Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8][C:9]1[C:10]2[C:15]([CH:16]=[C:17]3[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2.C([O-])([O-])=O.[K+].[K+].[CH2:29](Br)[CH3:30]>C(#N)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH2:8][C:9]1[C:10]2[C:15]([CH:16]=[C:17]3[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:29][CH3:30]
Reactant: CCBr
Reactant: OCCCCCNCc1c2ccccc2cc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CCCCCO)Cc1c2ccccc2cc2ccccc12
Yield: 3.3 %

Procedure:
9-((5-hydroxypentyl)aminomethyl)anthracene (1.00 g, 3.41 mol) and K2CO3 (0.518 g, 3.75 mmol) were taken up in 25 mL acetonitrile. Ethyl bromide (11.14 g, 102 mmol) was added and the mixture was refluxed under nitrogen for 24 h. The mixture was filtered on a sintered-glass frit and the solvent and excess ethyl bromide was removed under reduced pressure. Removal of the solvent afforded 1.07 g (98% yield) of 6 as a yellow solid; 1H NMR (300.13 MHz, CD3CN) δ1.15 (m, 2H), 1.38 (m, 5H), 1.81 (m, 2H), 3.05 (m, 4H), 3.49 (t, 2H), 5.21 (s, 2H), 7.45 (m, 2H), 7.62 (m, 2H), 8.05 (d, 2H), 8.44 (m, 3H); 13C-{1H} NMR (75.4 MHz, CDCl3) δ131.8, 131.3, 130.8, 129.6, 128.0, 125.6, 124.0, 61.7, 53.1, 49.4, 48.7, 31.4, 23.9, 23.3, 10.0.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=1)[CH2:3][NH2:4].[OH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[CH3:26])=[CH:20][CH:19]=1>>[OH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=2)[CH3:26])=[CH:20][CH:19]=1
Reactant: CC(=O)Cc1ccc(OCCO)cc1
Reactant: NCC(O)c1csc(C(F)(F)F)n1
Product: CC(Cc1ccc(OCCO)cc1)NCC(O)c1csc(C(F)(F)F)n1

Procedure:
Prepared by analogy to Example 13 by reaction of 2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with 1-(4-(2-hydroxyethoxy)phenyl)propan-2-one followed by purification on a silica gel column using ethyl acetate/methanol=9:1 as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:17][NH:18][CH3:19]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([N:18]([CH3:19])[CH3:17])=[O:10])[CH2:6]1
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)cc2Cl)C1
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CC(Oc2ccc(Cl)cc2Cl)C1
Reaction time: 5 h

Procedure:
A stirred solution of 4.8 g (0.017 mole) of 3-(2,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated with 5.8 mL (0.05 mole) of 40% aqueous dimethylamine. After stirring for 5 h, the reaction mixture was diluted with 200 mL of water and the oil which separated was extracted into methylene chloride (3×30 mL). The combined extracts were dried (Whatman PS paper) and concentrated in vacuo, (5 g). The crude oil solidified on standing and was recrystallized from ligroin yielding 3.4 g (69.2%) of silver plate-like crystals, mp 62°-63° C.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[F:12][C:13]1[CH:26]=[CH:25][C:16]([C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH:43][CH:44]2[CH2:53][CH2:52][C:51]3[C:50]([CH2:54][CH2:55][C:56]([O:58]C)=[O:57])=[CH:49][C:48]([CH2:60][CH2:61]OS(C4C=CC(C)=CC=4)(=O)=O)=[CH:47][C:46]=3[CH2:45]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1>CN(C=O)C>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([S:40]([NH:43][CH:44]2[CH2:53][CH2:52][C:51]3[C:50]([CH2:54][CH2:55][C:56]([OH:58])=[O:57])=[CH:49][C:48]([CH2:60][CH2:61][N:22]4[CH2:23][CH2:24][CH:19]([C:17](=[O:18])[C:16]5[CH:15]=[CH:14][C:13]([F:12])=[CH:26][CH:25]=5)[CH2:20][CH2:21]4)=[CH:47][C:46]=3[CH2:45]2)(=[O:42])=[O:41])=[CH:38][CH:39]=1
Reactant: COC(=O)CCc1cc(CCOS(=O)(=O)c2ccc(C)cc2)cc2c1CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCc1cc(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)cc2c1CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2

Procedure:
6.5 g (17.3 mmol) of 4-(4-fluorobenzoyl)piperidine tosylate and 2.4 g (17.3 mmol) of potassium carbonate are added to a solution of 3.5 g (5.7 mmol) of methyl 3-[6-{[(4-chlorophenyl)sulphonyl]amino}-3-(2-{[(4-methylphenyl)sulphonyl]oxy}ethyl)-5,6,7,8-tetrahydro-1-naphthyl]propanoate, described in Application EP 864 561, in 100 ml of DMF. The reaction mixture is heated at reflux for one hour, then concentrated. The residue is taken up in dichloromethane and washed with water. The organic phase is dried and concentrated and then purified by chromatography on silica gel, using as eluant a dichloromethane/methanol/ammonia mixture (98/2/0.2), to yield the expected compound.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]([CH3:22])=[CH2:21].CN(C=O)C>C1(C)C=CC=CC=1>[CH2:1]([N:5]([CH2:21][C:20]([CH3:22])=[CH2:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C)CCl
Reactant: CCCCNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=C(C)CN(CCCC)c1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of N-butylaniline (12.35 parts), anhydrous potassium carbonate (17.1 parts), 3-chloro-2-methylpropene (11.24 parts) and DMF (20 parts) was stirred at 90° C. for 8 hours. The cooled mixture was poured into toluene, washed with water (×2), 1N hydrochloric acid (30 parts) and water (×2). The dried organic phase was evaporated to leave N-butyl-N-(2-methylprop-2-eneyl)aniline (14.3 parts).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C@@H:13]([C:15](=[O:25])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH3:14])[CH:7]=1.O.Cl>CO>[C:23]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:15]([C@H:13]([O:12][C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[C:5]([OH:26])=[O:4])[CH3:14])=[O:25])=[CH:22][CH:21]=1)#[N:24]
Reactant: COC(=O)c1cccc(O[C@H](C)C(=O)Nc2ccc(C#N)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H](Oc1cccc(C(=O)O)c1)C(=O)Nc1ccc(C#N)cc1
Temperature: 50 °C
Yield: 218.8 %

Procedure:
Add 10% aqueous solution of sodium hydroxide (2.5 mL, 6.2 mmol) to a suspension of 3-[(R)-1-(4-cyano-phenylcarbamoyl)-ethoxy]-benzoic acid methyl ester (0.59 g, 0.81 mmol) in a 1:1 mixture of water: MeOH (20 mL). Heat the mixture at 50° C. for 1 h then cool to room temperature and adjust the pH of the mixture to approximately pH 5 by the addition of a 2 N solution of hydrochloric acid. Extract the mixture with EtOAc and wash the combined organic phase with brine, dry over anhydrous sodium sulfate and concentrate under reduced pressure to provide 0.55 g of 3-[(R)-1-(4-cyano-phenylcarbamoyl)-ethoxy]-benzoic acid as a foam.
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CN(C=O)C>[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:3]2[CH2:2][CH2:1][C@@H:10]3[C@H:5]([CH2:6][CH2:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=43)[CH2:4]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CN2CC[C@H]3c4ccccc4CC[C@@H]3C2)cc1
Yield: 19.8 %

Procedure:
Following the procedure of Example 3, step 4, 0.153 g (0.815 mmol) of crude trans-1,2,3,4,4a, 5,6,10b-octahydrobenz[f]isoquinoline in 10 ml of anhydrous DMF was reacted with 0.124 g (0.897 mmol) of anhydrous potassium carbonate and 0.184 g (0.852 mmol) of 4-nitrobenzyl bromide. Chromatography on flash silica, eluting with 30-40% ethyl acetate/petroleum ether, gave 0.052 g (20%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent and recrystallisation from ethanol/ethyl acetate/methanol, the title product hydrochloride was obtained as a white solid, m.p. 198°-201° C. NMR δ(D2O/CD3CN) 1.45-1.57 (1H, m), 1.61-1.74 (1H, m), 1.79-1.83 (2H, m), 2.60-2.69 (2H, m), 2.88-2.94 (3H, m), 3.20 (1H, t, of d), 3.44 (1H, m), 3.64 (1H, m), 4.44 (2H, d, J=2.9 Hz), 7.17-7.22 (3H, m), 7.26-7.28 (1H, m), 7.77 (2H, d, J=8.8 Hz), 8.34 (2H, d, J=8.8 Hz). m/z (CI+, NH3) 323 (M+H)+, 308 (M-O+H)+, 248, 211, 174, 133, 106. Analysis calcd. for C22H28ClN: C, 66.94; H, 6.46; N, 7.81%. Found: C, 66.83; H, 6.49; N, 7.81%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[CH3:18])[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: Cc1ccccc1CN
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccccc1CNc1nc(N)nc(-n2cccn2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 2-methyl-benzylamine and DBU in DME. ES-MS m/e (%): 328 (M+Na+, 35), 306 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:13][S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[CH2:9][N+:10]([O-])=O)=[CH:4][CH:3]=1.[NH4+].[Cl-]>[Zn].CC(C)=O.O>[NH2:10][CH2:9][C@H:8]([NH:13][S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: CC(C)(C)[S@@](=O)N[C@@H](C[N+](=O)[O-])c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)[S@@](=O)N[C@@H](CN)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
Zn powder (5.07 g, 77.6 mmol) was added to a solution of (R,R)-2-methyl-propane-2-sulfinic acid [1-(4-fluoro-phenyl)-2-nitro-ethyl]-amide (2.24 g, 7.76 mmol) and NH4Cl (4.15 g, 77.6 mmol) in 5:1 acetone/H2O (24 mL) at rt. After 10 min, the reaction mixture was filtered and the filtrate concentrated under reduced pressure. The crude residue was crystallized using CH2Cl2 (20 mL) and hexanes (50 mL) to provide (R,R)-2-methyl-propane-2-sulfinic acid [2-amino-1-(4-fluoro-phenyl)-ethyl]-amide (1.8 g, 89%). MS (ESI+): calcd for C12H19FN2OS m/z 258.12. found 259.1 (M+H)+.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=[CH:29][C:28](S(O)(=O)=O)=[CH:27][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl>[C:25]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=[CH:29][C:28]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:27][CH:26]=1
Reactant: O=S(=O)(O)c1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.1 %

Procedure:
Sulfuryl chloride (392 μl, 4.74 mmol) was added dropwise to a 0° C. suspension of triphenylphosphine-resin (1.58 g) in methylene chloride (10 ml). A solution of 4-biphenylsulfonic acid (400 mg, 1.58 mmol) and triethylamine (220 μl) in methylene chloride (5 ml) was added. The mixture was stirred at room temperature for 6 hours and stored at 5° C. for 3 days. This was filtered and the filtrate was evaporated. The residue was coevaporated with toluene twice to give the crude product as a white solid. Purification of the crude product by chromatography (silica, methylene chloride) gave 180 mg of the title product as a white solid.
Reaction SMILES: CN(C=O)C.[C:6]([NH2:9])(=[O:8])[CH3:7].[Cl:10][C:11]1[CH:12]=[C:13]([F:18])[C:14](F)=[N:15][CH:16]=1.Cl>C1COCC1>[C:6]([NH:9][C:14]1[C:13]([F:18])=[CH:12][C:11]([Cl:10])=[CH:16][N:15]=1)(=[O:8])[CH3:7]
Reactant: CC(N)=O
Reactant: Fc1cc(Cl)cnc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(Cl)cc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
Under a nitrogen atmosphere, DMF (200 mL) and THF (830 mL) were added to acetamide (94.8 g, 1.61 mol), and the mixture was warmed to 50° C. A 40 wt % sodium hexamethyldisilazide THF solution (629 g, 1.37 mol) was added dropwise thereto, and the mixture was stirred for 2 hours at the same temperature. 5-Chloro-2,3-difluoropyridine (100.0 g, 0.67 mol) was then added, THF (20 mL) was further added, and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was cooled to 0° C., 2.8 M HCl (500 mL) was added, the mixture was warmed to room temperature, and the organic layer was separated. The organic layer was washed with a 20 wt % sodium chloride aqueous solution (500 mL), and the solvent was distilled off under reduced pressure. THF (500 mL) was added to the residue, and the mixture was heated to 70° C. to dissolve the residue. After cooling to room temperature and confirming the precipitation of solids, n-heptane (1500 mL) was added, and the mixture was further cooled to 0° C. and stirred for 3 hours at that temperature. The precipitated crystals were collected by filtration, washed with a mixed solvent of THF (100 mL) and n-heptane (500 mL), and dried under reduced pressure to obtain the title compound (91.2 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[O:23]1[C:27]2([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[O:26][CH2:25][CH2:24]1>C(OCC)(=O)C>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:30]1[CH2:31][CH2:32][C:27]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:28][CH2:29]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 20 h
Yield: 95.3 %

Procedure:
To a mixture of 1-fluoro-2-methyl-4-nitrobenzene (3.0 g), potassium carbonate (5.35 g) and DMF (30 mL), 1,4-dioxa-8-azaspiro[4.5]decane (4.15 g) was added and stirred at 80° C. for 20 hours. After cooling, the reaction liquid was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol=100:0 to 100:1) to give 8-(2-methyl-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (5.13 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:26][O:27][C:28]1[C:38]([O:39][CH3:40])=[C:37]([O:41][CH3:42])[CH:36]=[CH:35][C:29]=1[CH:30]=[CH:31][C:32](O)=[O:33]>>[CH3:26][O:27][C:28]1[C:38]([O:39][CH3:40])=[C:37]([O:41][CH3:42])[CH:36]=[CH:35][C:29]=1[CH:30]=[CH:31][C:32]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH2:21][CH2:22]1)=[O:33]
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(C(=O)C=Cc4ccc(OC)c(OC)c4OC)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and 2,3,4-trimethoxycinnamic acid (65 mg) were reacted in the same manner as in Example 56 to obtain the title compound as a free base.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6].C1(N=C=NC2CCCCC2)CCCCC1.[N:30]12[CH2:38][CH2:37][CH:34]([CH2:35][CH2:36]1)[NH:33][CH2:32][CH2:31]2.O>O1CCOCC1>[N:30]12[CH2:38][CH2:37][CH:34]([CH2:35][CH2:36]1)[N:33]([C:9](=[O:11])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:12]=[CH:13][CH:14]=[C:2]([Br:1])[CH:3]=1)[CH2:32][CH2:31]2
Reactant: C1CN2CCC(CC2)N1
Reactant: O=C(O)CNC(=O)c1cccc(Br)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCC(=O)N1CCN2CCC1CC2)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.77 g (3 mmol) of N-(3-bromobenzoyl)glycine dissolved in 30 ml of dioxane is placed in a 100 ml round-bottomed flask, 0.68 g (3.3 mmol) of dicyclohexylcarbodiimide is added and the mixture is stirred at room temperature for 30 minutes, 0.38 g (3 mmol) of 1,4-diazabicyclo[3.2.2]nonane is added and the mixture is stirred for a further two hours. 30 ml of water are added and the precipitate formed is filtered off, the filtrate is extracted with chloroform and the organic phase is then extracted with aqueous 0.1N hydrochloric acid solution. The aqueous extraction phase is basified to pH 10 by addition of concentrated aqueous sodium hydroxide solution and extracted with chloroform. The organic phase is dried over sodium sulfate and concentrated under reduced pressure.
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.N.C(OC(C1C(C2[C:23]([Cl:29])=[N+:24]([O-:28])[CH:25]=CC=2)C(C(OCC)=O)=C(C)NC=1C)=O)C>C(O)C>[Cl:29][C:23]1[C:2]([CH:1]=[O:7])=[CH:3][CH:5]=[CH:25][N+:24]=1[O-:28]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccc[n+]([O-])c1Cl
Reactant: CCOC(=O)CC(C)=O
Agent: N
Solvent: CCO
Product: O=Cc1ccc[n+]([O-])c1Cl

Procedure:
Analogously to the process described in Example 1 there is obtained from 8.4 g of 2-chloropyridine-3-carboxaldehyde-1-oxide, 12.75 ml of ethyl acetoacetate and 5 ml of 30% aqueous ammonia in 35 ml of absolute ethanol, 2,6-dimethyl-4-(2-chloro-1-oxido-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester which, after recrystallisation from 500 ml of isopropanol, melts at 255°-256°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11]=[C:10]([O:12][C@H:13]3[C@H:17]4[O:18][CH2:19][C@@H:20]([OH:21])[C@H:16]4[O:15][CH2:14]3)[N:9]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:5]2=[N:6][C:7]=1I.[CH3:30][N:31]([CH3:56])[C:32](=[O:55])[O:33][CH:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:36][CH2:35]1>>[CH3:30][N:31]([CH3:56])[C:32](=[O:55])[O:33][CH:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43]([C:7]3[N:6]=[C:5]4[N:9]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:10]([O:12][C@@H:13]5[CH2:14][O:15][C@@H:16]6[C@H:20]([OH:21])[CH2:19][O:18][C@H:17]56)=[N:11][C:4]4=[CH:3][C:2]=3[Cl:1])=[CH:42][CH:41]=2)[CH2:36][CH2:35]1
Reactant: CN(C)C(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(I)nc21
Product: CN(C)C(=O)OC1CCN(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)CC1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-iodo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl dimethylcarbamate following a procedure analogous to that described for Intermediate 3. LC (method 1): tR=1.04 min; Mass spectrum (ESI+): m/z=674 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:25])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:5]=[C:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].[H][H]>C(OCC)(=O)C.CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:25])[C:15]=1[O:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH2:5][CH:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: COc1ccc(Oc2c(Cl)cc(C=C3SC(=O)NC3=O)cc2Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)cc1
Yield: 55.6 %

Procedure:
The title compound of Step C (93 mg) was dissolved in ethyl acetate/methanol (4 ml/2 ml) and then 10% palladium on carbon (70 mg) was added. The reaction mixture was placed on Parr shaker for four hours under 50 psi hydrogen at room temperature. The solution was filtered through diatomaceous earth, and concentrated. The residue was purified by preparative TLC (3% methanol in dichloromethane) to afford the title compound (52 mg) as a solid. MS (APCI−) Calc: 397.0, Found: 396.0 (M−1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)N(C1C=CC=CN=1)N=[CH:5]2.[Cl:17][C:18]1[N:19]=[N:20][C:21]([NH:24][NH2:25])=[CH:22][CH:23]=1>>[Cl:17][C:18]1[N:19]=[N:20][C:21]([N:24]2[C:8]3[C:4](=[CH:3][C:2]([I:1])=[CH:10][CH:9]=3)[CH:5]=[N:25]2)=[CH:22][CH:23]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: Ic1ccc2c(cnn2-c2ccccn2)c1
Product: Clc1ccc(-n2ncc3cc(I)ccc32)nn1

Procedure:
Prepared as described for 118b using 3-chloro-6-hydrazinopyridazine. Yield 687 mg (45%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([C:13]1[CH:22]=[CH:21][C:16]([C:17](=O)[CH2:18]Cl)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C(=O)(O)[O-].[Na+]>C(O)(C)C>[Br:8][C:7]1[C:2]2[N:3]([CH:18]=[C:17]([C:16]3[CH:15]=[CH:14][C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:22][CH:21]=3)[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)c1ccc(C(=O)CCl)cc1
Reactant: Nc1ncccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(-c2cn3cccc(Br)c3n2)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 77.5 %

Procedure:
2-Amino-3-bromopyridine (0.250 g, 1.45 mmol) and 4-tert-butylphenacyl chloride (0.306 g, 1.45 mmol) were dissolved in isopropanol (4.5 mL) and treated with sodium bicarbonate (0.146 g, 1.74 mmol). The mixture was stirred in a sealed tube at 80° C. for 48 h. The mixture was concentrated under reduced pressure and redissolved in ethyl acetate (30 mL). The organic mixture was washed with water and saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography, eluting with 10% acetone/hexane to give 0.370 g (77%) of the title compound. HPLC (Method B): r.t.=10.7 min., purity 100% at 210-370 nm, 99.3% at 252 nm. HRMS: calcd for C17H17BrN2+H+, 329.06478; found (ESI, [M+H]+), 329.0662.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=C[CH:7]=[C:8]([Br:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[Cl-].[NH4+:15]>C1COCC1.[Zn]>[Br:11][C:8]1[CH:9]=[C:10]2[C:5](=[N:15][CH:7]=1)[NH:4][C:3](=[O:12])[CH2:2]2
Reactant: O=C1Nc2ccc(Br)cc2C1(Br)Br
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Zn]
Solvent: C1CCOC1
Product: O=C1Cc2cc(Br)cnc2N1
Reaction time: 0.33 h

Procedure:
A solution of 3,3,5-tribromooxindole (5.0 g, 13.4 mmol) in fresh THF (100 mL) is stirred at room temperature and a saturated aqueous solution of ammonium chloride (100 mL) is added. The flask is placed in a water bath and activated zinc dust (15.0 g, 230 mmol) is added. The mixture is stirred for 20 min and the zinc is removed by filtration through a pad of diatomaceous earth. The organic layer is separated and the aqueous layer is extracted with THF (20 mL). The combined organic layers were washed with saturated brine solution, dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The brown residue is triturated with water (20 mL) and the tan solid is collected by filtration and dried under vacuum to give 5-bromo-7-azaoxindole as a tan solid, 2.02 g (71%). 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 8.15 (s, 1H), 8.76 (s, 1H), 3.57 (s, 2H). MS (AP−ve) 211 (100) (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13](=O)[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([F:12])[F:11].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([F:12])[F:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OCC(F)F)c(Cl)c1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)F)c(Cl)c1
Yield: 62 %

Procedure:
The title compound is prepared in 62% yield (780 mg, clear colorless oil) from 1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethanone (860 mg, 3.7 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.