Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][N:12]([CH3:34])[C:13]1[C:22](/[CH:23]=[CH:24]/[CH2:25][OH:26])=[C:21]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH3:34][N:12]([CH3:11])[C:13]1[C:22](/[CH:23]=[CH:24]/[CH:25]=[O:26])=[C:21]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: CN(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1/C=C/CO
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1/C=C/C=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
To a solution of oxalyl chloride (1.21 ml, 1.3 equivalents), in 40 ml of dichloromethane at -78° C. under an atmosphere of nitrogen, is added a solution of 2.0 ml (2.6 equivalents) of dimethylsulfoxide in 25 ml of dichloromethane. The reaction is stirred at -78° C. for 15 minutes and 3.45 g of (E)-3-[2-(dimethylamino)-4-(4-fluorophenyl)-3-quinolinyl]-2-propen-1-ol in 40 ml of dichloromethane added dropwise. The reaction is stirred for one hour at -78° C. and then quenched by adding 7.46 ml (5.0 equivalents) of triethylamine and warming to room temperature. A saturated aqueous solution of ammonium chloride, 20 ml, is added and the reaction is washed with water, dried (magnesium sulfate), and evaporated to give 3.14 g of (E)-3-[2-(dimethylamino)-4-(4-fluorophenyl)-3-quinolinyl]-2-propenal as an orange solid; 1H NMR (chloroform-d): δ 9.35 (d, 1H), 7.75 (d, 1H), 7.58-6.98 (m, 8H), 6.32 (dd, 1H), 2.99 (s, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#N)=[C:4]([F:11])[C:3]=1[Br:12].C(O)=[O:14]>[Ni]>[NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:14])=[C:4]([F:11])[C:3]=1[Br:12]
Reactant: O=CO
Reactant: N#Cc1cc(F)c(N)c(Br)c1F
Agent: [Ni]
Product: Nc1c(F)cc(C=O)c(F)c1Br
Temperature: 80 °C
Yield: 71 %

Procedure:
To a solution of 4-amino-3-bromo-2,5-difluoro-benzonitrile (7 g, 30 mmol) in 95-97% formic acid (40 mL) was added Raney nickel (7 g, previously washed with water and methanol). The reaction mixture was heated to 75-85° C. for 2 h. The reaction was then cooled to room temperature and filtered through Celite, washing with dichloromethane and water. The dichloromethane layer was washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated to afford 5 g (71%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 10.15 (s, 1H), 7.41-7.49 (m, 1H), 4.9 (br. s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([OH:22])=O)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[CH:4][N:3]=1.[NH2:24][C@@H:25]([CH3:28])[CH2:26][OH:27].FC(F)(F)[C@@H](N)C>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([NH:24][C@@H:25]([CH3:28])[CH2:26][OH:27])=[O:22])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[N:6][CH:7]=1
Reactant: C[C@H](N)CO
Reactant: Nc1cnc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Agent: C[C@H](N)C(F)(F)F
Product: C[C@@H](CO)NC(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 504 using 4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid and (S)-2-aminopropan-1-ol for (S)-1,1,1-trifluoropropan-2-amine. MS (ESI): mass calcd. for C20H19FN4O2, 366.15; m/z found, 367.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 8.05 (d, J=5.1, 2H), 7.93-7.83 (m, 1H), 7.54-7.43 (m, 3H), 7.37-7.28 (m, 2H), 6.72 (s, 2H), 4.66 (t, J=5.6, 1H), 3.82 (d, J=7.0, 1H), 3.35 (s, 1H), 3.16 (d, J=10.4, 2H), 0.98 (d, J=6.6, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:12][CH2:11][CH2:10][C:9]=1[C:13](OCC)=[O:14].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:12][CH2:11][CH2:10][C:9]=1[CH2:13][OH:14]
Reactant: CCOC(=O)C1=C(c2ccccc2F)CCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCC1=C(c2ccccc2F)CCC1
Reaction time: 1 h

Procedure:
A solution of ethyl 2-(2-fluorophenyl)cyclopent-1-enecarboxylate obtained in Preparation Example 3-(2) (7.60 g) in THF (100 mL) was added dropwise to a suspension of lithium aluminum hydride (1.34 g) in THF (300 mL) in an ice bath. The reaction solution was stirred at the same temperature for one hour. Then, water (1.35 mL), a 5 N sodium hydroxide solution (1.35 mL) and water (4.05 mL) were sequentially added dropwise in an ice bath. Anhydrous magnesium sulfate was added to the generated reaction mixture, followed by extraction with ethyl acetate. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain the title compound (6.50 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([OH:11])[CH:8]=2)[C:3]1=[O:14].[H-].COCCO[Al+]OCCOC.[Na+].[H-]>O1CCCC1>[CH3:1][C:2]1([CH3:15])[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([OH:11])[CH:8]=2)[CH:3]1[OH:14]
Reactant: CC1(C)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(O)c(Cl)c(Cl)c2C1O

Procedure:
2,2-Dimethyl-6,7-dichloro-1,5-indanediol is prepared following substantially the same procedure described in Example 4, Step E, using the following substances: 2,2-dimethyl-5-hydroxy-6,7-dichloro-1-indanone (6.1 g., 0.025 mole); sodium bis-(2-methoxyethoxy)-aluminum hydride (70% in benzene) 8 ml.; tetrahydrofuran (75 ml.). The above procedure gives 2,2-dimethyl-6,7-dichloro-1,5-indanediol.
Reaction SMILES: FC1C=CC(C[O:7][C:8](=[O:35])[C:9]2[C:10](=[CH:22][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[CH:24][CH:25]=2)[C:11]([O:13]CC2C=CC(F)=CC=2)=[O:12])=CC=1>O1CCCC1.O>[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][O:26][C:23]2[CH:22]=[C:10]([C:11]([OH:13])=[O:12])[C:9](=[CH:25][CH:24]=2)[C:8]([OH:35])=[O:7])=[CH:33][CH:32]=1
Reactant: O=C(OCc1ccc(F)cc1)c1ccc(OCc2ccc(F)cc2)cc1C(=O)OCc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OCc2ccc(F)cc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.9 %

Procedure:
A mixture of 4-(4-fluoro-benzyloxy)-phthalic acid bis-(4-fluoro-benzyl) ester (7.8 g, 15.4 mmol) lithium hydroxide monohydrate (1.8 g, 46.2 mmol) in tetrahydrofuran (60 mL) and water (60 mL) was stirred at room temperature for 72 h. The mixture was then evaporated followed by acidification to pH 2 at 0° C. with concentrated HCl. The organic layer was then diluted with ethyl acetate, separared, washed with water and dried over sodium sulfate. Filtration and half evaporation gave a white suspension which was filtered off and washed with ether to afford the title compound (2.5 g, 56%) as a white solid. MS: m/e=289.0 (M−H+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:18]([NH:22][NH2:23])(=O)[CH2:19][CH3:20]>C(O)CCC>[CH2:19]([C:18]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:23][N:22]=1)[CH3:20]
Reactant: CCC(=O)NN
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nn2)cc1
Solvent: CCCCO
Product: CCc1nnc2ccc(-c3ccc(C(F)(F)F)cc3)nn12

Procedure:
As in Example 65, 5.0 g. of 3-chloro-6-(α,α,α-trifluoro-p-tolyl)pyridazine and 3.40 g. of propionic acid hydrazide in 100 ml. of butanol is refluxed for 48 hr. to give 3.1 g of white crystals (from CHCl3 -hexane), m.p. 194°-196° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:12][S:13]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])(=[O:15])=[O:14].CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH:17]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2ncsc2n1
Reactant: CS(=O)(=O)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cccc(Nc2nc(Cl)nc3scnc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A mixture of 5,7-dichlorothiazolo[5,4-d]pyrimidine (200 mg, 0.97 mmol), 3-(methylsulfonyl)aniline (182 mg, 1.07 mmol) and DIEA (375 g, 2.91 mmol) in 20 mL of DMSO was stirred at room temperature overnight. The mixture was poured into 150 mL of water and filtered, the solid obtained was washed with petroleum ether dried to give crude product which was purified by silica gel chromatography, silica gel 200-300 mesh, eluting with ethyl acetate to give 5-chloro-N-(3-(methylsulfonyl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (220 mg, 66%) as a yellow solid. LC-MS: 341 [M+H]+, 3621 [M+Na]+, tR=1.48 min.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1C=C(Cl)C=C(C(OO)=[O:20])C=1.O>C(Cl)Cl>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:20][CH2:11]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=CCCCOC(=O)C(=C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: C=C(C)C(=O)OCCCC1CO1
Reaction time: 5 h

Procedure:
A solution of 4-pentenyl methacrylate (9 g) in methylene dichloride (15 ml) was added to a solution of m-CPBA (18 g) in methylene dichloride (150 ml) and the reaction was allowed to proceed for 5 hr. The reaction mixture was then poured into water, the organic phase was separated and then washed several times with a dilute solution of potassium carbonate. The reaction product was washed with water and then dried with anhydrous magnesium sulfate. A pure product was isolated by column chromatography on silica gel. Yield 7 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([C:18]3[N:22]([CH3:23])[N:21]=[N:20][CH:19]=3)[CH:17]=2)[C:11]([O:13]C)=[O:12])=[N:6][CH:7]=1.[OH-].[Na+].O.Cl>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([C:18]3[N:22]([CH3:23])[N:21]=[N:20][CH:19]=3)[CH:17]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2cnnn2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(-c3cnnn3C)c2)nc1
Reaction time: 16 h
Yield: 117 %

Procedure:
To a solution of methyl 3-(5-methylpyridin-2-yl)-5-(1-methyl-1H-1,2,3-triazol-5-yl)benzoate (85 mg, 0.276 mmol) in THF (5 mL) was added 1 M aqueous sodium hydroxide (0.827 mL, 0.827 mmol) and water (4 mL). After 16 h, the reaction was acidified to pH 1 by 1 M HCl. The solution was concentrated and dried under vacuum to give the hydrochloride salt of title compound (95 mg). MS 295.0 (M+1).
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.[C:6]1([C:12](=[O:14])[CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=1>>[C:6]1([C:12]([OH:14])([CH2:4][CH3:5])[CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=1
Reactant: CC[Zn]CC
Reactant: CC(=O)C1=CCCCC1
Product: CCC(C)(O)C1=CCCCC1
Yield: 56 %

Procedure:
Diethylzinc addition to 1-(1-cyclohexenyl)-ethanone (1.04 mL, 8.05 mmol) was performed according to general procedure A using 2 mol % of Compound B enantiomer (88 mg). The product was purified by column chromatography (hexanes/EtOAc: 96/4) to give 697.1 mg of 9 (56% yield, 96% ee) of a colorless oil: [60 ]D 20=+5.9 (c 3.0, MeOH). [Published [α]D 20=+0.7 (c 3.0, MeOH, 51% ee)].
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12)=[CH2:2].[H][H]>C(O)C.O.[Pd]>[CH2:1]([C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12)[CH3:2]
Reactant: [H][H]
Reactant: C=Cc1ncn2ccsc12
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCc1ncn2ccsc12
Yield: 25.1 %

Procedure:
To a solution of 5.0 g of 7-vinylimidazo[5,1-b]thiazole in 40 ml of ethanol and 8 ml of water was added 2.0 g of 10% Pd-C, and the mixture was stirred under the atmosphere of hydrogen at room temperature overnight. The catalyst was removed by filtration, and the filtrate was concentrated to a small volume. The concentrate was diluted with 10 ml of a saturated aqueous sodium hydrogen carbonate solution, and extracted with 100 ml of ethyl acetate. The organic layer was washed with aqueous saline and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:ethyl acetate=3:2) to give 1.27 g of 7-ethylimidazo[5,1-b]thiazole.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([S:10](CCC(OC)=O)(=[O:12])=[O:11])([CH3:9])[CH3:8])=[N:4][CH:3]=1.C[O-].[Na+].CC([O-])=O.[Na+].[NH2:27]OS(O)(=O)=O>C1COCC1.O>[Br:1][C:2]1[S:6][C:5]([C:7]([S:10]([NH2:27])(=[O:12])=[O:11])([CH3:9])[CH3:8])=[N:4][CH:3]=1
Reactant: COC(=O)CCS(=O)(=O)C(C)(C)c1ncc(Br)s1
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(c1ncc(Br)s1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
The product of Step 4 (2.50 g, 7.02 mmol) was taken up in THF (80 mL) at room temperature, and NaOMe (25% in MeOH, 1.52 g, 7.02 mmol) was added. After 30 min at room temperature, the suspension was evaporated to dryness, providing a white solid. The solid was taken up in water (50 mL), and a solution of NaOAc (3.17 g, 38.6 mmol) and hydroxylamine-O-sulfonic acid (3.97 g, 35.1 mmol) in water (25 mL) was added while cooling the reaction (0° C.). The reaction was vigorously stirred at room temperature overnight (a white solid precipitated after 15-30 min). The reaction was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. The resulting white residue was triturated with CH2Cl2 and filtered to provide 2-(5-bromo-1,3-thiazol-2-yl)propane-2-sulfonamide (1.58 g, 79%) as a white powder. ESI: [M+H]+ m/z 284.9/286.9.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][N:25]1[C:29](=[O:30])[CH2:28][NH:27][C:26]1=[O:31]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[CH2:28][C:29](=[O:30])[N:25]([CH3:24])[C:26]4=[O:31])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: CN1C(=O)CNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(=O)N(C)C4=O)nc3)CC2)c(C)c1
Yield: 40.4 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 127 and 3-methylimidazolidine-2,4-dione (46 mg) described in Preparation Example 214 and by the reaction and treatment in the same manner as in Example 536, the title compound (66 mg) was obtained.
Reaction SMILES: [CH:1]1([CH3:33])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([O:10][C:11]([CH:13]2[N:18]3[CH:19]=[CH:20][CH:21]=[C:17]3[C:16](=[O:22])[N:15]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=3[F:31])[C:14]2=[O:32])=[O:12])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CN(C)C=O>[C:45]([O:44][C:42](=[O:43])[CH2:41][C:13]1([C:11]([O:10][CH:3]2[CH:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][CH:1]([CH3:33])[CH2:2]2)=[O:12])[N:18]2[CH:19]=[CH:20][CH:21]=[C:17]2[C:16](=[O:22])[N:15]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=2[F:31])[C:14]1=[O:32])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1CCC(C(C)C)C(OC(=O)C2C(=O)N(Cc3ccc(Br)cc3F)C(=O)c3cccn32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCC(C(C)C)C(OC(=O)C2(CC(=O)OC(C)(C)C)C(=O)N(Cc3ccc(Br)cc3F)C(=O)c3cccn32)C1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
A mixture of 2-(4-bromo-2-fluorobenzyl)-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid (-)-menthyl ester (67.0 g), anhydrous potassium carbonate (36.0 g) and tert-butyl bromoacetate (33.0 g) in anhydrous dimethylformamide (200 ml) was stirred under the stream of nitrogen at 70° C. for 2.5 hours. After removal of the insoluble materials by filtration, the filtrate was poured into water and extracted with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was recrystallized from n-hexane to give the title compound (Diastereomer A) (23.5 g, 28.8%) as colorless crystals, mp 99°-100° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[N:19]1([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[N:19]1([CH:23]2[CH2:28][CH2:27][N:26]([CH2:11][C:9]3[S:8][C:6]4[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([N:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)[C:5]=4[N:10]=3)[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1
Reactant: C1CN(C2CCNCC2)C1
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Clc1nc(N2CCOCC2)c2nc(CN3CCC(N4CCC4)CC3)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
To a solution of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carbaldehyde (308 mg, 1.08 mmol) in DCE (8 mL) was added 4-azetidin-1-ylpiperidine (166 mg, 1.19 mmol). The resulting mixture was stirred at RT for 10 min then sodium triacetoxyborohydride (297 mg, 1.40 mmol) was added and stirring was continued for 18 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH and concentrated in vacuo to give the title compound as an off-white solid (263 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[CH:10]([CH:11]2[CH2:13][CH2:12]2)[CH2:9][NH:8][C:7](=[O:14])[C:6]1=[O:15].[C:24](=O)([O-])[O-].[Na+].[Na+].F[B-](F)(F)F.C([O+](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[CH:10]([CH:11]2[CH2:12][CH2:13]2)[CH2:9][N:8]=[C:7]([O:14][CH3:24])[C:6]1=[O:15]
Reactant: O=C([O-])[O-]
Reactant: O=C1NCC(C2CC2)N(Cc2cccc(C(F)(F)F)c2Cl)C1=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: COC1=NCC(C2CC2)N(Cc2cccc(C(F)(F)F)c2Cl)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
To an ice cooled solution of Intermediate 5 (400 mg, 1.2 mmol) and sodium carbonate (2.5 g, 23 mmol) in DCM (45 mL) was added triethyloxonium tetrafluoroborate (1M in DCM, 5.8 mL, 5.8 mmol) dropwise. The ice bath was removed and the reaction was stirred at rt for 1.5 h. Water was added and the mixture was extracted with DCM (×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford a yellow oil (432 mg, 100%), which was used directly without further purification. MS (ESI): mass calcd. for C17H18ClF3N2O2, 374.1; m/z found, 375.1 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:22][C:23](=[O:40])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]2[CH3:39])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][C:34]1[N:33]([C:29]2[CH:28]=[C:27]([C:25]3[CH2:24][C:23](=[O:40])[NH:22][C:9]4[CH:10]=[C:11]([C:14]#[C:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[CH:37]=[C:36]([CH3:38])[N:35]=1
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(C#Cc4ccccc4)ccc3NC(=O)OC(C)(C)C)c2)c(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cn(-c2cccc(C3=Nc4ccc(C#Cc5ccccc5)cc4NC(=O)C3)c2)c(C)n1

Procedure:
Prepared from (2-{3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example K60) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (57 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)([O-])=O.C(O)C.O.NN>O1CCOCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1
Reactant: O=[N+]([O-])c1cc(-c2ccncc2)c2occc2c1
Agent: [Ni]
Agent: NN
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccncc2)c2occc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(5-Nitro-1-benzofuran-7-yl)pyridine (125 mg, 0.520 mmol; Intermediate 11) was dissolved in 1,4-dioxane (15 mL). After addition of ethanol (20 mL), Raney-nickel (slurry in ethanol; 2 mL) and hydrazine hydrate (4 mL) were added and the mixture was left stirring at room temperature overnight. The product was used directly in the subsequent reaction after filtration through Celite and evaporation of solvent.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:15][CH2:14][C@:13]([OH:17])([CH3:16])[C:12]3([CH3:19])[CH3:18])=[C:8]([C:20]([NH2:22])=[O:21])[CH:7]=[N:6][N:5]2[CH:23]=1.C1(C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1P(C(C)(C)C)C(C)(C)C.C[C:54]([N:56](C)C)=O>[C-]#N.[C-]#N.[Zn+2].[Zn]>[C:54]([C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:15][CH2:14][C@:13]([OH:17])([CH3:16])[C:12]3([CH3:19])[CH3:18])=[C:8]([C:20]([NH2:22])=[O:21])[CH:7]=[N:6][N:5]2[CH:23]=1)#[N:56]
Reactant: CC(=O)N(C)C
Reactant: CC1(C)[C@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)CC[C@@]1(C)O
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Product: CC1(C)[C@H](Nc2c(C(N)=O)cnn3cc(C#N)cc23)CC[C@@]1(C)O
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-4-((1R,3R)-3-hydroxy-2,2,3-trimethylcyclopentylamino)pyrrolo[1,2-b]-pyridazine-3-carboxamide (Intermediate 51, 18 mg, 0.047 mmol), Zn(CN)2 (3 mg, 0.025 mmol), Pd(COCF3)2 1.6 mg, 0.005 mmol), 1,1′-binaphthyl-2-yldi-tert-butylphosphine (1.9 mg, 0.005 mmol), and zinc (0.62 mg, 0.09 mmol) in DMA (0.2 mL) was purged with N2 then heated at 90° C. for 8 h. The product was isolated via reverse-phase preparative HPLC to afford the title compound (1.1 mg) as a white solid. LCMS: 328.07 (M+H)+; HPLC (condition B): retention time=3.15 min. 1H NMR (MeOD, 400 MHz) δ 8.24 (s, 1H), 8.07 (d, J=1.8 Hz, 1H), 7.48 (d, J=1.8 Hz, 1H), 4.66 (t, J=9.0 Hz, 1H), 2.35 (m, 1H), 2.01 (m, 1H), 1.78 (m, 1H), 1.59 (m, 1H), 1.24 (s, 3H), 1.00 (s, 3H), 0.95 (s, 3H).
Reaction SMILES: C[Mg]I.[Mg].CI.BrC1C=CC([CH:14]([O:21][CH:22]([C:29]2[CH:34]=[CH:33][C:32](Br)=[CH:31][CH:30]=2)C2C=CC=CC=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17]C=2)=CC=1.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38].Cl>CCOCC.O>[CH2:40]([O:39][C:37]([C:19]1[CH:20]=[CH:15][C:14]([O:21][CH2:22][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:17][CH:18]=1)=[O:38])[CH3:41]
Reactant: Brc1ccc(C(OC(c2ccccc2)c2ccc(Br)cc2)c2ccccc2)cc1
Reactant: CCOC(=O)Cl
Agent: C[Mg]I
Agent: Cl
Agent: [Mg]
Solvent: CI
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 48 h

Procedure:
To a solution of methyl magnesium iodide prepared from magnesium (0.72g.; 0.03 mole) and methyl iodide (1.42g.; 0.01 mole) in ether (20ml) using standard methods, 4-bromo-phenylbenzyl ether in ether (20ml) was added dropwise with stirring then stirred until reaction was complete (1hr.). Ethyl chloroformate (3.24g.; 0.03 mole) in dry ether (20ml) was then added to the reaction mixture which was then boiled under reflux for 2 hrs. After cooling the reaction mixture was allowed to stand at room temperature for two days then worked up by the addition of water (40ml) and dilute hydrochloric acid (20ml). Separation of the ether layer followed by drying (anhyd. MgSO4), yielded 4-ethoxycarbonylphenoxy phenyl methane, m.p. 45° C.