Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]1(OCC)[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9])C.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C1C=CC=CC=1>[C:23]([C:22](=[C:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9])[C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=1)#[N:24]
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC1(OCC)CCCN1C
Solvent: c1ccccc1
Product: CN1CCCC1=C(C#N)c1ccc([N+](=O)[O-])cc1

Procedure:
Stir 29.9 g of 2,2-diethoxy-1-methylpyrrolidine and 28 g of 4-nitrophenylacetonitrile in 80 ml of benzene for one hour at room temperature. Distil off the solvent from the resulting reaction mixture under a vacuum to produce a crystalline residue. Recrystallize this residue from ethanol/diethyl ether. Concentrate the mother liquor to obtain a total of 29.5 g (70% of theory) of the title compound as dark-brown shiny crystals of m.p. 67°.
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@H:12]([CH3:13])[N:11]([O:14][CH2:15][C:16]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])[C:10]1=[O:25])=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C1(OC)C=CC=CC=1>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[NH2:8][C@H:9]1[CH:12]([CH3:13])[N:11]([O:14][CH2:15][C:16]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])[C:10]1=[O:25]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCC(=O)OC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC1[C@H](N)C(=O)N1OCC(=O)OC1CCCCC1

Procedure:
(3S-trans)-[[3-[(t-Butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid. cyclohexyl ester (2.23 g) prepared analogously to the procedure of example 91A was dissolved in a solution of 25 ml of trifluoroacetic acid and 2.5 ml of anisole at -10° C. The mixture was evaporated in vacuo 25 minutes later and the residue was stirred with ether, filtered off and dried over P2O5 to give colorless crystals of (3S)-[[3-amino-4 methyl2-oxo-1-azetidinyl]oxy]acetic acid, cyclohexyl ester, trifluoroacetate salt (yield 1.53). The salt (1.50 g) was suspended in 30 ml of acetonitrile. MSTFA (2.37 ml) was added at 0° C. and the solution was allowed to stand overnight. After evaporating in vacuo, the residue (1.75 g) was dissolved in dry tetrahydrofuran (25 ml), 1.4 g of (Z)-2-amino-α-methoxyimino)-4-thiazoleacetic acid, 1-hydroxybenzotriazole ester was added and the mixture was stirred at room temperature for 4 hours. Tetrahydrofuran was removed in vacuo at 30° C., the residue was taken up in ether, shaken with ice-cold aqueous NaHCO3 (in) and twice with cold water. The dried ethyl acetate layer was evaporated in vacuo. The resulting oil (2.14 g) chromatographed on silica gel with ethyl acetate to give 1.58 g of the title compound; melting point 85°-90° C. dec.
Reaction SMILES: Br[C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=[O:11])[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[C:14]([O:18]C(C)(C)C)(=[O:17])[CH:15]=[CH2:16].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:11]=[C:7]1[NH:6][C:5]2[N:12]=[CH:13][C:2](/[CH:16]=[CH:15]/[C:14]([OH:18])=[O:17])=[CH:3][C:4]=2[C:9](=[O:10])[NH:8]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=c1[nH]c(=O)c2cc(Br)cnc2[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCC#N
Product: O=C(O)/C=C/c1cnc2[nH]c(=O)[nH]c(=O)c2c1
Yield: 103.6 %

Procedure:
A suspension of 6-bromo-1H-pyrido[2,3-d]pyrimidine-2,4-dione (430 mg, 1.59 mmol) in propionitrile (8 mL) and DMF (2 mL) was treated with tert-butyl acrylate (0.93 mL, 6.4 mmol), (i-Pr)2EtN (0.6 mL, 3.3 mmol) and P(o-tol)3 (100 mg, 0.32 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (36 mg, 0.16 mmol) was added and the mixture was deoxygenated with a stream of Ar for 10 min. The mixture was heated to reflux for 17 h, then allowed to cool. The resulting precipitate was isolated by filtration to give the title compound (384 mg, 83%) as a gray solid: 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 11.54 (s, 1H), 8.96 (d, J=2.2 Hz, 1H), 8.53 (d, J=2.2 Hz, 1H), 7.65 (d, J=16.1 Hz, 1H), 6.72 (d, J=16.1 Hz, 1H), 1.49 (s, 9H); ESI MS m/e 290 (M+H)+.
Reaction SMILES: [NH:1]1CCCC[CH2:2]1.[NH2:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([OH:19])=[CH:13][C:9]=1[C:10](O)=[O:11].N1C=CC=NN=1>CO>[CH3:18][O:17][C:15]1[CH:16]=[C:8]2[C:9]([C:10]([OH:11])=[N:1][CH:2]=[N:7]2)=[CH:13][C:14]=1[OH:19]
Reactant: COc1cc(N)c(C(=O)O)cc1O
Reactant: C1CCNCC1
Agent: c1cnnnc1
Solvent: CO
Product: COc1cc2ncnc(O)c2cc1O
Temperature: 0 °C
Reaction time: 6 h
Yield: 107.1 %

Procedure:
Piperidine (3 mL, 31 mmol) was added to a mixture of 2-Amino-5-hydroxy-4-methoxy-benzoic acid (8.1 g, 44.26 mmol) and triazine (5.38 g, 66.4 mmol) in MeOH (60 mL). The reaction was then heated to reflux and stir for 6 hours. The reaction was cool to 0° C. The product was isolated by filtration and washed with cold MeOH to give 6.37 g (33.2 mmol, 75%) of desired product.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:4][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.91 g), ethyl 2-(2-hydroxyphenyl)acetate (1.00 g), anhydrous potassium carbonate (0.76 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate as an oil (1.35 g, 54%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][N:23]=[C:22]4[CH3:26])=[CH:17][CH:16]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2].OO.C(=O)([O-])[O-:30].[K+].[K+].O>CS(C)=O>[CH3:26][C:22]1[N:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:9]3[CH:8]=[C:7]([C:3]4([C:1]([NH2:2])=[O:30])[CH2:6][CH2:5][CH2:4]4)[CH:12]=[CH:11][CH:10]=3)=[CH:16][CH:17]=2)[CH:25]=[CH:24][N:23]=1
Reactant: Cc1nccn1-c1ccc(COc2cccc(C3(C#N)CCC3)c2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nccn1-c1ccc(COc2cccc(C3(C(N)=O)CCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 203.6 %

Procedure:
To a solution of 1-cyano-1-[3-[4-(2-methylimidazol-1-yl)benzyloxy]phenyl]-cyclobutane (2.90 g, 8.4 mmol) in DMSO (5 ml) cooled to 0° C. was added 30% H2O2 (2.0 ml) and potassium carbonate (0.4 g). The mixture was allowed to warm to room temperature and stirred overnight, and then stirred for 6 hrs at 60° C. Water (100 ml) was added and the mixture extracted with ethyl acetate (100 ml×3). The combined organic layers were extracted with 2N HCl (100 ml×2) and the aqueous layer washed with ethyl acetate (100 ml×3). The aqueous acidic layer was basified to pH=9 with 5N NaOH (150 ml) and extracted with ethyl acetate (100 ml×3). The combined organic extracts were washed with water (100 ml), brine (100 ml), dried (MgSO4) and concentrated in vacuo to afford crude product as white solid. Recrystallization from ethyl acetate gave 2.13 g (70%) of the titled compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[N:9])[CH:5]=[N:6][CH:7]=1.Cl.[CH2:11]([OH:14])[CH2:12][CH3:13]>>[NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[NH:9])[O:14][CH2:11][CH2:12][CH3:13])[CH:5]=[N:6][CH:7]=1
Reactant: N#Cc1cncc(N)c1
Reactant: CCCO
Agent: Cl
Product: CCCOC(=N)c1cncc(N)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 92 %

Procedure:
After 5-amino-3-cyanopyridine (380 mg, 3.19 mmol) was dissolved in 1-propanol (15 ml) and hydrogen chloride gas was passed into the solution at a temperature of 0°-5° C. for 15 minutes, the reactor was tight sealed for stirring the mixture at room temperature for 22 hours. After the completion of the reaction, the solvent was evaporated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution (50 ml) was added to the concentrated mixture to adjust the pH to alkaline. The mixture was extracted with chloroform (50 ml×3). The chloroform layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to silica gel column chromatography (Wako Gel C-200, 25 g), and elution was conducted with chloroform: methanol (8:1) to give propyl 5-amino-3-pyridinecarboximidate (526 mg, yield 92%) as a colorless oil.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(N(CCCC)CCCC)CCC.[CH:18]([N:21]1[CH2:25][CH2:24][NH:23][C:22]1=[O:26])=[CH:19][CH3:20]>C(OCC)(=O)C>[Cl:4][C:1]([N:23]1[CH2:24][CH2:25][N:21]([CH:18]=[CH:19][CH3:20])[C:22]1=[O:26])=[O:2]
Reactant: CC=CN1CCNC1=O
Reactant: O=C(Cl)Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Product: CC=CN1CCN(C(=O)Cl)C1=O
Reaction time: 8 h

Procedure:
First 6.3 pts. by wt. of phosgene and then 11.8 pts. by wt. of tri-n-butylamine are added to a suspension of 8.0 pts. by wt. of 1-propenyl-2-oxo-imidazolidine (prepared according to DAS (German Published Specification) No. 1,057,126) in 100 pts. by vol. of abs. ethyl acetate. The reaction mixture is stirred overnight and concentrated. The 1-chlorocarbonyl-2-oxo-3-propenyl-imidazolidine formed is used for Example 2 in a mixture with tributylammonium chloride. IR (liquid paraffin): 1,800 and 1,710 cm-1.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][C:4]=1[F:11])#[N:2].C(N(C(C)C)CC)(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[CH3:36][S:37]([O:40][C:41]1[CH:50]=[C:49]2[C:44]([CH:45]=[CH:46][CH:47]=[C:48]2[N:51]2[CH2:56][CH2:55][N:54]([CH2:57][CH2:58][C:59]3[N:60]=[CH:61][N:62](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:63]=3)[CH2:53][C:52]2=[O:83])=[CH:43][CH:42]=1)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:40][C:41]1[CH:50]=[C:49]2[C:44]([CH:45]=[CH:46][CH:47]=[C:48]2[N:51]2[CH2:56][CH2:55][N:54]([CH2:57][CH2:58][C:59]3[N:60]([CH2:7][C:6]4[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[C:4]([F:11])[CH:5]=4)[CH:61]=[N:62][CH:63]=3)[CH2:53][C:52]2=[O:83])=[CH:43][CH:42]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Oc1ccc2cccc(N3CCN(CCc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)CC3=O)c2c1
Reactant: N#Cc1ccc(CO)cc1F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc2cccc(N3CCN(CCc4cncn4Cc4ccc(C#N)c(F)c4)CC3=O)c2c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of the product from Step J (15 mg, 0.75 mmol) in 3 mL of dichloromethane at −78° C. was diisopropylethylamine (0.40 mL, 2.28 mmol), followed by triflic anhydride (0.128 mL, 0.76 mmol). After 20 minutes, a solution of the product from Step G (500 mg, 0.762 mmol) in 2 mL of dichloromethane was added, and the reaction was stirred at −78° C. for 30 minutes, and at room temperature for 1.5 hours. After concentrating the reaction in vacuo, 5 mL of methanol was added and the solution was heated at reflux for 30 minutes. The solution was concentrated in vacuo, acidified with 5% HCl solution, triturated with hexane, and partitioned between EtOAc and 20% NaOH solution. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to provide the titled product.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[OH-].[Na+].[C:18]([N:22]=[C:23]=[S:24])([CH3:21])([CH3:20])[CH3:19]>O.C(O)C>[C:1]([NH:4][CH:5]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:23]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[S:24])=[CH:13][CH:14]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C(=O)O)c1ccc(N)cc1
Reactant: CC(C)(C)N=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)NC(C(=O)O)c1ccc(NC(=S)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of α-acetamido-p-aminophenylacetic acid (1.04 g, 5 mmol) in water (5 ml) was added 10% NaOH until solution was effected. The solution was diluted with an equal volume of ethanol and then t-butyl isothiocyanate (1.64 g, 15 mmol) in ethanol was added. The reaction was stirred at room temperature overnight and then refluxed 24 hours. The ethanol was evaporated in vacuo and the aqueous phase was acidified and filtered. The aqueous filtrate was extracted with ethyl acetate. The dried extracts were evaporated to give α-acetamido-p-(3-t-butylthioureido)phenylacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH:12]=[O:13])[C:9]2[C:5](=[CH:6][N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=2)[CH:4]=1.[CH3:22][Mg]Br>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH:12]([OH:13])[CH3:22])[C:9]2[C:5](=[CH:6][N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[N:8]=2)[CH:4]=1
Reactant: COc1cc(C=O)c2nn(COCC[Si](C)(C)C)cc2c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1cc(C(C)O)c2nn(COCC[Si](C)(C)C)cc2c1
Temperature: 0 °C

Procedure:
To a solution of 5-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carbaldehyde (1.32 g, 4.31 mmol) in tetrahydrofuran (27 mL) at −78° C. was added methyl magnesiumbromide (3M in diethyl ether, 2.87 mL, 8.62 mmol). The reaction was allowed to gradually warm in the ice bath (ca. 1 h) to 0° C. The reaction which had been a suspension became a solution. The reaction was quenched by addition of saturated ammonium chloride and poured into diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated to give 1.44 g (quant.) as oil. 1H-NMR (CDCl3, 300 MHz) δ 7.92 (s, 1H), 6.88 (s, 1H), 6.75 (s, 1H), 5.63 (s, 2H), 5.26 (q, J=6 Hz, 1H), 3.8 (s, 3H), 3.6 (m, 2H), 1.65 (d, J=6 Hz, 3H), 0.9 (m, 2H), -0.06 (s, 9H); Mass spec.: 323.42 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]=[C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][CH2:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)[CH:5]=[CH:4][C:3]=1[OH:24].[CH2:25](C(CC)(CC)C([O-])([O-])[O-])[CH3:26]>>[CH:19]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]=3[C:9](=[CH:8][C:6]3[CH:5]=[CH:4][C:3]4[O:24][C:25]([CH3:26])=[N:1][C:2]=4[CH:7]=3)[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cc(C=C2c3ccccc3CCc3ccccc32)ccc1O
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Product: Cc1nc2cc(C=C3c4ccccc4CCc4ccccc43)ccc2o1
Temperature: 25 °C
Yield: 79 %

Procedure:
Dissolve 2-amino-4-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenol (60 mg, 0.191 mmol) in triethylorthoacetate (5 mL) and heat to reflux for 4 h. Cool to room temperature and concentrate in-vacuo to a brown oil. Chromatograph on 10 g silica gel eluting with 5% to 25% ethyl acetate/hexanes to afford S lmg (79%) of the title compound as a colorless oil. MS (ES) 338 (M+H); HPLC shows 98% purity.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1.[OH:25][CH2:26][CH2:27][NH2:28].CO.O>CN(C)C=O>[OH:25][CH2:26][CH2:27][NH:28][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(Sc2ccccc2)c(C#N)c1-c1ccccc1
Reactant: NCCO
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1c(NCCO)nc(Sc2ccccc2)c(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under argon, 0.7 g (2 mmol) of 2-chloro-4-phenyl-6-(phenylsulfanyl)-3,5-pyridine-dicarbonitrile (1st step) is dissolved in 2 ml of dimethylformamide (DMF), 0.27 g (4.5 mmol) of 2-hydroxyethylamine is added and the mixture is stirred at room temperature for 15 minutes. After addition of 2 ml of methanol, about 1 ml of water is added dropwise and the precipitate is filtered off with suction. The crystals are purified by boiling with 4 ml of methanol.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([F:22])[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=2)=[C:15]([F:22])[CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: COC(=O)c1cnccc1Cl
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cnccc1-c1ccc(Cl)cc1F
Yield: 46.1 %

Procedure:
To a stirred solution of methyl 4-chloronicotinate (7 g, 40.8 mmol), (4-chloro-2-fluorophenyl)boronic acid (7.11 g, 40.8 mmol) and cesium carbonate (26.6 g, 82 mmol) in a mixture of dioxane (60 mL) and water (8 mL) purged with nitrogen gas for 5 min, was added Pd(PPh3)4 (2.83 g, 2.448 mmol) and the resultant mixture was heated at 85° C. for 15 h. Water (30 mL) was added and the mixture was extracted with EtOAc (1×50 mL). The organic layer was washed with water (1×30 mL) and brine (1×30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel column (30% EtOAc in hexane) to give methyl 4-(4-chloro-2-fluorophenyl)nicotinate (5 g, 18.82 mmol, 40% yield). LCMS (ESI) m/e 266.7 [(M+H)+, calcd for C13H10ClFNO2 266.0]; LCMS retention time (Method C): tR=1.73 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.N1[CH:15]=[CH:14]N=C1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O>[Si:20]([O:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:14][CH3:15])=[O:9])[CH2:4][CH2:3]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C1CCC(O)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 25 g of 4-hydroxycyclohexanecarboxylic acid in 125 ml of N,N-dimethylformamide were sequentially added 21.7 g of imidazole and 39.6 ml of tert-butyl (diphenyl)silyl chloride under cooling with ice, followed by stirring the reaction mixture at room temperature for 3 hours. To the reaction mixture was added water and extracted with hexane. The resulting hexane solution was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound.
Reaction SMILES: FC1C=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4]C=1.[F:11][C:12]([F:30])([F:29])[O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:24][C@@H:23]3[C@@H:25]([NH2:28])[CH2:26][CH2:27][C@@H:22]3[CH2:21]2)=[CH:16][CH:15]=1.F[C:32](F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[C:5]([NH:8][C:9]([NH:28][C@@H:25]1[C@@H:23]2[C@@H:22]([CH2:21][N:20]([C:17]3[CH:16]=[CH:15][C:14]([O:13][C:12]([F:11])([F:29])[F:30])=[CH:19][CH:18]=3)[CH2:24]2)[CH2:27][CH2:26]1)=[O:10])([CH3:32])([CH3:6])[CH3:4]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(OC(F)(F)F)cc3)C[C@@H]21
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CC(C)(C)NC(=O)N[C@H]1CC[C@@H]2CN(c3ccc(OC(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting 2-isocyanato-2-methylpropane for 1-fluoro-4-isocyanatobenzene and (3aR,4S,6aS)-2-(4-(trifluoromethoxy)phenyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 716 Step 1 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 709: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.19 (d, J=9.0 Hz, 2H), 6.61-6.51 (m, 2H), 6.26 (d, J=7.1 Hz, 1H), 5.89 (s, 1H), 4.30-4.18 (m, 1H), 3.51 (dd, J=9.8, 3.2 Hz, 1H), 3.24 (dd, J=9.7, 7.8 Hz, 1H), 3.10 (dd, J=9.4, 7.8 Hz, 1H), 2.95 (dd, J=9.6, 3.5 Hz, 1H), 2.71-2.54 (m, 2H), 2.11-2.00 (m, 1H), 1.93-1.79 (m, 1H), 1.56-1.49 (m, 1H), 1.47 (s, 9H), 1.40-1.23 (m, 1H); MS (ESI+) m/z 386 (M+H)+.
Reaction SMILES: [CH:1]1([O:5][C:6]2[N:14]=[C:13]3[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]3[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)=[C:8]([NH2:23])[N:7]=2)[CH2:4][CH2:3][CH2:2]1.BrC1N(C2CCCCO2)[C:27]2[C:32](N=1)=C(N)N=C(OC1CCCCC1)N=2>>[CH:1]1([O:5][C:6]2[N:14]=[C:13]3[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]3[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)=[C:8]([NH2:23])[N:7]=2)[CH2:4][CH2:32][CH2:27][CH2:3][CH2:2]1
Reactant: Nc1nc(OC2CCCCC2)nc2c1nc(Br)n2C1CCCCO1
Reactant: COc1nc2c(N)nc(OC3CCC3)nc2n1C1CCCCO1
Product: COc1nc2c(N)nc(OC3CCCCC3)nc2n1C1CCCCO1

Procedure:
Prepared similarly to Intermediate 57 from 8-bromo-2-(cyclohexyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH:10]=[N:9]1)(=O)=O.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C)C=O.ClCCl>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([B:13]([OH:14])[OH:17])[CH:10]=[N:9]2)[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: CC1(C)OB(c2cnn(CCOS(C)(=O)=O)c2)OC1(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(CCn2cc(B(O)O)cn2)CC1
Temperature: 50 °C
Yield: 63.2 %

Procedure:
To a solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl methanesulfonate (0.080 g, 0.253 mmol) in 0.5 mL N,N-dimethylformamide was added 1-methylpiperazine (0.281 mL, 2.53 mmol) and the reaction was sealed under nitrogen and heated to 50° C. for 2.5 hours. The reaction mixture was diluted with dichloromethane (3 mL) and then loaded directly onto a silica gel column pre-wetted and eluted with 15% methanol in dichloromethane containing 1% ammonium hydroxide to afford 1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-ylboronic acid (0.038 g, 0.160 mmol, 63% yield) as a result of hydrolysis on silica in the presence of methanol and ammonium hydroxide. MS (apci) m/z=239.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14].CCN(CC)CC>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CNC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1ccc(Cl)nc1
Yield: 95 %

Procedure:
A solution of 6-chloropyridine-3-sulfonyl chloride (1 mmol), dimethylamine (2 mmol) and Et3N (2 mmol) in THF (2 mL) was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with brine, dried, filtered, and concentrated to give the title compound in 95% yield.