Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].[S:10]1(=[O:16])(=[O:15])[CH2:14][CH2:13][CH2:12][NH:11]1.[OH-].C[N+](C)(C)CC1C=CC=CC=1>O.C(Cl)(Cl)Cl>[N:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH2:2][N:11]2[CH2:12][CH2:13][CH2:14][S:10]2(=[O:16])=[O:15])=[CH:5][CH:6]=1
Reactant: O=S1(=O)CCCN1
Reactant: C=C(C)c1ccncc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(CN1CCCS1(=O)=O)c1ccncc1
Reaction time: 16 h

Procedure:
A mixture of 4-isopropenyl pyridine (1.79 g) and isothiazolidine-1,1-dioxide (1.81 g) was heated at 130° C. during the addition of "Triton B" (Trade Mark, trimethylbenzylammonium hydroxide) (0.25 g added every hour for four hours; 40% solution in water). After stirring for 16 hours at 130° the mixture was cooled and taken in chloroform (50 cm3) and water (50 cm3). The aqueous phase was extracted with chloroform (3×20 cm3) and the dried (MgSO4) extracts were evaporated to given an oil. Chromatography on silica ("Merck 60. 9385") eluting with ethyl acetate gave 2-[2-(4-pyridyl)prop-1-yl]isothiazolidine-1,1-dioxide which crystallised from ethyl acetate-hexane as needles, m.p. 90°-92° (1.01 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[C-:9]#[N:10].[Na+]>C(OCC)C.CN(C)C>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:9]#[N:10])[N:7]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: [C-]#N
Agent: CN(C)C
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccnc(C#N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a solution of 2-chloro-4-methylpyrimidine (3.00 g, 23.3 mmol; 3B Pharmachem International, China) in ethyl ether (24 mL) was added a solution of sodium cyanide (2.86 g, 58.3 mmol) in trimethylamine solution (1:3, trimethylamine:water, 24.0 mL). The reaction mixture was stirred at room temperature overnight. The aqueous layer was extracted with ethyl ether (3×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to yield the title compound, 4-methyl-pyrimidine-2-carbonitrile (1.80 g; 64.8%), which was used in the next step without further purification. 1H NMR (400 MHz, D2O) δ 8.64 (d, J=5.4 Hz, 1H), 7.59 (d, J=5.5 Hz, 1H).
Reaction SMILES: [Na].[CH:2]1[C:15]2[C:14](=[O:16])[C:13](=[N:17][OH:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[Na+]>CC(C)=O>[C:19]([O:18][N:17]=[C:13]1[C:14](=[O:16])[C:15]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1C(=NO)c2ccccc2-c2ccccc21
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)=O
Product: O=C(ON=C1C(=O)c2ccccc2-c2ccccc21)c1ccccc1
Reaction time: 0.25 h

Procedure:
24.6 g (0.1 mole) of the sodium salt of 9,10-phenanthrene-dione-9-oxime are suspended in 100 ml of acetone, whereupon a solution of 15.4 g (0.11 mole) of benzoyl chloride and 50 ml of acetone is added under stirring. A slightly exothermic reaction takes place, sodium chloride is precipitated and within about an hour a dark brown solution is formed. The reaction having been completed, the reaction mixture is heated to boiling for 15 minutes and evaporated in vacuo. Thus 28.2 g of 9,10-phenanthrene-dione-9-benzoyl-oxime are obtained, yield, 86.2%, mp.: 148°-149° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[N:13]=[N:14][C:15]([N:18]([CH3:29])[CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)=[CH:16][CH:17]=1)[C:6](O)=[O:7].[CH2:30]([NH2:33])[C:31]#[CH:32].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[N:13]=[N:14][C:15]([N:18]([CH3:29])[CH:19]2[CH2:20][C:21]([CH3:27])([CH3:28])[NH:22][C:23]([CH3:25])([CH3:26])[CH2:24]2)=[CH:16][CH:17]=1)[C:6]([NH:33][CH2:30][C:31]#[CH:32])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Reactant: C#CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CCNC(=O)c1ccc(-c2ccc(N(C)C3CC(C)(C)NC(C)(C)C3)nn2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
To a crude solution of 3-methoxy-4-(6-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzoic acid (620 mg, 1.56 mmol) in DMF (10 mL) and CH2Cl2 (10 mL) was added propargyl amine (129 mg, 2.33 mmol), DIPEA (0.82 mL, 4.67 mmol) and HATU (887 mg, 2.33 mmol). The reaction was stirred at RT overnight, then diluted with water and EtOAc. The layers were separated and the aqueous layer was concentrated and partially dissolved in MeOH. The resultant white precipitate was filtered, and the MeOH filtrate was concentrated. The filtrate was dissolved in MeOH and the resultant precipitate filtered. The filtrate was concentrated and purified via HPLC(C18 sunfire column, 20% CH3CN/H2O to 100% CH3CN, 0.1% NH4OH aq. as modifier to give 3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-N-(prop-2-yn-1-yl)benzamide (190 mg). LCMS Rt=0.86 min (condition B); MS (M+1)=436.3. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.82 (d, J=9.6 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.52 (dd, J=7.8, 1.5 Hz, 1H), 7.10 (d, J=9.6 Hz, 1H), 5.15-5.27 (m, 1H), 4.18 (d, J=2.3 Hz, 2H), 3.93 (s, 3H), 2.99 (s, 3H), 2.63 (t, J=2.5 Hz, 1H), 1.67 (dd, J=12.5, 3.4 Hz, 2H), 1.54 (t, J=12.5 Hz, 2H), 1.33 (s, 6H), 1.20 (s, 6H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11](N)=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[B-](F)(F)F.C([O+](CC)CC)C.[F:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:30]([NH2:33])=[CH:31][CH:32]=1>C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:10]1[N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:29]2[CH:28]=[C:27]([F:26])[CH:32]=[CH:31][C:30]=2[N:33]=1)[CH3:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: Nc1ccc(F)cc1Nc1ccccn1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of (S)-Boc-alaninamide (1.5 g, 7.9 mmol) in anhydrous THF (20 mL) was added triethyloxonium tetrafluoroborate (1.6 g, 8.3 mmol) in one portion under a nitrogen atmosphere. The resulting mixture was left to stir at RT for 2 h. The volatiles were removed in vacuo and the resulting residue redissolved in absolute EtOH (20 mL). To the mixture was added 4-fluoro-N2-pyridin-2-yl-benzene-1,2-diamine (1.0 g, 4.9 mmol) and the mixture stirred at 75° C. for 16 h. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM and the combined organic fractions washed with water, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-40% EtOAc in cHex) to afford the title compound as an orange oil (1.6 g, 92%). LCMS (Method B): RT 3.21 min [M+H]+ 357.0.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][C:59]1[CH:68]=[CH:67][C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[N:60]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([NH:58][C:59]2[CH:68]=[CH:67][C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[N:60]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccc2ccccc2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc3ccccc3n2)cc1[N+](=O)[O-]
Yield: 13.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (prepared as in Example 32, 150 mg, 0.439 mmol), triethylamine (0.184 mL, 1.32 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (291 mg, 0.659 mmol), and 2-aminoquinoline (95 mg, 0.659 mmol) in methylene chloride (4 mL) was stirred at 25° C. overnight. The crude reaction mixture was directly purified by Biotage chromatography (FLASH 40M, Silica, 1/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-quinolin-2-yl-propionamide (28 mg, 13.6%) as a white foam: mp 102-106° C. (foam to gel); EI-HRMS m/e calcd for C24H25N3O5S (M+) 467.1515, found 467.1513.
Reaction SMILES: [CH:1]1[C:2]([I:10])=[CH:3][C:4]([I:9])=[C:5]([OH:8])[C:6]=1[I:7].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20].O>CN(C)C=O>[I:7][C:6]1[CH:1]=[C:2]([I:10])[CH:3]=[C:4]([I:9])[C:5]=1[O:8][CH2:17]/[CH:18]=[C:19](\[CH3:20])/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25]
Reactant: Oc1c(I)cc(I)cc1I
Reactant: CC(C)=CCC/C(C)=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/COc1c(I)cc(I)cc1I
Temperature: 50 °C
Yield: 87 %

Procedure:
A mixture of triiodophenol (10.0 g, 21.2 mmol), milled potassium carbonate (3.1 g, 22.5 mmol, 1.06 eq) and geranyl bromide (4.0 ml, 20.2 mmol) in dimethyl formamide (25 ml) was heated to 50° C. for 2 hrs and cooled. The mixture was poured into 300 ml of water and extracted with ethyl acetate. The ethyl acetate extract was filtered through a short pad of silica gel, then alumina, eluting with ethyl acetate-hexanes (1:1). The eluent was concentrated under high vacuum to give the product in 87% yield as an oil. Title Compound: 1H (300 MHz) and 13C (75 MHz) NMR spectra were consistent with the desired structure. Calculated for C16H19I3O: C, 31.61; H, 3.15; I, 62.61. Found: C, 31.84; H, 3.06; I, 62.60.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1>>[CH:13]1([NH:23][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[O:12])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: NC1CCCc2ccccc21
Product: O=C(NC1CCCc2ccccc21)c1ccc2c(c1)OCO2

Procedure:
Prepared in a similar manner to example 4 using benzo[d][1,3]dioxole-5-carboxylic acid and 1,2,3,4-tetrahydronaphthalen-1-amine. MS (M+H, 296.6).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][C:6](=[O:8])[CH:7]=1)[CH3:2]>[Pd].CCOC(C)=O>[CH2:1]([CH:3]1[CH2:7][C:6](=[O:8])[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CCOC(=O)C1CC(=O)C=C1CC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC(=O)CC1CC
Temperature: 0 °C
Reaction time: 48 h
Yield: 99.1 %

Procedure:
A round-bottom flask was charged with 10% palladium on carbon (10 g, 9.4 mmol). The flask was cooled to about 0° C. and EtOAc (400 mL) was added under a nitrogen atmosphere. The cooling bath was removed and ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (47.8 g, 263 mmol) was added. Hydrogen gas was bubbled through the mixture for about 5 min and the mixture was then stirred under a hydrogen atmosphere for about 48 h. The hydrogen source was removed, the mixture was bubbled with nitrogen for about 5 min and was filtered through a pad of Celite®. The filter cake was rinsed with EtOAc (400 mL). The filtrate was concentrated under reduced pressure to give ethyl 2-ethyl-4-oxocyclopentanecarboxylate (48.0 g, 99%) as a yellow liquid: 1H NMR (CDCl3) δ 4.23-4.10 (m, 2H), 3.22 (m, 1H), 2.59-2.50 (m, 1H), 2.44-2.28 (m, 3H), 2.26-2.16 (m, 1H), 1.58-1.46 (m, 1H), 1.41-1.30 (m, 1H), 1.30-1.23 (m, 3H), 1.02-0.91 (m, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[N:2]1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=1[C:18]1[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[CH:22][N:23]=1>>[NH2:25][C:19]1[N:20]=[C:21]([NH:24][C:6]([C:3]2[CH:4]=[CH:5][O:1][N:2]=2)=[O:8])[CH:22]=[N:23][C:18]=1[C:11]1[CH:12]=[C:13]([Cl:17])[CH:14]=[C:15]([Cl:16])[C:10]=1[Cl:9]
Reactant: Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Reactant: O=C(O)c1ccon1
Product: Nc1nc(NC(=O)c2ccon2)cnc1-c1cc(Cl)cc(Cl)c1Cl

Procedure:
N-[6-amino-5-(2,3,5-trichlorophenyl)pyrazin-2-yl]isoxazole-3-carboxamide was prepared by a method analogous to Method B, as described above for Example 2, using 3-isoxazolecarboxylic acid and 3-(2,3,5-trichlorophenyl)pyrazine-2,6-diamine (Preparation 12).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1(O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>CCOC(C)=O.O.C1COCC1.C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: OC1CCCCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccc(OC2CCCCC2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
Under a nitrogen atmosphere add 6-chloro-pyridin-3-ol (2.5 g, 19.3 mmol), cyclohexanol (1.93 g, 19.3 mmol), tri-n-butylphosphine (5.07 g, 25.1 mmol), and ADDP (6.32 g, 25.1 mmol) to benzene (100 mL) and THF (10 mL) at 0° C. Stir the mixture at 0° C. for 1 h and at room temperature for 12 h. Dilute with EtOAc and water. Separate the layers and extract the aqueous layer with EtOAc. Wash the organic phase with water (30 mL) and brine (20 mL). Dry the organic phase over Na2SO4, filter, and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (400 g) eluting with hexane/EtOAc (1:0 to 98:2 gradient) to obtain the desired intermediate as clear oil (1.8 g, 58%). MS (APCI+) m/z: 212 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[C:18](Cl)(=[O:25])[O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22].CCN(C(C)C)C(C)C.O>C(Cl)Cl>[CH3:17][O:16][C:14]([C@@H:4]1[CH2:3][C@H:2]([NH:1][C:18]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:25])[CH2:6][N:5]1[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])=[O:15]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](NC(=O)OCC(Cl)(Cl)Cl)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,4S)-1-tert-butyl 2-methyl 4-aminopyrrolidine-1,2-dicarboxylate (4.6 g, 10.7 mmol) in CH2Cl2 (100 mL) were added 2,2,2-trichloroethyl carbonochloridate (1.73 mL, 12.88 mmol) and DIPEA (2.81 mL, 16.1 mmol). The reaction mixture was stirred at RT for 2 h then was poured into water. The desired compound was extracted with EtOAc (2×100 mL), the organic phases were joined, washed with 1N HCl then brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1). MS (UPLC): 421 [M+H]+, 419 [M−H]−; tR (HPLC conditions f): 1.11 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:27][CH2:26][CH2:25][C@H:8]3[S:9](=[O:24])(=[O:23])[C:10]([CH3:22])([CH3:21])[C:11]([NH:13]C(=O)OC(C)(C)C)=[N:12][C@:7]3([CH3:28])[C:6]=2[CH:29]=1.Cl[C:31]1[C:32]2[N:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:33]=2[N:34]=[CH:35][N:36]=1.CC(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C([O-])(O)=O.[Na+]>[NH2:13][C:11]1[C:10]([CH3:21])([CH3:22])[S:9](=[O:24])(=[O:23])[C@@H:8]2[CH2:25][CH2:26][O:27][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:31]4[C:32]5[N:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:33]=5[N:34]=[CH:35][N:36]=4)=[CH:29][C:6]=3[C@@:7]2([CH3:28])[N:12]=1
Reactant: COc1cnc2c(Cl)ncnc2c1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1cnc2c(Nc3ccc4c(c3)[C@@]3(C)N=C(N)C(C)(C)S(=O)(=O)[C@@H]3CCO4)ncnc2c1
Reaction time: 0.42 h
Yield: 61.3 %

Procedure:
A disposable tube was charged with tert-butyl ((4aR,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (60 mg, 0.142 mmol), 4-chloro-7-methoxypyrido[3,2-d]pyrimidine (30.5 mg, 0.156 mmol) and 2-propanol (708 μl, 0.142 mmol), followed by p-toluenesulfonic acid monohydrate (53.9 mg, 0.283 mmol). The resulting mixture was stirred from rt to 90° C. for 25 min. The reaction mixture was diluted with sat. NaHCO3 and extracted with EtOAc to yield the crude product as a yellow solid. The crude material was absorbed onto a plug of silica gel and purified by column chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 20% to 35% to 50% EtOAc/MeOH/NEt3 (80/20/2) in (40% EtOAc in Heptane), to provide (4aR,11bR)-2-amino-10-((7-methoxypyrido[3,2-d]pyrimidin-4-yl)amino)-3,3,11b-trimethyl-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazine 4,4-dioxide (42 mg, 0.087 mmol, 61.4% yield) as white solid. MS m/z=483.2 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[C:9]1([C@@H:15]([NH2:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[C:9]1([C@@H:15]([NH:17][C:6]([C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=C(Cl)c1ccc[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)c1ccc[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
To a solution of 1H-pyrrole-2-carbonyl chloride (1.3 g, 10 mmol) (from Example 30) in DCM (20 mL) was added (S)-1-phenyl-ethylamine (1.4 g, 11.55 mmol) (Aldrich, Milwaukee, Wis.), followed by triethylamine (1.5 mL). The reaction was stirred at room temperature for overnight. The reaction was washed with 1N NaOH, water, brine, dried and concentrated to give 867 mg (40%) of 1H-pyrrole-2-carboxylic acid ((S)-1-phenyl-ethyl)-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([N+:22]([O-])=O)[C:19]([F:25])=[CH:18][C:3]=1[CH:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1>C(O)C.[Pt](=O)=O>[NH2:22][C:20]1[C:19]([F:25])=[CH:18][C:3]([CH2:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)=[C:2]([Cl:1])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cc(F)c([N+](=O)[O-])cc2Cl)CC1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Cc2cc(F)c(N)cc2Cl)CC1
Reaction time: 0.75 h
Yield: 114.1 %

Procedure:
A slurry of platinum (IV) oxide (0.074 mmol, 16.84 mg) in ethanol was added to a solution of tert-butyl 4-(2-chloro-5-fluoro-4-nitrobenzylidene)piperidine-1-carboxylate (1.483 mmol, 550 mg) in ethanol and the resulting suspension was hydrogenated at 3 bar for 45 minutes. The reaction mixture was filtered through celite, washing with ethanol. The filtrate was concentrated under vacuum to afford the intermediate tert-butyl 4-(4-amino-2-chloro-5-fluorobenzyl)piperidine-1-carboxylate (580 mg).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH:8]=[CH:7][C:6]=1[O:28][CH3:29])C.[H-].[Na+]>CN(C=O)C>[CH2:4]([N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[C:18]([CH:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:9]3[CH:8]=[CH:7][C:6]([O:28][CH3:29])=[C:5]([CH:10]=3)[C:4]([OH:3])=[O:30])[CH2:13][CH2:14]2)=[CH:19]1)[CH2:5][CH2:6][CH3:7]
Reactant: CCOC(=O)c1cc(CN2CCC(c3c[nH]c4cc(F)ccc34)CC2)ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1cc(C2CCN(Cc3ccc(OC)c(C(=O)O)c3)CC2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
Under inert atmosphere, a solution of 0.07 g (0.17 mmol) of 5-[4-(6-fluoro-1H-indol-3-yl)-piperidin-1-ylmethyl]2-methoxybenzoic acid ethyl ester in 0.5 ml of anhydrous DMF was added dropwise to a suspension containing 0.012 g (0.24 mol) of sodium hydride (60% in mineral oil) in 1 ml of anhydrous DMF. After stirring at room temperature for 1 hour, a solution of 0.044 g (0.24 mol) of 1-bromobuthane in 0.5 ml of DMF was added. The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure. This ester was dissolved in a mixture of 1 ml of ethanol and hydrolysed with 2N NaOH at room temperature for 20 hours. The crude mixture was neutralised with 2N HCl aqueous solution and the solvent was removed under reduced pressure. The crude residue was purified by HPLC-MS chromatography affording 0.0053 g of the expected acid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[C:11]1[NH:19][C:18]2[C:13](=[N:14][CH:15]=[N:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[CH2:1]([C:4]1[CH:9]=[C:8]([O:10][S:21]([CH3:20])(=[O:23])=[O:22])[CH:7]=[CH:6][C:5]=1[C:11]1[NH:19][C:18]2[C:13](=[N:14][CH:15]=[N:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCc1cc(O)ccc1-c1nc2ncncc2[nH]1
Product: CCCc1cc(OS(C)(=O)=O)ccc1-c1nc2ncncc2[nH]1

Procedure:
Prepared analogously to Example 1 from 8-(2'-n-propyl-4'-hydroxy-phenyl)-purine and methanesulfonic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]#[N:10])[CH:5]=[CH:4][C:3]=1[NH:11][C@H:12]([C@@H:16]([OH:18])[CH3:17])[C:13]([OH:15])=O.[Cl:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1.ClC1C(CC)=C(N[C@H]([C@@H](O)C)C(NNC(=O)C2C=CC=CC=2)=O)C=CC=1C#N>>[Cl:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH:27][C:13](=[O:15])[C@H:12]([NH:11][C:3]2[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[C:7]([Cl:8])[C:2]=2[Cl:1])[C@@H:16]([OH:18])[CH3:17])=[O:25])=[CH:22][CH:21]=1
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1Cl)C(=O)O
Reactant: NNC(=O)c1ccc(Cl)cc1
Agent: CCc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1Cl)C(=O)NNC(=O)c1ccc(Cl)cc1
Yield: 52.3 %

Procedure:
(2R,3S)-2-(2,3-dichloro-4-cyanophenylamino)-3-hydroxybutanoic acid (1.0 g, 3.46 mmol) and 4-chlorobenzohydrazide (590 mg, 3.46 mmol) were reacted using the techniques described for the preparation of intermediate 11c to furnish the title compound (800 mg, 52%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 10.4 (br s, 2H), 7.98 (d, J=8 Hz, 2H), 7.61 (d, J=8 Hz, 1H), 7.43 (d, J=8 Hz, 2H), 6.84 (d, J=8 Hz, 1H), 6.18 (d, J=6 Hz, 1H), 5.0 (br s, 1H), 4.31-4.38 (m, 1H), 4.18-4.2 (m, 1H), 1.36 (d, J=6 Hz, 3H).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Cl[CH:7]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].O>CN(C=O)C>[C:1]([S:3][CH:7]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])[CH3:2]
Reactant: CCOC(=O)C(Cl)c1ccc(C)c(C)c1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(SC(C)=O)c1ccc(C)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
Potassium thioacetate (CH3COSK, 8.31 g) was added in small portions to a solution of ethyl 2-chloro-2-(3,4-dimethylphenyl)acetate (15 g) in DMF (80 ml). The mixture was stirred at room temperature for 2 hours, at the end of which time it was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give ethyl 2-acetylthio-2-(3,4-dimethylphenyl)acetate (16.5 g, 94%) as an oil.