Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](#[N:11])[CH:9]=[CH2:10].[CH2:12]([O:14][C:15](=[O:30])[CH2:16][CH2:17][NH:18][CH2:19][C:20]1[C:23]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=2[CH:21]=1)[CH3:13]>C(O)C>[CH2:12]([O:14][C:15](=[O:30])[CH2:16][CH2:17][N:18]([CH2:10][CH2:9][C:8]#[N:11])[CH2:19][C:20]1[C:23]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=2[CH:21]=1)[CH3:13]
Reactant: C=CC#N
Reactant: CCOC(=O)CCNCC1=Cc2ccc(OC)cc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CCN(CCC#N)CC1=Cc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
10.5 g (0.1 mol) of triethylamine and 5.84 g (0.11 mol) of acrylonitrile are added to 30.16 g (0.1 mol) of 3-(5-methoxybenzocyclobuten-1-ylmethylamino)-propionic acid ethyl ester in 250 ml of ethanol and the whole is stirred at room temperature for 15 hours. The reaction mixture is then concentrated under a water-jet vacuum, and the residue is taken up in diethyl ether and washed neutral with ice-water. The ethereal solution is dried over potassium carbonate, filtered and concentrated by evaporation; 3-{N-(2-cyanoethyl)-N-[(5-methoxybenzocyclobuten-1-yl)methyl]-amino}propionic acid ethyl ester is obtained in the form of a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=O>>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c(C)c1C(=O)N1CCN(C)CC1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde to give the title compound.
Reaction SMILES: Cl.C(CCP(CCC(O)=O)CCC(O)=O)(O)=O.[CH3:18][N:19]([CH2:33][C:34]([CH3:39])([S:36]SC)[CH3:35])[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[N:26]=[C:25]([CH2:31][OH:32])[CH:24]=1>O.CO>[SH:36][C:34]([CH3:39])([CH3:35])[CH2:33][N:19]([CH3:18])[CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][OH:32])[N:26]=[C:27]([CH2:29][OH:30])[CH:28]=1
Reactant: CSSC(C)(C)CN(C)CCOc1cc(CO)nc(CO)c1
Agent: Cl
Agent: O=C(O)CCP(CCC(=O)O)CCC(=O)O
Solvent: O
Solvent: CO
Product: CN(CCOc1cc(CO)nc(CO)c1)CC(C)(C)S
Reaction time: 2 h
Yield: 98 %

Procedure:
A solution of 198 mg of tris(2-carboxyethyl)phosphine hydrochloride in 730 μl of water is added to 80 mg of 4-{2-[methyl(2-methyl-2-(methyldisulphanyl)propyl)amino]ethoxy}-2,6-bis(hydroxymethyl)pyridine in solution in 1.95 ml of methanol. After 2 h at AT, the mixture is concentrated under RP and the residue is taken up in 10 ml of water. The aqueous phase is brought to pH=8 by addition of an aqueous sodium hydroxide solution and then extracted 2× with AcOEt. The combined organic phases are washed with a saturated aqueous NaCl solution and concentrated under RP. 68 mg of 4-{2-[(2-mercapto-2-methylpropyl)(methyl)amino]ethoxy}-2,6-bis(hydroxymethyl)pyridine are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.CN(C1C=CC=CN=1)C.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (16 g, 69 mmol) was dissolved in 100 mL DMF, added imidazole (12 g, 173 mmol), dimethylaminopyridine (0.85 g, 6.9 mmol), and tert-butyldimethylsilyl chloride (12.5 g, 83 mmol). Stirred at ambient temperature overnight, dissolved in 350 mL EtOAc, washed with 10% citric acid (3×200 mL), water (2×200 mL), brine, dried with MgSO4, filtered, and concentrated to yield title compound. (20 g, 84%) APCI (AP−): 344.2 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([C:13]([NH:15][CH2:16][CH2:17]Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([C:28]1([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:35](=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([C:13]([NH:15][CH2:16][CH2:17][N:31]2[CH2:32][CH2:33][C:28]([OH:34])([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH3:35])=[CH:26][CH:27]=3)[CH2:29][CH2:30]2)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCCCl)c1ccc(OCc2ccccc2)cc1
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1ccc(CC2(O)CCN(CCNC(=O)c3ccc(OCc4ccccc4)cc3)CC2)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 20.5 %

Procedure:
A mixture of 4-benzyloxy-N-(2-chloro-ethyl)-benzamide (2.1 g, 7.25 mmol), 4-benzyl-4-hydroxy-piperidine (1.386 g, 7.25 mmol), potassium carbonate (2.0 g, 14.5 mmol) and 2-butanone (40 ml) was stirred for 15 h at 60° C. After the addition of water, the mixture was extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica gel, methylene chloride methanol from 95:5 to 9:1) to give 4-benzyloxy-N-[2-[4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-yl]-ethyl]-benzamide (680 mg, 21%) as a light yellow solid. MS: me/e=445 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4](=[CH:13]N(C)C)[C:3]1=[O:17].[OH2:18]>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([CH:13]=[O:18])[C:3]1=[O:17]
Reactant: CN(C)C=C1C(=O)c2ccccc2N(C)C1=O
Reactant: O
Product: Cn1c(=O)c(C=O)c(O)c2ccccc21

Procedure:
The product from Step (1) was dissolved in distilled water (50 ml) by gentle warming and then the resulting solution was filtered. The clear filtrate was cooled in an ice bath and acidified to pH3 with mineral acid. The resulting crystalline precipitate was washed with water and dried to give 1-methyl-3-formyl-4-hydroxy-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS: m/e 203 (M.+); NMR (CDCl3): δ3.6 (s, 3H, NCH3), 10.28 (s, 1H, CHO) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:14]N1C(=O)CCC1=O.C(N(C(C)C)CC)(C)C.P([O-])(OCC)OCC>C(#N)C.N(C(C)(C)C#N)=NC(C)(C)C#N.O>[Br:14][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]=[CH:12][O:11][N:10]=2)=[CH:3][C:2]=1[F:1]
Reactant: Cc1ccc(-c2ncon2)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCOP([O-])OCC
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(-c2ncon2)ccc1CBr
Temperature: 70 °C
Yield: 92.1 %

Procedure:
3-(3-Fluoro-4-methylphenyl)-1,2,4-oxadiazole (101.8 g, 0.57 mol) and N-bromosuccinimide (206 g, 1.16 mol) were dissolved in acetonitrile (˜1 L) and azobisisobutyronitrile (4.2 g, 26 mmol) was added at room temperature. The mixture was heated to 70° C. for 2 hours at which point HPLC showed complete conversion of the starting material to a mixture of the monobromide and dibromide. The mixture was cooled to 0° C. and diisopropyl ethyl amine (73 mL, 54.2 g, 0.42 mol) was added while maintaining the reaction temperature below 5 C. Diethyl phosphite (54.7 mL, 58.6 g, 0.42 mol) was added slowly and the reaction mixture was warned to room temperature. After 2 hours HPLC showed complete conversion of the dibromide to the monobromide. Water (1.2 L) was added and the resulting precipitate was filtered. Washing with water (2×200 mL) and drying provided 3-(4-(bromomethyl)-3-fluorophenyl)-1,2,4-oxadiazole (135 g, 92% yield).
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[CH:16]1[CH2:20][CH2:19][N:18]([CH3:21])[C:17]1=[O:22]>ClCCCl>[C:1](=[N:14][CH:16]1[CH2:20][CH2:19][N:18]([CH3:21])[C:17]1=[O:22])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCC(N)C1=O
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: CN1CCC(N=C(c2ccccc2)c2ccccc2)C1=O

Procedure:
Benzophenone imine [CAS: 1013-88-3] (16.67 g, 91.98 mmol) was added dropwise to a solution of 3-amino-1-methylpyrrolidine-2-one [CAS 119329-48-5] (10 g, 87.60 mmol) in DCE (100 mL) under N2 and the reaction was heated at reflux for 18 hours. The solvent was evaporated to afford an amber oil. This was purified using flash silica in a large sinter funnel, eluting with 4:1 to 3:7 i-hexane:EtOAc. An incomplete separation was achieved. 3-(Benzhydrylidene-amino)-1-methyl-pyrrolidin-2-one (D1) was isolated (25 g) with approximately 11% of an impurity present, but was used in the next step without further purification;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:16]=1)[CH2:7][O:8][Si](C(C)(C)C)(C)C.C([Mg]Cl)(C)C.[CH:23]1[N:24]=[CH:25][N:26]2[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[C:27]=12.Cl>O1CCCC1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]2([OH:32])[CH2:29][CH2:30][CH2:31][N:26]3[CH:25]=[N:24][CH:23]=[C:27]23)=[C:6]([CH2:7][OH:8])[CH:16]=1
Reactant: O=C1CCCn2cncc21
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1I
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCc1cc(Br)ccc1C1(O)CCCn2cncc21
Reaction time: 1 h

Procedure:
A solution of 6.55 mmol of (5-bromo-2-iodo-benzyloxy)-tert-butyl-dimethyl-silane in 20 ml of tetrahydrofuran is cooled to −20° C. 6.55 mmol of an isopropymagnesium chloride solution (2M in tetrahydrofuran) is added dropwise and stirring continued for 1 h at −20° C. A solution of 4.37 mmol of 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [426219-51-4] in 40 ml of tetrahydrofuran is added dropwise and the reaction mixture stirred for 40 minutes at −20° C. The reaction mixture is poured into a mixture of 0.1N aqueous HCl and dichloromethane and the layers are separated. The aqueous layer is basified with sodium bicarbonate and extracted with ethyl acetate. The combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound is obtained as a white foam and used for the next step without further purification. Rt=4.61 (gradient II).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)C.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15](=[O:17])[NH:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:18][CH:19]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C(=O)O)cc1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Product: CC(C)(C)OC(=O)NCCc1ccc(C(=O)NCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
4-(2-tert-Butoxycarbonylaminoethyl)benzoic acid (0.307 g) was dissolved in methanol (5 mL) and treated with diethylisopropylamine (0.605 mL) and benzylamine (0.379 mL). The mixture was cooled (0° C.) then HATU (1.32 g) was added in portions. The reaction mixture was stirred for 48 h at room temperature, then partially concentrated in vacuo and partitioned between 2M aqueous hydrochloric acid and ethyl acetate. The organic layer was washed with further aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water, saturated aqueous sodium chloride, then dried (Na2SO4) and concentrated to afford a colourless oil (>0.41 g) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[Cl:16][S:17](O)(=[O:19])=[O:18].C(Cl)(=O)C(Cl)=O.CN(C)C=O>ClCCl>[CH3:1][O:2][C:3]1[C:4]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:5][C:6]2[CH2:7][CH2:8][C:9](=[O:15])[C:10]([CH3:13])([CH3:14])[C:11]=2[CH:12]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(cc1S(=O)(=O)Cl)CCC(=O)C2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the dichloromethane (2 ml) solution of 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 200 mg, 0.980 mmol), chlorosulfonic acid (110 μl, 1.70 eq.) was added and the mixture was stirred at room temperature for 2 hr. To the reaction solution, oxalyl chloride (297 μl, 3.0 eq.) and N,N-dimethyl formamide (45 μl, 0.6 eq.) were added in three divided portions, and the mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure to obtain the title compound (295 mg). Since the title compound is unstable, its structure was identified in the next step.
Reaction SMILES: [C:1]([CH:4](CC(O)=O)[CH2:5][S:6][C:7]1[S:11][C:10]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9][C:8]=1[N+:16]([O-])=O)([OH:3])=[O:2].C(Cl)(Cl)Cl.[CH3:27][OH:28]>O.C(O)(=O)C.[Cl-].[Cl-].[Cl-].[Ti+3]>[C:1]([CH2:4][CH:5]1[S:6][C:7]2[S:11][C:10]([S:12](=[O:13])(=[O:14])[NH2:15])=[CH:9][C:8]=2[NH:16][C:27]1=[O:28])([OH:3])=[O:2]
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])c(SCC(CC(=O)O)C(=O)O)s1
Reactant: CO
Agent: [Ti+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc2c(s1)SC(CC(=O)O)C(=O)N2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Titanium trichloride (256 ml, 15 wt % in 20-30 wt % HCl) was added in a steady stream to a stirred suspension of 5-(2,3-dicarboxypropylthio)-4-nitrothiophene-2-sulfonamide (21.8 g, 61.0 mmol) in water (128 ml) and acetic acid (128 ml). This mixture was stirred at ambient temperature for 18 hours and the yellow solid that precipitated was collected by filtration, washed with water and dried to yield 17.6 g. Chromatography over silica gel using chloroform/methanol/conc. aqueous ammonia (60:30:10; v/v/v) followed by recrystallization from water gave 3-carboxymethyl-2,3-dihydro-2-oxo-6-sulfamoyl-1H-thieno-[2,3-b][1,4]thiazine, mp 240° C.
Reaction SMILES: [OH:1][C@@H:2]([CH2:7][O:8][CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH3:6])=[O:4].Cl[C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[N:20]=[CH:21][C:14]=12>>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:19]1[C:15]2=[N:16][CH:17]=[N:18][C:13]([O:1][C@@H:2]([CH2:7][O:8][CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH3:6])=[O:4])=[C:14]2[CH:21]=[N:20]1
Reactant: COC(=O)[C@@H](O)COC(C)C
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Product: COC(=O)[C@H](COC(C)C)Oc1ncnc2c1cnn2-c1ccccc1Cl

Procedure:
D2a was prepared in an analogous fashion to D1b from (S)-methyl 2-hydroxy-3-isopropoxypropanoate C7a and B1.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:32]([C:33]([O:35]C)=[O:34])=[C:31]2[C:26]([CH:27]3[CH2:37][CH:28]3[CH2:29][O:30]2)=[CH:25][CH:24]=1)(=[O:21])=[O:20])=[O:9])[CH3:2].[OH-].[Li+].C(O)=O>O1CCOCC1.O>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:32]([C:33]([OH:35])=[O:34])=[C:31]2[C:26]([CH:27]3[CH2:37][CH:28]3[CH2:29][O:30]2)=[CH:25][CH:24]=1)(=[O:20])=[O:21])=[O:9])[CH3:2]
Reactant: CCN1CCC[C@H]1C(=O)NCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Solvent: C1COCCO1
Product: CCN1CCC[C@H]1C(=O)NCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Yield: 31 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-2-yl)cabonylaminomethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 101, 0.212 g) and lithium hydroxide (0.05 g) in dioxane (5.5 mL) and water (2.5 mL) was irradiated in the microwave at 150° C. for 30 minutes. After cooling, the mixture was diluted with water, acidified with formic acid to pH5 and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4) and filtered. The filtrate was evaporate to dryness and the residue was purified by HPLC (C18) eluting with a mixture of methanol and water, containing 0.1% formic acid, with a gradient of 35-75% to give (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-2-yl)cabonylaminomethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (0.064 g) as a white solid.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:14])[C@H:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[NH2:8])[CH3:4].C(N([CH2:20][CH3:21])CC)C.[C:22]([O:47]N1C(=O)CCC1=O)(=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>C(Cl)(Cl)Cl>[CH2:3]([O:5][C:6](=[O:14])[C@H:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:22](=[O:47])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:20][CH3:21])[NH:8][C:22](=[O:47])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH3:4]
Reactant: CCOC(=O)[C@@H](N)CCCCN
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)NCCCC[C@H](NC(=O)CCCCCCCCCCCCC/C=C\CCCCCCCC)C(=O)OCC
Reaction time: 8 h

Procedure:
To a stirred suspension of L-lysine ethyl ester dihydrochloride (6 mmol, 1.4 g, commercially available) and triethylamine (36 mmol, 3.6 g) in chloroform (80 mL), succinimidyl nervonate (18 mmol, 8.4 g, prepared as described in Example 1) was added in portions at room temperature. Stirring was continued overnight and, after removal of the solvent under reduced pressure, the product was crystallised from ethanol:water (1:1), yielding the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C(O[CH2:18][CH3:19])(OCC)(OCC)C.[ClH:20].[C:21](O)(=O)[CH3:22]>CCOCC>[ClH:20].[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:2](=[N:1][C:22]1[CH:21]=[CH:8][CH:3]=[CH:4][C:18]=1[CH3:19])[CH3:7]
Reactant: CCOC(C)(OCC)OCC
Reactant: CC(=O)O
Reactant: Cc1ccccc1N
Agent: Cl
Solvent: CCOCC
Product: CC(=Nc1ccccc1C)Nc1ccccc1C
Yield: 88 %

Procedure:
According to literature ((Taylor, E. C. et al., J. Org. Chem. 28:1108 (1963)), a solution of o-toluidine (4.28 g, 40.0 mmol) and triethyl orthoacetate (3.24 g, 290 mmol) in acetic acid (1 ml) was heated to reflux for 2 h. Volatile compounds were distilled off (120°-140°, 20 mm) and the solid residue was extracted with ether (total of 50 ml) in presence of 1N solution of Na2CO3 in water (100 ml). Two fold recrystallization from hexane-5% toluene gave white but still impure amidine (1.85 g, 38%); Mp 65°-68° (Lit (Taylor et al., supra) 70°, Lit (Barluenga, J. et al., Perkin 1 2732 (1980) 134°-135°). On chromatography with hexanes-ether 2:1 some unreacted o-toluidine was removed as the least polar fraction (TLC ether 0.75). Intermediate fractions contained colorless N-tolyl acetimidate. Almost pure amidine (TLC ether 0.46) was eluted with hexanes-ether 1:1. This compound was further purified by chromatography with THF-hexanes 1:1 then 1:0 and filtration of the eluents through celite for the removal of turbid matter. The addition of HCl gas saturated ether (5 ml) to a solution of the amidine (313 mg, 1.31 mmol) in ether (10 ml) gave the new hygroscopic, hydrochloride of the title compound (318 mg, 88%), Mp 237°-239°.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl.[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26](Cl)=[O:27])[CH:21]=1>C1COCC1.CCOC(C)=O>[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]([NH:8][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:27])[CH:21]=1
Reactant: CN1CCC(N)CC1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCC(NC(=O)c2cc(Cl)ccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
A 0° C. solution of 1-methyl-4-amino-piperidine (0.860 g, 7.53 mmol) and DIEA (2.63 mL, 15.06 mmol) in THF (15 mL) was treated with 4-chloropicolinoyl chloride hydrochloride (0.8 g, 3.77 mmol) in one portion, stirred at RT for 2 h, diluted with EtOAc and washed with satd. NaHCO3, then brine. The organic layer was dried over Na2SO4 and concentrated to dryness to afford 4-chloro-N-(1-methylpiperidin-4-yl)picolinamide (1.07 g, 112%). 1H NMR (400 MHz, DMSO-d6): δ 8.61-8.60 (m, 2H), 8.00 (d, J=2.1 Hz, 1H), 7.75 (dd, J=5.3, 2.2 Hz, 1H), 3.74-3.72 (m, 1H), 2.71 (d, J=11.3 Hz, 2H), 2.13 (s, 3H), 1.93 (m, 2H), 1.69-1.67 (m, 4H); MS (ESI) m/z: 254.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[F:20][CH:21]([F:31])[C:22]1[N:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[N:26][CH:27]=1>>[CH:28]([OH:30])=[O:29].[NH2:17][C:10]1[CH2:11][O:12][CH2:13][C:14]([F:15])([F:16])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[N:23][C:22]([CH:21]([F:31])[F:20])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:19])([CH3:18])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Reactant: O=C(O)c1cnc(C(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3cnc(C(F)F)cn3)ccc2F)N=C(N)COCC1(F)F
Product: O=CO

Procedure:
The coupling of (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A10A) and 5-difluoromethyl-pyrazine-2-carboxylic acid (prepared according to Suzuki, Y. et al., Int. Patent Application Publ. No. WO2009091016) yielded the title compound as a white solid. MS (ISP): m/z=430.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:44][CH:43]([OH:45])[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([OH:46])[CH:41]=3)[O:36]2)=[CH:31][CH:30]=1>>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:44][CH:43]([OH:45])[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([O:46][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:41]=3)[O:36]2)=[CH:31][CH:30]=1
Reactant: COc1ccc(C2CC(O)c3cc(O)ccc3O2)cc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: COc1ccc(C2CC(O)c3cc(Oc4ccc([N+](=O)[O-])cn4)ccc3O2)cc1

Procedure:
2-(4-Methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 2-(4-methoxyphenyl)chroman-4,6-diol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.40 (d, 2H, J 8.7 Hz), 7.24 (d, 1H, J 2.8 Hz), 7.22 (d, 1H, J 9.1 Hz), 7.00 (dd, 1H, J 8.7, 2.8 Hz), 6.97 (d, 2H, J 8.7 Hz), 6.84 (d, 1H, J 8.7 Hz), 5.63 (d, 1H, J 6.4 Hz), 5.23 (d, 1H, J 10.8 Hz), 4.95-5.02 (m, 1H), 3.78 (s, 3H), 2.25-2.29 (m, 1H), 1.98-2.04 (m, 1H).