Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][N:14]=[C:7]1[CH:6]=[CH:5]2.[SH:15][C:16]1[CH:17]=[C:18]([C:22]2([OH:28])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:12]1[N:8]2[C:9]3[C:4]([CH:5]=[CH:6][C:7]2=[N:14][CH2:13]1)=[CH:3][C:2]([S:15][C:16]1[CH:17]=[C:18]([C:22]2([OH:28])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1)=[CH:11][CH:10]=3
Reactant: Ic1ccc2c(c1)C=CC1=NCCN12
Reactant: OC1(c2cccc(S)c2)CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: OC1(c2cccc(Sc3ccc4c(c3)C=CC3=NCCN34)c2)CCOCC1
Temperature: 80 °C

Procedure:
2a (175 mg, 0.59 mmol) and 4-(3-mercapto-phenyl)-tetrahydro-pyran-4-ol (2b, 150 mg, 0.71 mmol) were combined in 1,4-dioxane (6 mL) and degassed with N2 for 10 minutes. iPr2NEt (0.33 mL, 1.8 mmol) was added, followed by Pd2dba3 (14 mg, 0.02 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (16 mg, 0.03 mmol). The mixture was degassed with N2 for an additional 10 minutes, and then heated to 80° C. for 24 hours. The reaction was cooled to room temperature, concentrated, and purified by silica gel chromatography (0-20% MeOH in EtOAc) to give the desired product, 2c.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][C:24]=1[F:31].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)=[CH:25][C:24]=1[F:31]
Reactant: OCc1ccc(Cl)c(F)c1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)c(F)c4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 4 h
Yield: 22.1 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (4-chloro-3-fluorophenyl)methanol (170 mg) and tributylphosphine (322 mg) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg) in THF (5 ml). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM, and the DCM layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (50 mg) as a white solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[OH:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH2:31][CH2:30]1>>[OH:28][CH:29]1[CH2:30][CH2:31][N:32]([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH:40]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:38][CH:37]=2)[CH2:33][CH2:34]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(CN2CCC(O)CC2)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCC(O)CC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((4-hydroxy-piperidin-1-yl)-methyl)-aniline Rf value: 0.1 (silica gel, methylene chloride/methanol=10:1) C29H29N3O3
Reaction SMILES: IC1C=CC(C2NC([C@@H](N3C(=O)[C@@H](CCC(O)=O)NC3=O)C(C)C)=NC=2)=CC=1.[Cl:29][C:30]1[CH:35]=[C:34]([I:36])[CH:33]=[CH:32][C:31]=1I.C1(C[C@H]2NC(=O)[N:44]([C@H:48]([C:57]3[NH:58][C:59]([C:63]4C=CC(I)=CC=4F)=[C:60](C)[N:61]=3)[C@H:49]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH3:50])C2=O)CC1.C([Mg]Br)C.C(O[C:81]([NH:83][C@H:84]([C:88]1[CH:93]=[CH:92][C:91]([O:94][CH2:95][C:96](=[O:100])N(C)C)=[CH:90][CH:89]=1)[C:85]([OH:87])=O)=[O:82])(C)(C)C.ClN1C(=O)CCC1=O>>[Cl:29][C:30]1[CH:35]=[C:34]([I:36])[CH:33]=[CH:32][C:31]=1[C:60]1[NH:61][C:57]([C@@H:48]([N:44]2[C:85](=[O:87])[C@@H:84]([C:88]3[CH:89]=[CH:90][C:91]([O:94][CH2:95][CH2:96][OH:100])=[CH:92][CH:93]=3)[NH:83][C:81]2=[O:82])[C@H:49]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH3:50])=[N:58][C:59]=1[CH3:63]
Reactant: CN(C)C(=O)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: Clc1cc(I)ccc1I
Reactant: Cc1nc([C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](CC3CC3)C2=O)[nH]c1-c1ccc(I)cc1F
Agent: CC(C)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CCC(=O)O)C1=O
Agent: CC[Mg]Br
Agent: O=C1CCC(=O)N1Cl
Product: Cc1nc([C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(OCCO)cc3)C2=O)[nH]c1-c1ccc(I)cc1Cl

Procedure:
Prepared by the same method as described in example 1 except that (i) in step 94-A 2-chloro-1,4-diiodo-benzene was used in place of 2-fluoro-1,4-diiodo-benzene; (ii) in step 93-B ethylmagnesium bromide was used in place of methylmagnesium chloride and (iii) chlorination of the 5-position of the imidazole ring with N-chlorosuccinimide in step 94-F was omitted. HR-MS: calcd for C30H28ClIN4O4 [M+H+] 671.0917. Found 671.0917.
Reaction SMILES: [O:1]1[CH2:6][CH2:5]OCC1.[OH-:7].[Na+].[CH3:9][N:10]([CH3:27])[CH2:11][CH2:12][N:13]([CH3:26])[C:14]1[CH:21]=[CH:20]C(C#N)=[CH:16][C:15]=1[C:22]([F:25])([F:24])[F:23]>O>[CH3:9][N:10]([CH3:27])[CH2:11][CH2:12][N:13]([CH3:26])[C:14]1[CH:21]=[CH:20][C:5]([C:6]([OH:1])=[O:7])=[CH:16][C:15]=1[C:22]([F:25])([F:24])[F:23]
Reactant: CN(C)CCN(C)c1ccc(C#N)cc1C(F)(F)F
Reactant: C1COCCO1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CN(C)CCN(C)c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 95 °C
Reaction time: 16 h

Procedure:
A mixture consisting of 25 mL dioxane, 12.5 mL water and 9.4 mL 2M aqueous sodium hydroxide solution is added to 4-[[2-(dimethylamino)ethyl]methylamino]-3-(trifluoromethyl)-benzonitrile (1.35 g, 5 mmol) and the reaction mixture shaken in for 16 hours at 95° C. After cooling, the mixture is evaporated is evaporated to dryness under reduced pressure. The resulting residue is treated with water, the pH adjusted to ˜5 with 1M hydrochloric acid and the mixture evaporated to dryness under reduced pressure. The solid residue is treated with methanol, the suspension filtered and the filtrate evaporated to yield the title compound.
Reaction SMILES: O[N:2]1[CH2:7][CH2:6][CH2:5][C:4]2[S:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]1=2.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][N:2]1[CH2:7][CH2:6][CH2:5][C:4]2[S:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]1=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1csc2c1N(O)CCC2
Product: CCOC(=O)c1csc2c1N(Cl)CCC2

Procedure:
A solution of 2.25 g of ethyl 4-hydroxy-6,7-dihydrothieno[3,2-b]pyridine-3-carboxylate (see example 20) in 10 ml of phosphorous oxychloride is refluxed for 1 hour. After cooling excess reagent is distilled off under reduced pressure, the residue dissolved in 40 ml of dichloromethane and washed with 20 ml of 2N NaOH solution and 20 ml of water. After drying over magnesium sulfate, the filtrate is slurried with 5.00 mg of charcoal, filtered and evaporated to dryness. The residue is recrystallized from ether/pentane to yield ethyl 4-chloro-6,7-dihydrothieno[3,2-b]pyridine-3-carboxylate, mp69°-70°.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:14])[CH:10]=2)[CH:5]=1)(=O)[CH3:2].[H-].[Na+].C(OP([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(OCC)=O)C>C1COCC1>[CH3:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[C:4](/[C:1](/[CH3:2])=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:13]=[CH:12]2
Reactant: CC(=O)c1ccc2cc(C)ccc2c1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)c1ccc2cc(C)ccc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 46.3 %

Procedure:
2-Acetyl-6-methylnaphthalene (5.08 g) was added to a cooled (0° C.) mixture of NaH (60% oil dispersion, 2.34 g) in THF (150 ml) and ethyl diethylphosphonoacetate (14.12 g) and the mixture was stirred at room temperature for 14 hours. The reaction was quenched by the addition of water. The organic layer was washed with water and brine, dried and concentrated. Recrystallization of the residue from hexane gave the titled compound (3.25 g) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=[O:6].[CH2:12]1COCC1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH3:12])[CH:7]=[C:8]([F:11])[C:9]=1[F:10]
Reactant: C1CCOC1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Product: CC(O)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An ethereal solution (17.41 ml, 52.24 mmol, 3M) of MeMgEr was slowly added at −78° C. to a solution of 3,4,5-trifluorobenzaldehyde (6.96 g, 43.53 mmol) in THF (125 ml). The reaction mixture was stirred at room temperature for 16 h and was cooled (0° C.) and was quenched, sequentially, with excess ethyl acetate (10 ml) and water (5 ml). Excess anhydrous MgSO4 (5 g) was added and stirred for 30 minutes at room temperature. The suspension was filtered over celite and the solids were washed with ethyl acetate (2×25 ml). The combined filtrate was evaporated to obtain the product in quantitative yield (7.65 g).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@H:5]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:6][NH:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[C:11]2[C:22](=[O:25])[NH:23][CH2:24][C:10]=2[CH:9]=1)[CH3:2].[B-](F)(F)(F)[F:35].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][CH2:4][C@H:5]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:6][NH:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[C:11]2[C:22](=[O:25])[NH:23][CH2:24][C:10]=2[C:9]=1[F:35])[CH3:2]
Reactant: CCOC[C@@H](CNc1cc2c(c(Nc3cccc(C)c3)n1)C(=O)NC2)NC(=O)OC(C)(C)C
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC[C@@H](CNc1nc(Nc2cccc(C)c2)c2c(c1F)CNC2=O)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a chilled solution of (R)-tert-butyl 1-ethoxy-3-(3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)propan-2-ylcarbamate (94.7 mg, 0.208 mmol) in CH2Cl2 (5 mL) at 0° C. was added SELECTFLUOR® (73.6 mg, 0.208 mmol). The mixture was left stirring in an ice bath and warmed slowly to RT for 6 h. Afterwards, the mixture was diluted with EtOAc (10 mL) and washed with saturated aq NaHCO3 (5 mL) followed by water (5 mL) and brine (5 mL). The organic layers were combined, dried over Na2SO4, and concentrated to a brown residue. The resulting crude material was reconstituted in MeOH/DCM (5 mL) and purified via preparative HPLC. The collected fractions were collected and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3 and washed with EtOAc (2×200 mL), dried over Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation to yield the title compound. [M+H] calc'd for C24H32FN5O4, 474; found, 474.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH2:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br.C(O)(=O)C>O>[NH2:13][C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(O)cc(C(F)(F)F)c1
Temperature: 140 °C
Yield: 81 %

Procedure:
To a round bottom flask was added 3-methoxy-5-trifluoromethyl-phenylamine (1.0 g, 5.23 mmol), 10 mL HBr (49% aq.), and 8 mL glacial acetic acid. A reflux condenser was attached and the solution heated to 140° C. for 20 h. The reaction was then diluted with water and neutralized to ˜pH 7 by slow addition of saturated NaHCO2. The aqueous solution was then extracted into EtOAc twice. The organic layers were combined, washed once with brine, dried over Mg2SO4, filtered, and concentrated in vacuo to yield the title compound as a tan solid (750 mg). MS (M+H)+=178; Calc'd 177.12 for C7H6F3NO.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:17]([O-])=O.C(NS(C1C(Cl)=C([N+]([O-])=O)C=C(C=1)C(O)=O)(=O)=O)CCC.N[C:42]1[CH:43]=[C:44]([CH:48]=[C:49](S(=O)(=O)NC)[C:50]=1[O:51]C1C=CC=CC=1)C(O)=O.CNC.C(N)CCC.NC1CC(S(=O)(=O)NCCCC)(OC2C=CC=CC=2)C=C(C(O)=O)C=1>>[NH2:17][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13])[C:2]=1[O:51][C:50]1[CH:49]=[CH:48][CH:44]=[CH:43][CH:42]=1)[C:6]([OH:8])=[O:7]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: CNS(=O)(=O)c1cc(C(=O)O)cc(N)c1Oc1ccccc1
Agent: CCCCNS(=O)(=O)C1(Oc2ccccc2)C=C(C(=O)O)C=C(N)C1
Agent: CCCCNS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: CNC
Solvent: CCCCN
Product: CN(C)S(=O)(=O)c1cc(C(=O)O)cc(N)c1Oc1ccccc1

Procedure:
The starting materials, 4-chloro-5-dimethylsulphamyl-3-nitro-benzoic acid and 5-n-butylsulphamyl-4-chloro-3-nitro-benzoic acid, were new and were obtained as described for the starting material of Example 2 by substituting aqueous dimethylamine (3.6 g containing 1.5 g of dimethylamine) and n-butylamine (2.2 g), respectively, for the aqueous methylamine, and had melting points of 233-235° C, and 196-198° C, respectively.
Reaction SMILES: O[CH2:2][C:3]1[CH:14]=[CH:13][C:6]2[O:7][CH2:8][C:9](=[O:12])[N:10]([CH3:11])[C:5]=2[CH:4]=1.C([C:17]1[C:21]([C:22]([O-:24])=[O:23])=[CH:20][NH:19][N:18]=1)C.[C:25]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:26]=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:11][N:10]1[C:9](=[O:12])[CH2:8][O:7][C:6]2[CH:13]=[CH:14][C:3]([CH2:2][N:18]3[CH:17]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:20]=[N:19]3)=[CH:4][C:5]1=2
Reactant: CCc1n[nH]cc1C(=O)[O-]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CN1C(=O)COc2ccc(CO)cc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2ccc3c(c2)N(C)C(=O)CO3)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred, cooled (0° C.) solution of 6-(hydroxymethyl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (122 mg, 0.631 mmol), ethylpyrazol-4-carboxylate (88 mg, 0.631 mmol) and triphenylphosphine (248 mg, 0.947 mmol) in THF (5 ml) was added dropwise a 40% solution of DEAD in toluene (0.375 ml, 0.947 mmol). The reaction mixture was stirred for 2 h at 0° C., then over night at 20° C. Saturated aqueous NaHCO3 was added and the mixture was extracted with AcOEt. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound. MS (Method A) [M+H]+=316.9
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.C(OCC)(=O)C.[H][H]>CO.[Rh]>[O:1]1[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH:3]([C:10]([O:12][CH3:13])=[O:11])[CH2:2]1
Reactant: COC(=O)c1cocc1C(=O)OC
Reactant: [H][H]
Agent: [Rh]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C1COCC1C(=O)OC
Reaction time: 8.5 h
Yield: 98.7 %

Procedure:
Dimethyl 3,4-furandicarboxylate (5.20 g, 28.0 mmol) was combined with 5% Rhodium/C in methanol (30 mL) and ethyl acetate (10 mL) in a Parr shaker bottle. The reaction was charged to 50 psi hydrogen and was shaken for 8.5 h. The reaction was filtered over celite, concentrated in vacuo to give the dimethyl 3,4-tetrahydrofuran dicarboxylate (5.2 g, 100%) as an oil MS (M−CH3OH)+=156.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[Br:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:20][CH:19]=[C:18]([C:29]([OH:31])=O)[CH:17]=2.[CH3:32][N:33]([CH3:38])[S:34]([NH2:37])(=[O:36])=[O:35].C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O>[Br:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:20][CH:19]=[C:18]([C:29]([NH:37][S:34]([N:33]([CH3:38])[CH3:32])(=[O:36])=[O:35])=[O:31])[CH:17]=2
Reactant: CN(C)S(N)(=O)=O
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
Carbonyl diimidazole (6.0 g, 37 mmol) was added to a solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (10 g, 31 mmol) in THF (30 mL) and the reaction was stirred at 50° C. for 2 h (a white precipitate had formed). The reaction was cooled to rt and treated with N,N-dimethylsulfamide (4.6 g, 37 mmol). Then DBU (6.7 mL) in THF (20 mL) was added dropwise and the reaction was stirred at rt overnight. The solution was diluted with EtOAc (300 mL) and washed with H2O (150 mL), 1N aqueous HCl (2×100 mL) and brine (100 mL). The combined aqueous layers were extracted with EtOAc (200 mL) and the organic layer was washed with 1N aqueous HCl (150 mL) and brine (50 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to an oil. The oil was diluted with Et2O and concentrated to a semi-solid which was triturated with Et2O to yield 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (6.1 g, 14 mmol, 46%) as a light yellow solid. The organic washes where concentrated and purified by silica gel chromatography (20-35% EtOAc/hexanes) to yield additional 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (2.5 g, 6 mmol, 19%). 1HNMR (500 MHz, CD3OD) δ 7.90 (d, J=1.8 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.56 (dd, J=1.8, 8.5 Hz, 1H), 3.01 (s, 6H), 2.93-2.86 (m, 1H), 2.04-1.76 (m, 7H), 1.54-1.37 (m, 3H). LCMS: m/e 426 (M−H)−, ret time 1.55 min, column A, 2 minute gradient.
Reaction SMILES: C([C:3]1[C:4]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:26])[CH:22]=[C:23]([CH3:25])[CH3:24])[CH:17]=[CH:18][CH:19]=2)=[N:5][N:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH:7]=1)=O.[CH3:27][N:28]([CH2:36][CH2:37][NH:38][CH3:39])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].[BH3-][C:41]#N.[Na+].O>CO.[Cl-].[Cl-].[Zn+2]>[CH3:27][N:28]([CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][C:3]1[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:26])[CH:22]=[C:23]([CH3:25])[CH3:24])[CH:15]=2)=[N:5][N:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH:7]=1)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: [BH3-]C#N
Reactant: CC(C)=CC(=O)Nc1cccc(-c2nn(C3CCCCO3)cc2C=O)c1
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CO
Solvent: O
Product: CC(C)=CC(=O)Nc1cccc(-c2nn(C3CCCCO3)cc2CN(C)CCN(C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 46 %

Procedure:
To a solution of N-(3-(4-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)phenyl)-3-methylbut-2-enamide (0.210 g, 0.00062 mol) in methanol (4 mL) were added TEA (313 mg, 0.0031 mol), ZnCl2 (0.008 g, 0.000062 mol) and tert-butyl methyl(2(methylamino)ethyl)carbamate (0.138 g, 0.00074 mol). The reaction mixture was stirred at rt for 45 min. NaCNBH3 (0.580 g, 0.00913 mol) was added and stirred for 2 h at rt. The reaction was poured into water (100 mL) and extracted with EtOAc (100 mL×2). The combined extracts was washed with brine (200 mL), dried over sodium sulphate and concentrated under vacuum. The residue was purified by SGC using DCM:MeOH (0%-4%) as eluent to obtain tert-butyl methyl(2-(methyl((3-(3-(3-methylbut-2-enamido)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)amino)ethyl)carbamate (0.150 g, Yield: 47%). LCMS (ESI): RT=2.03 min, m/z=526.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:14])[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:14][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[NH:25][CH:26]=[N:27]4)[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:6]=2[CH:21]=1
Reactant: COC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COCC(Nc1ncnc2nc[nH]c12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Yield: 32.4 %

Procedure:
A mixture of (R)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)-2-methoxyethylamine (110 mg, 0.39 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (93 mg, 0.39 mmol) and DIPEA (340 mL, 1.9 mmol) in n-butanol (2.5 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 171 as a white solid (51 mg, 32%). LCMS (Method B): RT 3.52 min [M+H]+ 404.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.25-8.01 (2H, m), 7.87 (1H, s), 7.77-7.47 (6H, m), 7.15-7.05 (1H, m), 6.87 (1H, dd, J=8.93, 2.37 Hz), 5.64 (1H, s), 3.84 (2H, d, J=6.60 Hz), 3.14 (3H, s). Signals split due to presence of rotamers/tautomers
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[NH:4][N:3]=1.C(SCCSCCSC1N=C2N(N=1)[C:38]([OH:41])=[CH:37][C:36]([CH3:42])=N2)CCCCC>>[CH2:11]([S:10][CH2:9][CH2:8][S:7][C:5]1[N:6]=[C:2]2[N:3]([N:4]=1)[C:38]([OH:41])=[CH:37][C:36]([CH3:42])=[N:1]2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCSCCSc1nc(N)n[nH]1
Reactant: CCCCCCSCCSCCSc1nc2nc(C)cc(O)n2n1
Product: CCCCCCCCSCCSc1nc2nc(C)cc(O)n2n1

Procedure:
Compound 14 was prepared from Compound 7 using a procedure analogous to that described previously for Compound 20. Recrystallization of the crude product from ethyl acetate gave a 59% yield of a white solid, m.p. 125.5°-127° C. Analysis: Calculated for C16H26N4OS2 : C, 54.21; H, 7.39; N, 15.80. Found: C, 53.51; H, 7.21; N, 15.72.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16]([NH:17][C@H:18]([CH3:23])[C:19]([F:22])([CH3:21])[CH3:20])=[C:15]([C:24]([NH2:26])=[O:25])[CH:14]=[N:13][N:12]3[CH:27]=2)[CH:6]=[CH:7][CH:8]=1.[C:28]([N:35]1[CH:39]=[CH:38]N=C1)(N1C=CN=C1)=[O:29].[CH3:40]CN(CC)CC.C1(N)CC1>C(Cl)CCl>[CH:39]1([NH:35][C:28]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[C:11]4[C:16]([NH:17][C@H:18]([CH3:23])[C:19]([F:22])([CH3:21])[CH3:20])=[C:15]([C:24]([NH2:26])=[O:25])[CH:14]=[N:13][N:12]4[CH:27]=3)[CH:6]=[CH:7][CH:8]=2)=[O:29])[CH2:38][CH2:40]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(CC)CC
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3cccc(CN)c3)cc12)C(C)(C)F
Agent: NC1CC1
Solvent: ClCCCl
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3cccc(CNC(=O)NC4CC4)c3)cc12)C(C)(C)F
Temperature: 80 °C
Yield: 62.8 %

Procedure:
A solution of (R)-6-(3-(aminomethyl)phenyl)-4-(3-fluoro-3-methylbutan-2-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 68, 18.5 mg, 0.050 mmol), 1,1′-carbonyldiimidazole (16.24 mg, 0.100 mmol), and Et3N (0.017 mL, 0.125 mmol) in C1CH2CH2Cl (1 mL) was stirred at 23° C. for 1 hr then cyclopropanamine (8.67 μl, 0.125 mmol) was added and the resulting mixture was heated to 80° C. for 30 minutes. The reaction was cooled, concentrated and redissolved in 1 mL of MeOH with a few drops of DMF. The reaction mixture was purified by reverse-phase preparative HPLC (condition C) to yield the title compound (14.2 mg, 61%). HPLC (condition H): retention time=1.42 minute. LC/MS (M+H)+=453.4.