg, 6.040 mmol) and the mixture was stirred at RT for 10 min before 4-chloro-3-nitro-pyridine (191.5 mg, 1.208 mmol) was added. The mixture was stirred at RT for 60 h. The reaction mixture was partitioned between EtOAc and NH4Cl aq satd. Combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo yielding an oil that purified by SCX column, yielding N,N-dimethyl-1-(5-((3-nitropyridin-4-yl)oxy)pyridin-2-yl)methanamine as a colourless oil. MS (ES+) 275.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.[Cl:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O>[Cl:13][CH2:14][C:15]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:12])[NH:10]2)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: O=c1ccc2cccc(O)c2[nH]1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(CCl)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 70 °C
Reaction time: 20 h

Procedure:
27 g of 8-hydroxycarbostyril (VII) and 37 ml of chloroacetyl chloride were dissolved in 250 ml of nitrobenzene, and to the resulting solution was added 85 g of aluminum chloride followed by stirring at 70° C. for 20 hours. 500 ml of 10% aqueous hydrochloric acid was added to the reaction mixture and the nitrobenzene was removed by steam distillation. After cooling the mixture, the precipitated crystals were collected by filtration which were then washed with 300 ml of hot water. Recrystallization from methanol gave 14.0 g of 5-chloroacetyl-8-hydroxycarbostyril (IV) having a melting point of 285°-287° C. (with decomposition) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2OS(C(F)(F)F)(=O)=O.ClCCl.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[CH:7]=[CH:8][N:9]=2)[N:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2nccc(C#C[Si](C)(C)C)c2n1

Procedure:
1,1,1-Trifluoro-methanesulfonic acid 6-methoxy-[1,5]naphthyridin-4-yl ester (10 g, 32 mmol) was partially dissolved in triethylamine (80 mL) and dichloromethane was added in small portions until solid was completely dissolved. The resulting solution was degassed and purged with nitrogen, then treated with (trimethylsilyl)acetylene (5 mL, 36 mmole), bis-(triphenylphosphine)palladium (II) chloride (456 mg, 0.65 mmole), and copper (I) iodide (125 mg, 0.65 mmol) at room temperature overnight. Reaction mixture was concentrated to near dryness, then redissolved in ethyl acetate and washed with water and brine. Insoluble material was filtered off and aqueous layer was dried over sodium sulfate, filtered and concentrated. The resulting brown thick oil was used without further purification.
Reaction SMILES: [BH4-].[Na+].C(O)(=O)C.[H][H].Cl.[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=1)[NH:16][CH:15]=[C:14]2[C:23]1[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=1.Cl.[OH-].[Na+]>C1COCC1.O>[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=1)[NH:16][CH:15]=[C:14]2[CH:23]1[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]1
Reactant: [H][H]
Reactant: NC(=O)c1cc(Br)cc2c(C3=CCNCC3)c[nH]c12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NC(=O)c1cc(Br)cc2c(C3CCNCC3)c[nH]c12
Temperature: 12.5 °C

Procedure:
Sodium borohydride (2.0 eq, 0.212 wt) was suspended in dry THF (10 vol) with stirring at 10-15° C. under nitrogen. Glacial acetic acid (2.0 eq, 0.321 vol) was then added dropwise over at least 15 mins at 10-25° C. at such a rate as to control effervescence (small exotherm, evolves hydrogen). Once the addition was complete, the resultant suspension was stirred for at least 15 mins under a flow of nitrogen until all visible effervescence has ceased. 5-bromo-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole-7-carboxamide hydrochloride (which may be prepared, for example, by following the method outlined for Intermediate 8) (1 wt) was then added as a solid. The resultant suspension was then stirred at 20-25° C. under nitrogen for 3.5-4.5 hrs with HPLC monitoring. The batch was then cooled to 0-4° C. Hydrochloric acid (36% w/v, 0.90 vol) was then added in a dropwise manner over at least 30 mins maintaining the internal temperature at 0-4° C. throughout (exothermic, evolves hydrogen). The resultant slurry was stirred at 0-4° C. for 2 hrs, warmed to 20-25° C. and stirred for a further 2 hrs before recooling to 0-4° C. Water (8 vol) was then added slowly over at least 15 mins maintaining the internal temperature at 0-10° C. throughout (exothermic, evolves hydrogen). The resultant acidic solution was then stirred for at least 1 hr. A solution of aqueous sodium hydroxide (40% w/v, ca 2.5 vols) was added in a dropwise manner to neutralize to pH>12, maintaining the temperature at 0-15° C. throughout1. The resultant biphase was settled and separated. The aqueous was back-extracted with ethyl acetate (4 vols) and then discarded. The combined organics are washed with saturated brine (2×2 vols) before being concentrated in vacuo to ca 4 vols2. Ethyl acetate (8 vols) was added, and the batch was reconcentrated in vacuo to ca 4 vols. The resultant slurry was cooled to 0-5° C. and stirred for at least 30 mins. Solids are then collected by vacuum filtration and washed with ethyl acetate (2×1 vol). Dried in vacuo at 40-45° C. to constant weight.