Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]1[C:18]2[N:19]=[CH:20][N:21]=[C:22]([NH2:23])[C:17]=2[C:16]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][C:25]=2[F:37])=[CH:15]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:37][C:25]1[CH:26]=[C:27]([O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:28]=[CH:29][C:24]=1[C:16]1[C:17]2[C:22]([NH2:23])=[N:21][CH:20]=[N:19][C:18]=2[N:14]([CH2:13][CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1Cn1cc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)cn2CC1CCCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a solution of 2-[4-amino-5-(2-fluoro-4-phenoxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-ylmethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg, 0.79 mmol) in 10 ml of DCM, was added TFA (10 ml). The reaction mixture was stirred at RT for 2 h. The mixture was then concentrated to give 5-(2-fluoro-4-phenoxy-phenyl)-7-pyrrolidin-2-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (320 mg), which was used in the next step without any further purification.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.Cl.[C:18]([NH:22][NH2:23])([CH3:21])([CH3:20])[CH3:19]>C(O)C>[C:18]([N:22]1[C:8]([NH2:9])=[CH:7][C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])=[N:23]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 31.5 %

Procedure:
A solution of pivaloylacetonitrile (300 mg, 2 mmol, 1.0 equiv), triethylamine (1.16 mL, 8.3 mmol, 3.2 equiv), and tert-butylhydrazine hydrochloride (1.03 g, 8.3 mmol, 3.2 equiv) in 10 mL of ethanol was heated at 100° C. in a sealed tube. After 4 days, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified via automated flash chromatography (40 g SiO2, ethyl acetate to 20% methanol in ethyl acetate) to afford the product as an off-white solid (123 mg, 20%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[N:24][C:23]=2[CH:32]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:18][C:19]3[CH:20]=[CH:21][C:22]4[O:26][C:25]([C:27]5[S:28][CH:29]=[CH:30][CH:31]=5)=[N:24][C:23]=4[CH:32]=3)=[CH:3][CH:4]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Reactant: ClCc1ccc2oc(-c3cccs3)nc2c1
Product: c1csc(-c2nc3cc(COc4ccc(CCCCn5ccnc5)cc4)ccc3o2)c1
Yield: 81 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with 5-chloromethyl-2-(2-thienyl)benzoxazole to give 5-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(2-thienyl)benzoxazole. The yield was 81%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 130-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].CCN(CC)CC.N1C=CC=CC=1.N#N.[SH2:26]>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4](=[S:26])[NH2:5]
Reactant: S
Reactant: N#Cc1c(F)cccc1Cl
Agent: N#N
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1c(F)cccc1Cl
Temperature: -7 °C
Reaction time: 16 h
Yield: 66.9 %

Procedure:
2-Chloro-6-fluorobenzonitrile (1230 g, 7.91 mol) was weighed into a 22 L jacketed glass reactor (without bottom drain), along with Et3N (1.5 L, 10.76 mol) and pyridine (2.4 L, 29.67 mol) and the stirring solution was cooled to −18° C. under a blanket of N2. The reactor N2 purge mineral oil bubbler was vented to a carboy containing 16 L of 12% bleach solution. Hydrogen sulfide gas (407 g, 11.94 mol) was introduced below the surface of the cold reactor solution over a period of 5.5 hrs. During this time the reactor temperature rose from −18 to −4° C. The solution was stirred overnight at −7° C. (16 hrs), sampled by GC to ensure complete conversion of 2,6-CFBN, then quenched by vacuum transfer of the reactor solution into a second 22 L flask containing 14 L of cold water stirring at 300 RPM (Note: Quenching into a well-stirred tank of cold water produces small white particles of easily filtered product). After the vacuum transfer was completed, another 2 L of cold water was added to the stirring slurry. The light yellow slurry of white solid was drained from the quench tank into bottles, and the solid product was collected by filtration through a course glass buchner funnel, followed by washing of the solid product with an excess of de ionized water. The white solid was air suction dried for 3 h, air dried in a glass pan overnight, then dried in a vacuum oven at 50° C. at 0.3 mm Hg for 8 hrs to give 1004 g (67%) of dry 2-chloro-6-fluorobenzenecarbothioamide, m.p. 153-157° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:19]([OH:25])[CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:26])[CH:3]=1.C([O-])(O)=O.[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19](=[O:25])[CH2:20][S:21]([CH3:24])(=[O:22])=[O:23])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:26])[CH:3]=1
Reactant: CS(=O)(=O)CC(O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)CC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl

Procedure:
The title compound is prepared from 1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-methanesulfonyl-ethanol 10t by the procedure described in Example 42, Step B except that the reaction mixture is not treated with saturated aqueous NaHCO3 containing sodium thiosulfate pentahydrate: MS APCI (+) m/z 460, 462 (M+, Br pattern) detected; 1H NMR (400 MHz, acetone-d6) δ 8.44 (s, 1H), 8.33 (s, 1H), 7.59 (s, 1H), 7.32 (d, 1H), 6.68 (dd, 1H), 5.00 (s, 1H), 3.15 (s, 3H); 19F NMR (376 MHz, acetone-d6) −132.97 (s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]2[N:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=O)=[N:17][CH:18]=2)[CH2:8]1.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][NH2:34].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]2[N:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]([NH:34][O:33][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][O:27]3)=[O:23])=[N:17][CH:18]=2)[CH2:8]1
Reactant: NOC1CCCCO1
Reactant: COc1cccc(CN2CC[C@@H](Nc3cnc(/C=C/C(=O)O)cn3)C2)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cccc(CN2CC[C@@H](Nc3cnc(/C=C/C(=O)NOC4CCCCO4)cn3)C2)c1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
To a mixture of (2E)-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylic acid (crude of reaction), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (166.4 mg), and 1-hydroxybenzotriazole (191.9 mg) in DMF (3.4 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (251 uL), which was stirred at room temperature for 16.5 hours. To the resultant was added sat. NaHCO3 aq. The mixture was extracted with CH2Cl2. The organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give (2E)-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (312 mg) as a yellow amorphous.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][C@@H:11]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[C@@H:15]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:14][CH2:13][C@H:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[F:35])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.O>[C:3]([O:7][C:8]([NH:10][C@@H:11]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[C@@H:15]([CH2:22][C:23]([OH:25])=[O:24])[CH2:14][CH2:13][C@H:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[F:35])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)C[C@H]1CC[C@@H](c2cccc(F)c2F)[C@H](NC(=O)OC(C)(C)C)c2cccnc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@@H](CC(=O)O)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C

Procedure:
A mixture of lithium hydroxide (11.2 mg, 0.468 mmol) and ethyl 2-((5S,6S,9R)-5-(tert-butoxycarbonylamino)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetate (118.1 mg, 0.256 mmol) in tetrahydrofuran (3 mL) and water (0.3 mL) was stirred at room temperature over night. LCMS showed complete conversion. The reaction was dried under high vacuum and the crude product (MS(ESI)[M+H+]=433.17) was used as is in the next step.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:9][CH:10]=3)[C@@:5]3([CH2:26][O:25][C:24]([NH2:27])=[N:23]3)[C:4]=2[CH:3]=1.[CH3:28][C:29]([CH3:33])([CH3:32])[C:30]#[CH:31].CN(C=O)C.C(NC(C)C)(C)C>O.CO.C(Cl)Cl.[OH-].[NH4+].[Cu]I.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.C(OCC)(=O)C>[CH3:28][C:29]([CH3:33])([CH3:32])[C:30]#[C:31][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:9][CH:10]=3)[C@@:5]3([CH2:26][O:25][C:24]([NH2:27])=[N:23]3)[C:4]=2[CH:3]=1
Reactant: C#CC(C)(C)C
Reactant: NC1=N[C@]2(CO1)c1cc(Br)ccc1Oc1ccc(Oc3ccccn3)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)C#Cc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(Oc3ccccn3)ccc1O2
Temperature: 90 °C
Yield: 64.3 %

Procedure:
(4S)-2′-Bromo-7′-(2-pyridinyloxy)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (380 mg, 0.896 mmol), copper(i) iodide (34.1 mg, 0.179 mmol), tetrakis(triphenylphosphine)palladium (104 mg, 0.090 mmol), 3,3-dimethylbut-1-yne (221 mg, 2.69 mmol) and DMF (3583 μL, 0.896 mmol) were combined in a sealable tube. The reaction vessel was flushed with argon then di-isopropyl amine (3766 μL, 26.9 mmol) was added and the vessel was sealed and heated at 90° C. for 2 hours. The reaction was diluted with water (50 mL) and poured into a separatory funnel containing ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water and then brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown foam that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to (4R)-2′-(3,3-dimethyl-1-butyn-1-yl)-7′-(2-pyridinyloxy)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (245 mg, 0.576 mmol, 64.3% yield) as a light yellow solid. MS m/z=426.2 [M+H]+. Calc'd for C26H24N3O3: 426.2.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]4[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[K+].[K+].[CH3:70][O:71][C:72]1[CH:73]=[C:74]([CH:76]=[CH:77][C:78]=1[O:79][CH3:80])[NH2:75]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:21][O:20][C:18]1[CH:17]=[CH:16][C:14]2[S:15][C:11]([C:8]3[N:6]4[N:7]=[C:2]([NH:75][C:74]5[CH:76]=[CH:77][C:78]([O:79][CH3:80])=[C:72]([O:71][CH3:70])[CH:73]=5)[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)=[CH:12][C:13]=2[CH:19]=1
Reactant: COc1ccc2sc(-c3cnc4ccc(Cl)nn34)cc2c1
Reactant: COc1ccc(N)cc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc2sc(-c3cnc4ccc(Nc5ccc(OC)c(OC)c5)nn34)cc2c1
Temperature: 110 °C
Yield: 59.8 %

Procedure:
To a solution of 6-chloro-3-(5-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (80 mg, 0.254 mmol, 1.0 equiv), xantphos (29 mg, 0.0506 mmol, 0.2 equiv), palladium acetate (6 mg, 0.0254 mmol, 0.1 equiv), and potassium carbonate (700 mg, 5.06 mmol, 20 equiv) in dioxane (5.0 mL) was added 3,4-dimethoxyaniline (47 mg, 0.304 mmol, 1.1 equiv) and heated to 110° C. for 2 h. Purification by column chromatography using 2% methanol in dichloromethane elution gave 62 mg, 0.152 mmol of the yellow solid, 60%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:12](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([O:10][CH3:12])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)cc(F)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1c(F)cc(Cl)cc1C=O
Reaction time: 18 h
Yield: 49.5 %

Procedure:
To 5 g (34 mmol) 4-Chloro-2-fluorophenol and 416 mg (3.41 mmol) 4-dimethylaminopyridine in 18 ml THF are added 3.7 ml (37.5 mmol) isopropyl isocyanate and the mixture is heated for 20 hours at 60° C. After cooling down to room temperature 2 M HCl is added and the aqueous phase is extracted with diethyl ether. The combined organic phases are washed with brine, dried over sodium sulfate and evaporated to yield 7.2 g isopropylcarbamic acid 4-chloro-2-fluorophenyl ester as the crude product. To 7.2 g (31 mmol) isopropylcarbamic acid 4-chloro-2-fluorophenyl ester and 5.1 ml tetramethylene diamine in 300 ml diethyl ether are added 5.9 ml (32.5 mmol) (trimethylsilyl)(trifluoromethan)sulfonate at room temperature. After 30 minutes the mixture is cooled to −70° C., 10.2 ml tetramethylene diamine and 27 ml of a 2.5 M n-BuLi solution are added successively. After one hour at −70°24 ml DMF in are added at −70° C. and the mixture is stirred another hour at −70° C. 130 ml ethanol and 36 ml of a 2 M aqueous NaOH are added and the reaction is warmed to ambient temperature over 18 hours. The reaction mixture is set acidic by addition of 100 ml 2 M aqueous HCl and partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, the combined organic phases are washed with brine, dried over sodium sulphate and evaporated. The crude product is purified by chromatography on silica gel to yield 1.1 g 5-chloro-3-fluoro-2-hydroxybenzaldehyde. 1.1 g (6.1 mmol) 5-chloro-3-fluoro-2-hydroxybenzaldehyde and 1.56 g (11.3 mmol) potassium carbonate are stirred vigorously in 11 ml DMF while 0.7 ml methyliodide are added. Stirring is continued for 18 hours and water is added. The aqueous phase is extracted with diethyl ether, the combined organic phases are dried over sodium sulfate and evaporated. The crude product is purified by chromatography on silica gel (ethyl acetate in hexane 0 to 10%) to yield 570 mg 5-chloro-3-fluoro-2-methoxybenzaldehyde. 1H-NMR (CDCl3); δ=4.10 (d, 3H), 7.35 (dd, 1H), 7.59 (m, 1H), 10.35 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]1[CH2:18][CH2:19][CH2:20][C:21](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13]1=[CH:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>C1COCC1.CO.[OH-].[Pd+2].[OH-]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]1[CH2:18][CH2:19][CH2:20][CH:21]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13]1=[CH:12]2
Reactant: CCOC(=O)C=C1CCCn2c1cc1cc(OCc3ccccc3)ccc12
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCCn2c1cc1cc(O)ccc12
Yield: 87.4 %

Procedure:
Ethyl 2-(2-(benzyloxy)-7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate (608 mg, 1.682 mmol) was dissolved in THF/MeOH (1:1) (4 mL). Ammonium formate (648 mg, 10.28 mmol) and palladium hydroxide (20 wt % Pd on carbon) (60 mg) was added under nitrogen protection. The reaction was heated at reflux for 5 h. The solid was filtered. The filtrate was concentrated, dissolved in ethyl acetate, washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to give the title compound (402 mg) as colorless oil. LCMS m/z=274.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (t, J=7.1 Hz, 3H), 1.50-1.61 (m, 1H), 1.98-2.08 (m, 1H), 2.08-2.22 (m, 2H), 2.55 (dd, J=15.6 and 8.7 Hz, 1H), 2.94 (dd, J=15.6, 5.5 Hz, 1H), 3.44-3.52 (m, 1H), 3.80-3.88 (m, 1H), 4.07-4.13 (m, 1H), 4.24 (q, J=7.1 Hz, 2H), 4.95 (s, 1H), 6.12 (s, 1H), 6.74 (dd, J=8.6, 2.4 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=O)[O:10][C:8](=[O:9])[C:7]=12.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:13][C:5]1[C:4]([Cl:14])=[C:3]([Cl:15])[C:2]([Cl:1])=[C:7]2[C:6]=1[CH2:11][O:10][C:8]2=[O:9]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: O=C1OCc2c(Cl)c(Cl)c(Cl)c(Cl)c21

Procedure:
Gazzetta Chimica Italiana, 87, p. 1147 (1957) describes, as a method for producing a halogen-substituted phthalide, for example, a method in which tetrachlorophthalic anhydride is reacted with lithium aluminum hydride to obtain 4,5,6,7-tetrachloro-1(3H)-isobenzofuranone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:16])[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[O:13]>O1CCOCC1.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C=CC(=O)c1cc(F)ccc1N
Agent: [Pd]
Solvent: C1COCCO1
Product: COC(=O)CCC(=O)c1cc(F)ccc1N
Yield: 89.9 %

Procedure:
A solution of 9.342 g (41.854 mM) of methyl 4-(2-amino-5-fluorophenyl)-4-oxo-2-butenoate in 200 ml of dioxane is hydrogenated in the presence of 10% of Pd-C at room temperature under atmospheric pressure. The reaction mixture is concentrated after removal of the catalyst. The resulting residue is chromatographed on a column of silica gel (463 g), eluting with toluene-ethyl acetate (19:1 v/v) to give 8.47 g of methyl 4-(2-amino-5-fluorophenyl)-4-oxobutyrate as orange crystals. Recrystallization from CH2Cl2 -Et2O-n-hexane gives 7.615 g (Yield: 80.8%) of the objective compound melting at 102°-103° C. as white needles.
Reaction SMILES: C([O:8][C:9](=[O:42])[C@H:10]([CH3:41])[CH2:11][C@H:12]([NH:26][C:27]([C:29]1[N:33](CC2C=CC=CC=2)[N:32]=[N:31][N:30]=1)=[O:28])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)C1C=CC=CC=1.C(OC(=O)[C@H](C)C[C@H](NC(C1N=NN(CC2C=CC=CC=2)N=1)=O)CC1C=CC(C2C=CC=CC=2)=CC=1)C1C=CC=CC=1>CO.[Pd]>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:19][C:14]([CH2:13][C@@H:12]([NH:26][C:27]([C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[O:28])[CH2:11][C@@H:10]([CH3:41])[C:9]([OH:42])=[O:8])=[CH:15][CH:16]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nnnn1Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nnn(Cc2ccccc2)n1)C(=O)OCc1ccccc1
Solvent: CO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nnn[nH]1)C(=O)O

Procedure:
A mixture of Intermediate 31: (2R,4S)-4-[(1-benzyl-1H-tetrazole-5-carbonyl)-amino]-5-biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester and (2R,4S)-4-[(2-benzyl-2H-tetrazole-5-carbonyl)-amino]-5-biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester (126 mg, 0.225 mmol) in MeOH is hydrogenated with 10% Pd/C for 6 h. The reaction mixture is concentrated and purified by reverse phase HPLC to give (2R,4S)-5-biphenyl-4-yl-2-methyl-4-[(1H-tetrazole-5-carbonyl)-amino]-pentanoic acid. HPLC Retention time 1.16 minutes (condition H); MS 380.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (d, J=7.20 Hz, 3H), 1.63-1.73 (m, 1H), 1.86-1.95 (m, 1H), 2.40-2.50 (m, 1H), 2.80-2.95 (m, 2H), 4.22-4.34 (m, 1H), 7.29-7.35 (m, 1H), 7.43 (dd, J=7.83, 7.83 Hz, 2H), 7.55 (d, J=10.23 Hz, 2H), 7.61-7.64 (2H, m), 9.16 (d, J=9.09 Hz, 1H), 12.03, (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Cl)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[CH3:14][O:15][CH2:16][CH2:17][NH2:18].CS(C)=O>C(OCC)(=O)C>[CH3:14][O:15][CH2:16][CH2:17][N:18]1[CH2:2][CH2:3][N:4]2[N:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]2[CH2:9]1
Reactant: O=[N+]([O-])c1cc(CCl)n(CCBr)n1
Reactant: COCCN
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCCN1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 120 °C
Yield: 75.1 %

Procedure:
A microwave vial equipped with a magnetic stirrer was charged with 296c (2.67 g, 10.0 mmol), 2-methoxyethanamine (2.25 g, 30.0 mmol), and DMSO (14 mL). The reaction mixture was heated at 120° C. under microwave irradiation for 1.0 h. It was cooled to room temperature and diluted with ethyl acetate (40 mL). The mixture was washed with water (3×15 mL). The organic layer was dried and filtered. The filtrate was concentrated under pressure and the residual was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 296d (1.7 g, 75%) as a yellow solid. MS-ESI: [M+H]+ 227.0
Reaction SMILES: [N+:1]([C:4]1[C:5](SC#N)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:22])([F:21])[F:20])=[N:8][CH:9]=1)([O-:3])=[O:2].[NH2:26][CH2:27][C@@H:28]1[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[N+:1]([C:4]1[C:5]([NH:26][CH2:27][C@@H:28]2[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]2)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:21])([F:20])[F:22])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC[C@H]1CC[C@@H](O)CC1
Reactant: N#CSc1nc(NCc2ccccc2OC(F)(F)F)ncc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@@H](O)CC1
Reaction time: 8 h

Procedure:
(5-Nitro-4-thiocyanato-pyrimidin-2-yl)-(2-trifluoromethoxy-benzyl)-amine (10 g, 26.9 mmol) was dissolved in DCM (100 ml). cis-4-aminomethyl-cyclohexanol (3.48 g, 26.9 mmol) and diisopropylethylamine (10 mL, 53.8 mmol) were added to the solution and stirred overnight. The reaction mixture was evaporated in-vacuo and purified by column chromatography (1% MeOH/99% CH2Cl2). The resulting solid was washed with cold methanol to give a pale yellow solid as cis-4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexanol (11.3 g, 25.6 mmol, 95.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:17][NH:18][C:19]3[N:24]=[C:23]([N:25]4[CH2:30][CH2:29]C(C)(O)CC4)[CH:22]=[CH:21][N:20]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.ClC1C=CN=C(NCC2N3C=C(Cl)C=CC3=NC=2C2C=CC=CC=2)N=1.N1CC[CH2:60][C@@H:59]1[CH2:63][OH:64]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:17][NH:18][C:19]3[N:24]=[C:23]([N:25]4[CH2:30][CH2:29][CH2:60][C@@H:59]4[CH2:63][OH:64])[CH:22]=[CH:21][N:20]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: CC1(O)CCN(c2ccnc(NCc3c(-c4ccccc4)nc4ccc(Cl)cn34)n2)CC1
Reactant: OC[C@H]1CCCN1
Agent: Clc1ccc2nc(-c3ccccc3)c(CNc3nccc(Cl)n3)n2c1
Product: OC[C@H]1CCCN1c1ccnc(NCc2c(-c3ccccc3)nc3ccc(Cl)cn23)n1

Procedure:
The title compound was prepared in the same fashion as that described for compound 187 from 4-chloro-N-((6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine and (R)-pyrrolidin-2-ylmethanol. m/e 435 (M+H)+.