Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)([CH2:12][OH:13])[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:25][C:26]([CH3:28])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:25][C:26]1([CH3:28])[O:11][CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)([CH2:14][O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH2:12][O:13]1
Reactant: COc1ccc(COCC(CO)(CO)c2ccc(F)c(F)c2)cc1
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc(COCC2(c3ccc(F)c(F)c3)COC(C)(C)OC2)cc1

Procedure:
2-(3,4-Difluorophenyl)-2-(4-methoxybenzyloxymethyl)propane-1,3-diol (16.5 g, 50 mmol), acetone (7.5 ml) and p-toluene sulphonic acid (100 mg) were heated to reflux in benzene (100 ml) and water was removed using Dean and Stark apparatus. After refluxing overnight the cooled solution was washed with saturated aqueous sodium bicarbonate solution and was dried over anhydrous magnesium sulphate. Evaporation gave 2,2-dimethyl-5-(3,4-difluorophenyl)-5-(4-methoxybenzyloxymethyl)-1,3-dioxane as a yellow oil (17.7 g, 97%, Nmr δ 7.2-6.8 (7H,m), 4.4 (2H,s), 4.05 (2H,d), 3.95 (2H,d), 3.8 (3H, s), 3.7 (2H,s), 1.4 (6H,s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[Mg].[CH3:19]I>CCOCC>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][CH2:8][C:7]([OH:10])([CH3:19])[C:6]=2[CH:11]=1
Reactant: O=C1COc2cc(N3CCCCC3)c(Cl)cc21
Reactant: CI
Agent: [Mg]
Solvent: CCOCC
Product: CC1(O)COc2cc(N3CCCCC3)c(Cl)cc21

Procedure:
A solution of 5.03 g (20.0 mmole) of crude 5-chloro-6-(piperidin-1-yl)-benzofuran-3(2H)-one in 30 ml of absolute ether is added dropwise at room temperature to a freshly prepared Grignard solution of 750 mg (30.8 mmole) of magnesium filings and 4.0 g (28.2 mmole) of methyl iodide in 30 ml of absolute ether. The whole is subsequently boiled under reflux for 45 minutes and poured onto ice/ammonium chloride. The ether phase is separated off and the aqueous phase is extracted twice more with ether. The organic phases are washed with water, combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. Chromatography over silica gel with chloroform/ethyl acetate (10:1) yields 5-chloro-3-hydroxy-3-methyl-6-(piperidin-1-yl)-2,3-dihydrobenzofuran in the form of an oil having an Rf of 0.24 [silica gel, chloroform/ethyl acetate (10:1)].
Reaction SMILES: [O:1]1CCC[CH2:2]1.C([N-]C(C)C)(C)C.[Li+].C1CCCCC1.[Cl:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[C:24]([O:31][CH3:32])[CH:25]=[CH:26][CH:27]=2)[N:22]=1.CN(C=O)C>C1COCC1>[Cl:20][C:21]1[C:30]([CH:2]=[O:1])=[CH:29][C:28]2[C:23](=[C:24]([O:31][CH3:32])[CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: C1CCOC1
Reactant: COc1cccc2ccc(Cl)nc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: COc1cccc2cc(C=O)c(Cl)nc12
Reaction time: 0.67 h

Procedure:
To a cooled solution of lithium diisopropylamide mono(tetrahydrofuran), 1.5 M sol. in cyclohexane (25.82 mL, 38.73 mmol) in 72 mL of THF at −75° C. was added a solution of 2-chloro-8-methoxyquinoline (5.0000 g, 25.82 mmol) in 26 mL of THF dropwise over 35 min (10:00 am˜10:35 am) with stirring and keeping the temperature below −65° C. After 40 min, to the cooled mixture was added DMF (2.999 mL, 38.73 mmol) dropwise and the mixture was stirred at −72° C. for 30 min. After 30 min, the reaction was quenched with NH4Cl (20 mL) and partitioned between EtOAc (150 mL) and water (100 mL). The combined organic layers were washed with water (100 mL×1), brine (100 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow solid. The yellow solid was purified by flash column chromatography on a silica gel column using 20% of EtOAc in hexane as eluent to give 2-chloro-8-methoxyquinoline-3-carbaldehyde as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.38 (1H, s), 8.92 (1H, s), 7.79 (1H, dd, J=8.4, 1.0 Hz), 7.67 (1H, t, J=8.0 Hz), 7.44 (1H, dd, J=7.8, 1.2 Hz), 4.00 (3H, s); LC-MS (ESI) m/z 222.1 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)=[C:4]2[CH:3]=[CH:2]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(OCC)(=O)C>[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([O:10][C:9]3[CH:8]=[CH:7][N:6]=[C:5]4[NH:1][CH:2]=[CH:3][C:4]=34)=[CH:12][CH:13]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ccnc3[nH]ccc23)cc1

Procedure:
After dissolving 90 mg of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline in ethyl acetate at room temperature, 0.05 ml of parafluorophenyl isocyanate was added dropwise. The precipitated white crystals were filtered out to obtain 65 mg of the target substance.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]([N:28]2[C:36]3[C:31](=[CH:32][C:33]([F:37])=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)=[O:27])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[F:37][C:33]1[CH:32]=[C:31]2[C:36](=[CH:35][CH:34]=1)[N:28]([C:26]([C:22]1[CH:21]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:25]=[CH:24][N:23]=1)=[O:27])[CH2:29][CH2:30]2
Reactant: O=C(c1cc(Cl)ccn1)N1CCc2cc(F)ccc21
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ccn1)N1CCc2cc(F)ccc21
Temperature: 130 °C
Reaction time: 30 h

Procedure:
314 mg (1.08 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloride were added to 300 mg (1.08 mmol) (4-chloropyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 373 mg (2.70 mmol) potassium carbonate in 5.0 mL N-methylpyrrolidone. The reaction mixture was stirred for 30 h at 130° C. Then the mixture was poured onto 100 mL water and extracted with EtOAc (3×100 mL). The combined organic phases were dried and evaporated down using the rotary evaporator. The residue was purified by preparative HPLC. The product fractions were combined and evaporated down i. vac. The residue was triturated with 30 mL diethyl ether. The precipitated solid was suction filtered and dried in the air.
Reaction SMILES: [F:1][C@@H:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][C@@H:12]2O)([CH3:10])[C:8](=[O:23])[CH2:7][CH2:6]3)[CH2:3]1.F[C@@H:25]1C2[C@](C)(C=CC(=O)C=2)C2[C@H]([C@H]3[C@@](CC=2)(C)C(=O)CC3)C1>>[F:1][C@@H:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH:12]=2)([CH3:10])[C:8](=[O:23])[C:7](=[CH2:25])[CH2:6]3)[CH2:3]1
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C(=O)CC[C@@H]12
Product: C=C1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)C1=O

Procedure:
Likewise diflorasone diacetate (6α,9α-difluoro-11β,17α,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17,21-diacetate) can be produced using the process of the present invention. First, 6α-fluoro-11β-hydroxyandrosta-1,4-diene-3,17-dione (U.S. Pat. No. 2,867,630) is dehydrated to 6α-fluoroandrost-1,4,9(11)-triene-3,17-dione by means well known to those skilled in the art, see Steroid Reactions, C. Djerassi, Holden-Day, San Francisco, 1963 p. 238 & 239. The 16-methylene group is then added by the process of U.S. patent application Ser. No. 349,490 to produce 6α-fluoro-16-methyleneandrosta-1,4,9(11)-triene-3,17-dione (IIIB) which is converted by the process of the present invention to 6α-fluoro-17α-hydroxy-16-methylenepregna-1,4,9(11)-triene-3,20-dione (VIIB). The 21-hydroxy function of the corticoids is next introduced as described above followed by transformation of the 16-methylene group to a 16β-methyl group also described above to give 6α-fluoro-17α,21-dihydroxy-16β-methylpregna- 1,4,9(11)-triene-3,20-dione 21-acetate which is acylated according to the procedure described in U.S. Pat. No. 4,154,748 (Examples 6 and 7) to produce 6α-fluoro-17α,21-dihydroxy-16β-methylpregna-1,4,9(11)-triene-3,20-dione 17,21-diacetate (U.S. Pat. No. 3,980,778, Example 6). 6α-fluoro-17α,21-dihydroxy-16β-methylpregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate is then converted to diflorasone diacetate by the process of U.S. Pat. No. 3,980,778 (Examples 7 and 8).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.C([Sn](CCCC)(CCCC)[C:33]1[S:37][CH:36]=[N:35][CH:34]=1)CCC>CC(N(C)C)=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>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:33]3[S:37][CH:36]=[N:35][CH:34]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cncs4)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Yield: 50 %

Procedure:
A suspension of 2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, (144 mg, 0.33 mmol), 5-tributylstannanyl-thiazole (187 mg, 0.5 mmol), and Pd(PPh3)4 (19 mg, 0.017 mmol) in anhydrous DMA was heated in a microwave at 150° C. for 10 mins. The crude reaction was loaded onto a preconditioned SCX cartridge, washing the cartridge with methanol and dichloromethane before eluting with 7N ammonia in methanol to give crude material. This was purified by on silica using 5% methanol in ethyl acetate as the eluent to give 152 as an off-white solid (80 mg, 50%). NMR (CDCl3, 400 MHz), 2.68-2.72 (4H, m), 2.83 (3H, s), 3.32-3.36 (4H, m), 3.88-3.93 (6H, m), 4.03-4.06 (4H, m), 7.32 (1H, s), 8.67 (1H, m), 8.84 (1H, s). MS: (ESI+): MH+=481
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:24][CH3:25])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27]>C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].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:3]([CH2:24][CH3:25])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]4[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=4)[C:26]#[N:27])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
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: Cc1ccccc1
Product: CCN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Yield: 4.2 %

Procedure:
Pd(PPh3)4 (40 mg, 0.10 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-ethyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (42 mg, 0.10 mmol) in toluene (5 mL), Na2CO3 (2 N, 2 mL), and 4-cyanophenylboronic acid (31 mg, 0.21 mmol). The mixture refluxed under Ar overnight. The reaction mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-(2′-amino-1′-ethyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (1.76 mg, 3%). 1H-NMR (MeOD): 1.31 (m, 3H), 2.55 (m, 2H), 3.84 (m, 2H), 5.26 (m, 1H), 5.86 (m, 1H), 7.14 (m, 1H), 7.47 (m, 6H), 7.59 (m, 1H), 7.28 (m, 2H), 7.90 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(Cl)=[S:10]>C1COCC1>[N:1]1[C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[O:8][C:9]=1[SH:10]
Reactant: S=C(Cl)Cl
Reactant: Nc1cccnc1O
Solvent: C1CCOC1
Product: Sc1nc2cccnc2o1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-amino-pyridin-2-ol (5.51 g, 50.0 mmol, 1.0 equiv) in anhydrous THF (175 mL) was added slowly thiophosgene (6.90 g, 4.57 mL, 60.0 mmol, 1.2 equiv) via syringe pump over a time period of 1 h. After stirring for 24 h at rt, excess thiophosgene was quenched by addition of a conc. solution of ammonium chloride (100 mL) and the majority of solvent was removed by evaporation under reduced pressure. A solution of 10 N NaOH (50 mL) was added and the residue extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4 yielding 5.2 g (69%) of crude product, which was used in the subsequent reaction step without further purification. 1H NMR (300 MHz, DMSO): δ 6.30 (t, J=7.0 Hz, 1H), 7.29 (dd, J=7.0 Hz, 1=1.8 Hz, 1H), 7.45 (dd, J=7.0 Hz, J=1.8 Hz, 1H), 13.04 (br s, 1H). MS (ISP): 152.9 [M+H]+.
Reaction SMILES: Br[CH2:2][CH:3]([N:8]=[C:9]=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].[NH3:11].O>COCCOC>[NH2:11][C:9]1[O:10][CH2:2][CH:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[N:8]=1
Reactant: N
Reactant: CC(C)CC(CBr)N=C=O
Solvent: O
Solvent: COCCOC
Product: CC(C)CC1COC(N)=N1
Reaction time: 0.25 h

Procedure:
21 g (0.1 mole) of 1-bromomethyl-3-methyl-butyl-isocyanate were added dropwise within 1 hour, at 8°-11° C, to a mixture of 25 ml of concentrated ammonia, 25 ml of water and 7 ml of 1,2-dimethoxyethane. Stirring was continued for 15 minutes at 12°-14° C, and then working up was carried out as described in Example 1. 11.6 g (82 percent of the theory) of oily 2-amino-4-isobutyl-2-oxazoline were obtained, which had been previously dissolved and reprecipitated from a mixture of isopropyl ether and hexane and finally evaporated in a high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].Br[CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[O:9][CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCOc1c(Cl)cccc1Cl
Temperature: 100 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
A mixture of 2,6-dichlorophenol (2.0 g, 12 mmol), N-(3-bromopropyl)phthalimide (3.29 g, 12 mmol) and potassium carbonate (1.69 g, 12 mmol) in anhydrous N,N-dimethylformamide (40 ml) was stirred at 100° C. for 4 hours under an atmosphere of nitrogen. The mixture was then poured into 200 ml of distilled water to give a white precipitate, which was filtered and washed with distilled water. The solid was dried in a vacuum desiccator to yield 4.17 g of N-[3(2,6-dichlorophenoxy)propyl] phthalimide which was dissolved in absolute ethanol (75 ml) and hydrazine hydrate (3 ml, 73 mmol) was added and the mixture refluxed for one hour. After cooling to room temperature, the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed on silica gel column and eluted with dichloromethane/methanol/ammonium hydroxide (9:2:0.2) to yield 3.2 g of 3-(2,6-dichorophenoxy)propylamine.
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([Cl:10])[N:4]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[NH2:2][C:3]1[NH:8][C:7](=[O:9])[C:6]([N+:11]([O-:13])=[O:12])=[C:5]([Cl:10])[N:4]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1nc(O)cc(Cl)n1
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1nc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Following the method of O'Brien and Cheng (J. Med. Chem. 1966, 9, 573), to a stirred solution of 10.0 g (61.1 mmol) 2-amino-6-chloro-4-pyrimidinol monohydrate in 46 ml 98% sulfuric acid was added dropwise 9 ml 65% nitric acid at a rate such that the reaction temperature remainded around 40° C. After the addition was complete, stirring was continued for 1 hour at room temperature. The reaction mixture was then poured onto 150 ml ice-water and the resulting crystals were collected by filtration and washed sequentially with water, ethanol and ether to afford 12.6 g (99%) 2-amino-6-chloro-5-nitro-3H-pyrimidin-4-one as a light yellow crystalline solid. ES-MS m/e (%): 191 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:16][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.CCO>[CH:10]12[O:15][CH:13]([CH2:12][CH2:11]1)[CH2:14][N:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:20]3[CH:21]=[CH:22][C:17]([NH2:16])=[CH:18][CH:19]=3)[N:7]=1)[CH2:9]2
Reactant: Clc1nccc(N2CC3CCC(C2)O3)n1
Reactant: Nc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1ccc(-c2nccc(N3CC4CCC(C3)O4)n2)cc1
Yield: 82 %

Procedure:
3-(2-Chloro-pyrimidin-4-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane (3, 564 mg, 2.5 mmol) and 4-aminophenylboronic acid, pinacol ester (602 mg, 2.75 mmol) are dissolved in toluene (25 mL) and EtOH (15 mL). A 2M solution of Na2CO3 is added (5 mL) and the mixture is degassed by leading a stream of nitrogen through the solution. Tetrakis(triphenylphosphine) palladium is added (144 mg, 5 mol %) and the mixture is heated under reflux for 48 hours. The mixture is diluted with EtOAc, washed with saturated NaHCO3, the organic phase is dried (MgSO4), filtered, and concentrated. The mixture is purified by silica gel chromatography using a gradient of ethyl acetate in hexanes (40-100%) to give 576 mg (2.04 mmol, 82%) of 4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]aniline. RT 1.51, M+H=283.1
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH2:21])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7].[CH:23]([S:26](Cl)(=[O:28])=[O:27])([CH3:25])[CH3:24]>>[CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][S:26]([CH:23]([CH3:25])[CH3:24])(=[O:28])=[O:27])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CN
Reactant: CC(C)S(=O)(=O)Cl
Product: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CNS(=O)(=O)C(C)C

Procedure:
From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid (3-methyl-butyl)amide (precursor 5c) and isopropylsulfonyl chloride, according to the general working procedure followed by purification by flash chromatography 16 mg of 2′-(isopropylsulfonylaminomethyl)biphenyl-2-carboxylic acid (3-methylbutyl)amide were obtained as an oil. MS (ES+): m/e 403 (M+1).
Reaction SMILES: [S:1]1[C:12]2[C:4](=[CH:5][CH:6]=[C:7]3[C:11]=2[C:10](=O)[C:9](=[O:14])[NH:8]3)[N:3]=[CH:2]1.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]/[N:24]=[C:10]2\[C:9](=[O:14])[NH:8][C:7]3[C:11]\2=[C:12]2[S:1][CH:2]=[N:3][C:4]2=[CH:5][CH:6]=3)=[CH:19][CH:18]=1
Reactant: O=C1Nc2ccc3ncsc3c2C1=O
Reactant: NNc1ccc(F)cc1
Agent: Cl
Product: O=C1Nc2ccc3ncsc3c2/C1=N/Nc1ccc(F)cc1
Yield: 49 %

Procedure:
Prepared according to Example 96 with 6H-1-thia-3,6-diaza-as-indacen-7,8-dione (Procedure A) and 4-fluorophenylhydrazine hydrochloride in 49% yield.
Reaction SMILES: [I:1][CH:2]1[CH:8]2[CH2:9][C:5]([CH3:11])([C:6](=[O:10])[NH:7]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.C(=O)(OC(C)(C)C)[O:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[I:1][CH:2]1[CH:8]2[CH2:9][C:5]([CH3:11])([C:6](=[O:10])[N:7]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH2:4][CH2:3]1
Reactant: CC12CCC(I)C(C1)NC2=O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(=O)C2(C)CCC(I)C1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-iodo-1-methyl-6-azabicyclo[3.2.1]octan-7-one, 52c, (9.5 g, 35.8 mmol) in CH2Cl2 (100 mL) was added DMAP (0.2 g, 1.8 mmol), triethylamine (15.0 mL, 107.5 mmol) and tert-butoxycarbonyl tert-butyl carbonate (7.8 g, 35.8 mmol). The reaction was stirred overnight at room temperature. The product was extracted into CH2Cl2 and water. The organic layer was concentrated in vacuo and the residue was purified via silica gel chromatography (4:1 Hexanes:EtOAc), yielding 7.6 g.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3]O.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>>[CH:5]([C@H:2]1[CH2:3][CH2:8][S:9](=[O:11])(=[O:10])[NH:1]1)([CH3:7])[CH3:6]
Reactant: CC(C)[C@H](N)CO
Reactant: CS(=O)(=O)Cl
Product: CC(C)[C@H]1CCS(=O)(=O)N1

Procedure:
Using (S)-2-amino-3-methyl-1-butanol (5.0 g) and methanesulfonyl chloride (7.7 mL) and by the reaction and treatment in the same manner as in Preparation Example 1, the title compound (1.55 g) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11]Br)=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:7]=1)=[O:5])[CH3:2].[CH:27]([NH2:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][NH:30][CH:27]([CH3:29])[CH3:28])=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1CBr
Reactant: CC(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1CNC(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 21 %

Procedure:
A mixture of 4-bromomethyl-1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester I-4b (200 mg, 0.44 mmol), isopropyl amine (26 mg, 0.44 mmol), K2CO3 (182 mg, 1.32 mmol) in CH3CN (5 ml) was stirred for 17 hours at room temperature. The reaction mixture was filtered to remove insoluble material and concentrated under vacuum. The residue was diluted with EtOAc and the organic solution was washed with H2O and sat'd aq. NaCl, dried, and concentrated in vacuo. The crude residue was purified on SiO2-gel chromatography using a solvent gradient of 20% EtOAc/hexanes to 75% EtOAc/hexanes to give the product (I-4c) as an amorphous solid (40 mg, 21%): +APCI MS (M+1) 432.2.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[F:19][C:20]1([F:28])[CH2:24][NH:23][C@@H:22]([C:25]([NH2:27])=[O:26])[CH2:21]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([N:23]3[CH2:24][C:20]([F:28])([F:19])[CH2:21][C@H:22]3[C:25]([NH2:27])=[O:26])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: NC(=O)[C@H]1CC(F)(F)CN1
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Agent: Cl
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)c1cc(OCC2CC2)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and (R)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 719267-96-6) as starting materials and isolated (160 mg, 51%); MS (ESI, m/z): 366.2 (M+H+).