Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@@H:12]3[CH2:14][C@H:9]2[CH2:10][N:11]3[CH3:15])[C:5]([F:16])=[C:4]([NH:17][NH2:18])[N:3]=1.[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:39]=[O:40])[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][NH:18][C:26](=[O:27])[C@H:25]([CH2:24][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:29][N:30]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:39]=[O:40])[C:5]([F:16])=[C:6]([N:8]2[CH2:13][C@@H:12]3[CH2:14][C@H:9]2[CH2:10][N:11]3[CH3:15])[N:7]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: CN1C[C@@H]2C[C@H]1CN2c1nc(Cl)nc(NN)c1F
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN1C[C@@H]2C[C@H]1CN2c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
(1S,4S)-2-(2-Chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (170 mg, 0.62 mmol), (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (190 mg, 0.62 mmol), and HOAt (93 mg, 0.68 mmol) were dissolved in 4 mL of DMF. NMM (0.27 mL, 2.5 mmol) was added, followed by EDC (131 mg, 0.36 mmol). After stirring overnight at room temperature, the reaction mixture was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (90 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.Br[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[C:4]([CH3:9])[CH:3]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: Cc1cc(Cl)ccc1O
Product: Cc1cc(Cl)ccc1Oc1ccc2ccccc2c1
Yield: 9 %

Procedure:
Following Example 1, the title compound was synthesized (yield; 9%) from 4-chloro-2-methylphenol and 2-bromonaphthalene.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]2[CH2:25][CH2:24][N:23]([CH:2]3[C:7](=[O:8])[NH:6][C:5]4[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=4[S:3]3)[CH2:22][CH2:21]2)[CH:15]=1
Reactant: Cc1ccnc(N2CCNCC2)c1
Reactant: O=C1Nc2ccccc2SC1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccnc(N2CCN(C3Sc4ccccc4NC3=O)CC2)c1
Yield: 16.8 %

Procedure:
7 g (=0.035 m) of 2-chloro-2H-1,4-benzothiazine-3(4H)-one, 6.2 g of N-(4-methylpyridin-2-yl)-piperazine, and 7 g of triethylamine were heated at reflux with stirring for 5 hours in 100 ml of toluene. The suspension was worked up by diluting it with 200 ml of toluene, and the resulting precipitate was filtered out and dissolved in 20% strength aqueous hydrochloric acid solution. The solution was rendered alkaline by adding an ammonium hydroxide solution, and the resulting precipitate was filtered out, washed with water and dried. 2 g of beige-colored crystalline 2-[4-(4-methylpyridin-2-yl)-piperazin-1-yl]-2H-1,4-benzothiazine-3(4H)-one having a melting point of 245° C. were obtained.
Reaction SMILES: [I:1]Cl.[Cl:3][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][N:5]=1.C([O-])(=O)C.[K+]>C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([I:1])=[CH:6][N:5]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1cc(Cl)ncc1I
Yield: 39.8 %

Procedure:
Iodine monochloride (0.758 g, 4.67 mmol) was added to a solution of 2-chloro-4-amino pyridine (0.500 g, 3.89 mmol) and potassium acetate (0.763 g, 7.78 mmol) in acetic acid (30 mL). The reaction mixture was heated under reflux for 4 hr. The solvent was removed in vacuo and the residue was partitioned between aqueous sodium hydrogenocarbonate (50 mL) and ethyl acetate (50 mL). The organic phase was dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified by flash silica chromatography, eluting with ethyl acetate and hexane (1/9), to give the title compound as a pink solid (0.394 g, 40%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24]>CN(C)C=O>[F:24][C:23]([F:26])([F:25])[CH2:22][CH2:21][C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:16])([F:17])[F:1])=[CH:15][CH:14]=1)([C:12]#[N:13])[C:10]#[N:11]
Reactant: FC(F)(F)CCBr
Reactant: N#CC(C#N)Cc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(OC(F)(F)F)cc1
Yield: 20 %

Procedure:
Using 0.50 g of (4-(trifluoromethoxy)benzyl)malononitrile, 8 ml of N,N-dimethylformamide, 96 mg of sodium hydride (60% in oil), and 0.74 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.14 g of 2-(3,3,3-trifluoropropyl)-2-(4-(trifluoromethoxy)benzyl)malononitrile (the present compound (50)).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH2:24]([N:27]([CH2:36][CH2:37][CH3:38])[C:28]([CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])=[O:29])[CH2:25][CH3:26]>>[CH2:36]([N:27]([CH2:24][CH2:25][CH3:26])[C:28](=[O:29])[CH2:30][CH2:31][CH2:32][C:33]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:34])[CH2:37][CH3:38]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CCCN(CCC)C(=O)CCCC(=O)O
Product: CCCN(CCC)C(=O)CCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-dipropylcarbamoyl-butyric acid to yield (3aR,4S,7aR)-methyl 4-(5-(dipropylamino)-5-oxopentanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [2M+H+NH4]=1039; RT=1.41 min; UPLC Method I
Reaction SMILES: CC(N)C1C=CC=CC=1.C(OC([NH:20][CH:21]([PH:26](=[O:28])[OH:27])[C:22]([SH:25])([CH3:24])[CH3:23])=O)C1C=CC=CC=1.Cl.Br>O.C(O)(=O)C.C(OCC)C>[NH2:20][CH:21]([PH:26](=[O:27])[OH:28])[C:22]([SH:25])([CH3:24])[CH3:23]
Reactant: CC(C)(S)C(NC(=O)OCc1ccccc1)[PH](=O)O
Agent: Br
Agent: CC(N)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(S)C(N)[PH](=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The (+)-α-methylbenzylamine salt of (-)-(1-benzyloxycarbonylamino-2-mercapto-2-methylpropyl)phosphinic acid [paragraph (c)] was suspended in water, the suspension was acidified to pH 1 with 2N hydrochloric acid and extracted with two 25 ml portions of diethyl ether. The combined ethereal extracts were dried over magnesium sulphate. Removal of the solvent by evaporation gave an oil which was dissolved in 2 ml of glacial acetic acid and treated with 5 ml of 45% hydrogen bromide in acetic acid. The solution was stored at room temperature overnight. 200 ml of diethyl ether were added and the cloudy suspension was cooled at 0° C. for 2 hours. The ethereal layer was decanted off and the residue was dissolved in 15 ml of methanol. 10 ml of acetone were then added. The solution was heated under reflux for 1 hour, cooled and filtered. The filtrate was adjusted to pH 5 by adding propylene oxide. The acetone adduct crystallized out at 0° C. and was collected. The acetone adduct, which melted at 183°-185° C., was dissolved in 5 ml of boiling water, filtered and concentrated to 3 ml by boiling off excess water. 15 ml of isopropanol were added and the mixture was allowed to cool slowly to room temperature. The mixture was then cooled at 0° C. for 16 hours. The resulting crystalline solid was collected and dried, there being obtained (-)-(1-amino-2-mercapto-2-methylpropyl)phosphinic acid of melting point 211°-212° C. (decomposition; [α]D25 =-4.5° (c=1.5% in water).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:13])[C:5]=1[F:14])[CH3:2].[C:15]1([Si:21]2(CCCC)[CH2:26][CH2:25][CH:24]([CH:27]3[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]3)[CH2:23][CH2:22]2)C=C[CH:18]=[CH:17][CH:16]=1>>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][C@H:30]2[CH2:29][CH2:28][C@H:27]([CH:24]3[CH2:23][CH2:22][SiH:21]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:26][CH2:25]3)[CH2:32][CH2:31]2)=[O:9])=[C:6]([F:13])[C:5]=1[F:14])[CH3:2]
Reactant: CCOc1ccc(C(=O)O)c(F)c1F
Reactant: CCCC[Si]1(c2ccccc2)CCC(C2CCC(O)CC2)CC1
Product: CCCC[SiH]1CCC([C@H]2CC[C@H](OC(=O)c3ccc(OCC)c(F)c3F)CC2)CC1

Procedure:
The general procedure of Example 31 was repeated using 4-ethoxy-2,3-difluorobenzoic acid and 4-(4-phenyl-4-n-butyl-4-silacyclohexyl)cyclohexanol, thereby obtaining the intended product.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]([CH3:21])[C:9](=[O:20])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)Cl.[OH-].[Na+]>CC(O)C>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C@@H:10]2[C:9](=[O:20])[N:8]([CH3:21])[C@H:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]3[O:1]2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(C(Cl)C(=O)N(C)[C@@H]2CCCC[C@H]2O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1cccc([C@H]2O[C@H]3CCCC[C@@H]3N(C)C2=O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The crude chloroacetamide (3.1 g) was dissolved in propan-2-ol (30 cm3) and treated with 10 N sodium hydroxide solution (3 cm3). The mixture was stirred at room temperature for 5 hrs. and was left overnight. The phases were separated and the organic phase was concentrated under reduced pressure. The residue was dissolved in ether-dichloromethane (1:1 v/v, 70 cm3) and washed with the alkaline phase diluted with water. The aqueous phase was extracted with dichloromethane (2×30 cm3). The combined organic phases were washed with saturated brine, dried (Na2SO4), and evaporated, leaving crude mixture of the title compounds as a brown oil (2.11 g).
Reaction SMILES: [C:1]1(C2(C(O)=O)CCCC2)C=CC=CC=1.[CH3:15][CH:16]([CH3:46])[CH:17]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19].C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[CH3:15][C:16]([CH3:1])([CH3:46])[CH:17]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19]
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: CC(C)(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 3,3-dimethyl-2-phenylbutanoic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.32 (d, J=6.7, 0.5H), 8.13 (d, J=7.1, 0.5H), 7.74-7.70 (m, 1H), 7.69-7.66 (m, 1H), 7.61 (t, J=8.6, 3H), 7.48-7.43 (m, 1H), 7.37-7.24 (m, 3H), 4.48-4.39 (m, 0.5H), 4.36-4.28 (m, 0.5H), 3.51 (q, J=13.1, 0.5H), 3.41 (d, J=17.1, 1H), 3.35 (d, J=13.3, 0.5H), 3.13 (d, J=13.4, 0.5H), 2.98 (qd, J=4.0, 8.2, 0.5H), 2.81 (dd, J=3.9, 9.5, 0.5H), 2.74 (ddd, J=3.4, 7.8, 16.6, 0.5H), 2.49-2.37 (m, 2H), 2.31 (dd, J=3.4, 9.6, 0.5H), 2.24-2.15 (m, 2H), 2.01-1.94 (m, 0.5H), 1.84 (ddd, J=8.1, 11.7, 14.5, 0.5H), 1.73-1.65 (m, 1H), 1.64-1.56 (m, 0.5H), 1.52-1.38 (m, 1H), 1.27 (dt, J=5.6, 12.2, 1H), 1.16 (s, 4.5H), 1.11 (s, 4.5H); MS (ESI+) m/z 459 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][O:13][N:14]2C(=O)C3=CC=CC=C3C2=O)=[N:7][CH:8]=1.C(Cl)(Cl)Cl.O.NN.C(O)(C)C>CCCCCC>[F:25][C:2]([F:1])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][O:13][NH2:14])=[N:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1OCCCOc1ccc(C(F)(F)F)cn1
Agent: NN
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: NOCCCOc1ccc(C(F)(F)F)cn1
Reaction time: 3 h
Yield: 84.8 %

Procedure:
To a mixture of 12.8 g of N-(3-(5-trifluoromethyl-2-pyridyloxy)propyloxy)phthalimide and 150 ml of chloroform was slowly added dropwise a mixture of 1.74 g of hydrazine hydrate and 1.5 ml of isopropyl alcohol at room temperature. After stirring for 3 hours with heating under reflux, the reaction mixture was returned to room temperature, in which 150 ml of hexane was poured. The reaction mixture was filtered through Celite, and the filtrate was concentrated to give a residue, in which 100 ml of hexane was again poured. This hexane solution was left stand in a refrigerator in 3 days. The deposited crystals were collected by filtration, and dried under reduced pressure, which afforded 7.0 g (yield, 85%) of O-(3-(5-trifluoromethyl-2-pyridyloxy)propyl)hydroxylamine, nD24.0 1.4652.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:48]=[CH:49][CH:50]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH2:33][CH2:34][CH2:35][OH:36])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:47])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:48]=[CH:49][CH:50]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH2:33][CH2:34][CH2:35][OH:36])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:47])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(OCCCO)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(OCCCO)c(NS(C)(=O)=O)c3)cc12
Yield: 11.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3-hydroxypropoxyl)phenyl) methanesulfonamide (60 mg, 0.08 mmol) was hydrolyzed by lithium hydroxide (6 mg, 0.25 mmol), THF/methanol/water (1/1/0.5 ml) to afford 5 mg (1.1% yield) of the titled compound. 1H NMR (DMSO-d6, 400 MHz): δ 11.85 (s, 1H), 8.90 (s, 1H), 8.47 (s, 1H), 7.77 (s, 1H), 7.52-7.41 (m, 4H), 7.15-7.00 (m, 4H), 5.32 (s, 2H), 4.60 (b, 1H), 4.13 (t, 2H), 3.63-3.61 (t, 2H), 2.97 (s, 3H), 2.17-2.13 (d, 6H), 1.93 (m, 2H). MS: m/z=564.1 (M+1), HPLC: 98.85% (method-B).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][CH2:25][CH2:26]Br>CC(C)=O>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([O:17][CH2:24][CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: O=c1c2ccccc2sc2c(O)ccc(Cl)c12
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc(Cl)c2c(=O)c3ccccc3sc12
Yield: 75.5 %

Procedure:
1-Chloro-4-hydroxythioxanthone (7.8 g; 0.03 mol) prepared as above and potassium carbonate (5.0 g; 0.036 mol) was stirred and refluxed for 10 minutes in acetone (50 ml). n-Propyl bromide (5.5 g; 0.045 mol) was added and the resulting mixture heated under reflux for 16 hours. The mixture was then cooled and quenched on to water (250 ml). The solid was filtered and washed with water the resulting damp solid recrystallised from ethanol (50 ml) to afford the title compound (6.9 g; 75.5%) of mp 102°-3°. Analysis C16H13ClO2S=304.777 Requires C 63.05%; H 4.30%; Cl 11.63%; S 10.52% Found C 63.14%; H 4.37%; Cl 11.66%; S 10.63%
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:10]([O:20]C)=[N:11][C:12]([CH3:19])=[CH:13][C:14]=1[O:15][CH:16]([F:18])[F:17])(C)(C)C>Cl>[NH2:7][CH2:8][C:9]1[C:10](=[O:20])[NH:11][C:12]([CH3:19])=[CH:13][C:14]=1[O:15][CH:16]([F:17])[F:18]
Reactant: COc1nc(C)cc(OC(F)F)c1CNC(=O)OC(C)(C)C
Agent: Cl
Product: Cc1cc(OC(F)F)c(CN)c(=O)[nH]1
Yield: 80.7 %

Procedure:
To a solution of tert-butyl((4-(difluoromethoxy)-2-methoxy-6-methylpyridin-3-yl)methyl)carbamate (830 mg, 2.61 mmol) in HCl (10 mL) was stirred at 100° C. for 1.5 hours under N2. The mixture was concentrated to afford 3-(aminomethyl)-4-(difluoromethoxy)-6-methylpyridin-2(1H)-one (430 mg, yellow solid, 80.8% yield). LCMS (M+H+) m/z: calcd 204.07. found 205.0. 1H NMR (400 MHz, DMSO): δ 7.621-7.258 (t, 1H), 6.26 (s, 1H), 3.837-3.822 (d, J=6.0 Hz, 2H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:55]1[CH:59]=[C:58]([CH2:60][NH2:61])[O:57][CH:56]=1>C(Cl)Cl.CCOCC>[O:57]1[CH:56]=[CH:55][CH:59]=[C:58]1[CH2:60][NH:61][C:29]([C:28]1[CH:32]=[CH:33][C:25]([C:7]2[C:8]3[C:15](=[O:16])[N:14]4[C@H:10]([C:9]=3[N:17]=[C:18]([CH2:19][C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][CH2:13]4)=[CH:26][CH:27]=1)=[O:30]
Reactant: CCOC(=O)c1c(Cc2ccsc2)nc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Reactant: NCc1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1c(Cc2ccsc2)nc2c(c1-c1ccc(C(=O)NCc3ccco3)cc1)C(=O)N1CCC[C@@H]21
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
A stirred solution of 28 mg (0.060 mmol) of 4-[(9aS)-3-(ethoxycarbonyl)-5-oxo-2-(3-thienylmethyl)-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl]benzoic acid, 14 mg (1.2 equiv, 0.072 mmol) of EDCI and 10 mg (1.2 equiv., 0.072 mmol) of HOBT in 1 mL of DCM was treated with 13 mg (2.2 equiv., 0.133 mmol) of 2-furfurylamine. The resulting solution was stirred at room temperature for 3 h. The reaction mixture was then poured into Et2O (10 mL) and extracted with H2O (1×10 mL) and NaHCO3 (1×10 mL). The organic layer was separated, dried (MgSO4), filtered to remove solids, and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography on an Elution Solutions medium pressure chromatography system using a gradient elution of hexanes/EtOAc 1:1 to 1:4 to afford a clear golden oil. The oil was then triturated with Et2O to afford 22 mg (68%) the title compound as a light yellow solid: 1H NMR (CDCl3, 400 MHz) δ 7.78 (d, 2H, J=7.9), 7.40 (d, 2H, J=7.9), 7.35 (s, 1H), 7.19 (m, 1H), 7.02 (s, 1H), 6.97 (d, 1H, J=4.8), 6.47 (m, 1H), 6.29 (d, 2H, J=15.4), 4.70 (dd, 1H, J=6.3, 10.2), 4.61 (d, 2H, J=5.4), 4.33 (AB quartet, 2H, J=14.5, 41.7), 3.86 (q, 2H, J=6.9), 3.65 (m, 1H), 2.47 (m, 1H), 2.30 (m, 2H), 1.41 (m, 1H), 1.22 (m, 2H), 1.18 (t, 3H, J=6.9); low resolution MS (ES+) m/e 543, (MH+1), 542 (MH+); TLC (hexanes/EtOAc (1:5)): Rf=0.25; HPLC (Dynamax RP-18, 4.6 mm×25 cm; 50–100% CH3CN/H2O with 0.1% TFA; 25 minutes; 1 mL/min): tR=7.73 min, 97% purity; Anal. (C30H27N3O5S) Calc. C, 66.53; H, 5.02; N, 7.76. Found C, 66.26; H, 4.87; N, 7.96.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:26])[C:12]([C:16]1[N:17]=[C:18]([NH:21]C(=O)CCl)[S:19][CH:20]=1)=[N:13][O:14][CH3:15])(=[O:3])[CH3:2].COC(=S)N.[Na]>CN(C=O)C>[C:1]([O:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:26])[C:12]([C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1)=[N:13][O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N[C@H]1OC(C)=O)c1csc(NC(=O)CCl)n1
Agent: COC(N)=S
Agent: [Na]
Solvent: CN(C)C=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@H]1OC(C)=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of 500 mg of (3S,4S)-4-acetoxy-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine (syn-isomer) in 10 ml of DMF is added 0.245 g of sodium monomethyithiocarbamate and the mixture is stirred at room temperature for one hour. The solvent is distilled off under reduced pressure, the residue is washed three times with ethyl acetate and the insolubles are filtered off after addition of ethanol. The filtrate is concentrated under reduced pressure. Then, purifying the residue on a silica gel column (ethyl acetate:CHCl3 :CH3OH=2:2:1) yields 0.270 g of (3S,4S)-4-acetoxy-3-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine (syn-isomer).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[O:25]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:35]3[CH:36]=[CH:37][C:32]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:33][CH:34]=3)[C:3]=12
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 90 °C
Reaction time: 24 h
Yield: 63.9 %

Procedure:
A mixture of (R)-tert-butyl 3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (1 g, 2.25 mmol, 1.00 equiv), (4-phenoxyphenyl)boronic acid (530 mg, 2.48 mmol, 1.10 equiv), sodium carbonate (480 mg, 4.53 mmol, 2.01 equiv) and tetrakis(triphenylphosphine)palladium (78 mg, 0.07 mmol, 0.03 equiv) in 1,4-dioxane (60 mL) and water (15 mL) was stirred under nitrogen at 90° C. for 24 h. The reaction mixture was cooled to room temperature and then concentrated under vacuum. The residue was dissolved in 500 mL of dichloromethane. The resulting solution was washed with 200 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 700 mg (64%) of (R)-tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:3]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=2)=[CH:19][CH:18]=1
Reactant: Cc1cnc(Oc2ccccc2)c(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cnc(Oc2ccccc2)c(-c2ccc(Cl)cc2)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 68.7 %

Procedure:
3-Bromo-5-methyl-2-phenoxy-pyridine (0.79 g, 3.0 mmol) was dissolved in toluene (5 mL). To this solution was added [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) dichloro-methane complex (120 mg), 4-chlorophenyl-boronic acid (0.7 g, 4.5 mmol), and 2 N sodium carbonate solution (4.7 mL). The whole mixture was heated with stirring at 90° C. for 18 h, cooled to room temperature and eluted with ethyl acetate over 10 g ChemElut (Varian). The solvent was evaporated and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 0.61 g of the title compound as a yellowish oil, MS (ISP) 296.4 (M+H)+.