Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]([N:26](OC)C)=O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH:9]=2)=[CH:6][N:7]=1.[CH3:30][Mg]Cl.Cl.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>C1COCC1.C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[C:14]([NH:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=[N:4][C:3]=1/[C:24](=[N:26]/[NH:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=1)/[CH3:30]
Reactant: C[Mg]Cl
Reactant: COc1ccc(NN)cc1
Reactant: CON(C)C(=O)c1nc(-c2cccc(C(=O)NCc3ccccc3)c2)cnc1N
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(N/N=C(\C)c2nc(-c3cccc(C(=O)NCc4ccccc4)c3)cnc2N)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of 3-amino-6-{3-[(benzylamino)carbonyl]phenyl}-N-methoxy-N-methylpyrazine-2-carboxamide (0.10 g, 0.25 mmol) in THF (5 mL) was cooled to 0° C., and a solution of CH3MgCl (0.75 mL, 1 M in THF, 3.0 equiv.) was added slowly. The mixture was allowed to warm to room temperature over 1.5 hr. The mixture was then cooled to 0° C. and quenched slowly with saturated NH4Cl solution. The mixture was extracted with ethyl acetate, washed with brine then water. The ethyl acetate extract was evaporated to afford the corresponding methyl ketone as a yellow solid. To a portion of this residue (35 mg, 0.1 mmol) in ethanol in a pressure tube (5 mL) was added 4-methoxyphenylhydrazine hydrochloride (52 mg, 3 mmol). This mixture was then heated to for 12 h. The solvent was removed under reduced pressure and the crude mixture was dissolved in a minimal amount of methanol and run through a plug of silica gel to give the product as a white solid (33 mg, 70% yield). 1H NMR (400 MHz, CDCl3): δ 8.40 (m, 1H), 8.0 (m, 2H), 7.80 (m, 2H), 7.25 (m,1H), 7.2 (m, 4H), 6.9 (m, 4H), 4.8 (s, 2H), 3.8 (s, 3H), 2.6 (s, 3H). MS (EI) for C27H26N6O2: 467 (MH+).
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:4])[NH2:3].C(N(CC)CC)C.[C:20]([C:23]1[C:24](=[O:34])[O:25][C:26]([OH:33])=[C:27]([C:30](=O)[CH3:31])[C:28]=1[OH:29])(=[O:22])[CH3:21]>CO>[C:20]([C:23]1[C:24](=[O:34])[O:25][C:26](=[O:33])[C:27](=[C:30]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([O:5][C:2](=[O:4])[NH2:3])=[CH:7][CH:8]=2)[CH3:31])[C:28]=1[OH:29])(=[O:22])[CH3:21]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: NC(=O)Oc1ccc(N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(OC(N)=O)cc2)C(=O)OC1=O

Procedure:
A solution of 1.88 g. (0.01 m.) of p-carbamoyloxyaniline hydrochloride and 1.0 g. (0.01 m.) of triethylamine in 50 ml. of methanol is added to a hot solution of 2.21 g. (0.01 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml. of methanol. The resulting mixture is refluxed for two hours, cooled and the filtered solid recrystallized to give 5-acetyl-3-[1-(p-carbamoyloxyphenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 213°-215° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([NH2:14])=[O:13])=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[CH3:15][C@H:16]1[CH2:24][C:23]2[C:18](=[CH:19][C:20]([CH3:25])=[CH:21][CH:22]=2)[C@@H:17]1[NH2:26].C(N(CC)CC)C>CN(C)C(=O)C>[Cl:1][C:2]1[C:3]([C:12]([NH2:14])=[O:13])=[N:4][C:5]([NH:26][C@H:17]2[C:18]3[C:23](=[CH:22][CH:21]=[C:20]([CH3:25])[CH:19]=3)[CH2:24][C@@H:16]2[CH3:15])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1ncc(Cl)c(C(N)=O)n1
Reactant: Cc1ccc2c(c1)[C@H](N)[C@@H](C)C2
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: Cc1ccc2c(c1)[C@H](Nc1ncc(Cl)c(C(N)=O)n1)[C@@H](C)C2
Yield: 17.4 %

Procedure:
0.30 g (1.27 mmol) of 5-chloro-2-(methylsulfonyl)pyrimidine-4-carboxamide, 0.25 g (1.53 mmol) of (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine and 0.28 g (2.54 mmol) of triethylamine in 1.5 ml of N,N-dimethylacetamide are heated in a closed cuvette in the microwave at 120° C. for 45 minutes (Biotage Initiator, http://www.biotage.com/DynPage.aspx?id=22001). The crude mixture obtained in this manner is applied to silica gel and purified by column chromatography using the mobile phase heptane/ethyl acetate. Concentration gives initially 0.07 g of 5-chloro-2-{[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}pyrimidine-4-carboxamide (wax-like) and then 0.252 g of 5-{[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-2-(methylsulfonyl)pyrimidine-4-carboxamide (yield 52% at a purity of 95%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4[NH2:28])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:29]1([CH:35]=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C([O-])(O)=O.[Na+].O>[CH:29]1([CH2:35][NH:28][C:19]2[CH:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[CH:22]=[CH:23][C:18]=2[C:14]2[CH:13]=[C:12]([O:11][C:8]3[CH:9]=[C:10]4[C:5]([CH:4]=[CH:3][CH:2]=[N:1]4)=[CH:6][CH:7]=3)[N:17]=[CH:16][N:15]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ncn2)c(NCC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamine, (Example 163), (0.40 g, 1.1 mmol) in 1,2-dichloroethane (11 mL) was added cyclohexanecarboxaldehyde (0.32 mL, 2.6 mmol, Aldrich) and the mixture was stirred at room temperature for 18 h. NaBH(OAc)3 (0.55 g, 2.6 mmol) was added and stirring was continued for 8 h at 40° C. The reaction was diluted with satd NaHCO3 and H2O, and extracted with EtOAc (2×75 mL). The combined extracts were washed with H2O (75 mL) and brine (75 mL), dried over Na2SO4, filtered and concentrated onto silica gel. Purification by silica gel chromatography (gradient, 10 to 40% EtOAc/hexanes) afforded the title compound as a yellow solid. Mp: 137–138° C. MS (ESI, pos. ion) m/z: 479.2 (M+1).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([NH2:19])=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].C1COCC1>CO.[Pd]>[CH:1]([S:4]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]([NH2:19])=[N:17][CH:18]=2)=[CH:11][CH:12]=1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C#Cc3ccccc3)n2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(CCc3ccccc3)n2)cc1
Reaction time: 1 h
Yield: 127.6 %

Procedure:
Pd/C5% (20 mg, 0.1879 mmol) was added to a suspension of 5-(4-isopropylsulfonylphenyl)-3-(2-phenylethynyl)pyrazin-2-amine (100 mg, 0.1602 mmol) in MeOH (5 mL)/THF (5 mL) and the reaction stirred under an atmosphere of H2 for 1 hour. The catalyst was removed by filtration and the filtrate concentrated in vacuo. The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, and freeze-dried to give the di-TFA salt of the title compound as a yellow solid (78 mg, 80% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.17-1.20 (m, 6H), 2.99-3.03 (m, 2H), 3.10-3.14 (m, 2H), 3.43 (q, 1H), 7.19 (t, 1H), 7.33 (m, 4H), 7.87 (d, 2H), 8.22 (d, 2H) and 8.56 (s, 1H) ppm; (ES+) 382.0.
Reaction SMILES: [OH-].[Na+].[C:3]1([C:11]([O:13]CC)=[O:12])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1>O.C(O)C>[CH2:9]([O:8][C:6]([C:3]1([C:11]([OH:13])=[O:12])[CH2:4][CH2:5]1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of sodium hydroxide (2.15 g, 54 mmol) in water (15 ml) was added dropwise to a stirred solution of diethyl 1,1-cyclopropanedicarboxylate (10 g, 54 mmol) in ethanol (30 ml) while the temperature was maintained below 25° C. After the completion of the addition, the resulting mixture was stirred at room temperature for 60 hours. Most of ethanol was removed by evaporation in vacuo and the residue was diluted with brine, acidified with 6N hydrochloric acid and extracted with diethyl ether. The extract was dried over magnesium sulfate, filtered and concentrated. The residue was purified by distillation to give the title compound (bp 66°-9° C./0.15 mm) as a viscous oil.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]1[CH:30]=[CH:29][C:17]([CH2:18][C:19]2[CH:28]=[C:27]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=[CH:26]3)[CH:20]=2)=[CH:16][C:15]=1Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:32]([O:39][C@@H:40]1[C@@H:46]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@H:45]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@@H:44]([CH2:63][O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[O:43][C:41]1=[O:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH:20]1[C:21]2[C:27]([CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:28][C:19]=1[CH2:18][C:17]1[CH:29]=[CH:30][C:14]([O:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:15]([C:41]2([O:43][C@H:44]([CH2:63][O:64][CH2:65][C:66]3[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=3)[C@@H:45]([O:55][CH2:56][C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[C@H:46]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C@H:40]2[O:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[OH:42])[CH:16]=1
Reactant: Brc1cc(Cc2cc3cccccc-3c2)ccc1OCc1ccccc1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2cc(Cc3cc4cccccc-4c3)ccc2OCc2ccccc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 0.17 h
Yield: 468.1 %

Procedure:
A 1.6 M n-hexane solution of n-butyl lithium (0.32 ml) was added dropwise to a solution of 2-[4-(benzyloxy)-3-bromobenzyl]azulene (0.17 g) in THF (3.0 ml) at −55° C. and the mixture was stirred at the same temperature for 10 minutes. A solution of 2,3,4,6-tetra-O-benzyl-glucono-1,5-lactone (0.12 g) in THF (3.0 ml) was added dropwise to the reaction mixture and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain 1-C-[5-(azulen-2-ylmethyl)-2-(benzyloxy)phenyl]-2,3,4,6-tetra-O-benzyl-D-glucopyranose (0.9 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[CH:4]=1)=[O:2].[OH:14]OS([O-])=O.[K+].Cl.O>CN(C=O)C>[CH3:13][O:12][C:10]([C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([CH3:9])[N:6]=1)[C:1]([OH:14])=[O:2])=[O:11]
Reactant: O=S([O-])OO
Reactant: COC(=O)c1cc(C=O)cc(C)n1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C(=O)O)cc(C)n1
Reaction time: 2 h

Procedure:
To a stirring solution of 216 mg (1.20 mmol) of methyl 4-formyl-6-methylpicolinate in 4 mL of DMF was added 790 mg (1.29 mmol) of Oxone. After about 2 h, 5 mL of 1N HCl and 5 mL of H2O were added, and the aqueous layer was extracted with EtOAc (3×). The combined extracts were dried over Na2SO4, filtered, and concentrated. The desired product (2-(methoxycarbonyl)-6-methylisonicotinic acid) was used in the next reaction without further purification.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>O1CCCC1>[CH:1]1([NH:7][C:11](=[O:12])[CH2:10][C:9](=[O:13])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
A solution of 23.6 g (0.24 mol) of cyclohexylamine in 50 ml tetrahydrofuran was added dropwise to a solution of 20 g of diketene (0.24 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue is recrystallized from 100 ml of ethyl acetate. This gave 30.0 g (0.16 mol, 69% yield) of a white solid.
Reaction SMILES: [O:1]=[C:2]([CH:5]([CH2:14][NH:15]C(OCC=C)=O)[CH2:6][NH:7]C(OCC=C)=O)[CH2:3][CH3:4].C(OC(NCC(CNC(OCC=C)=O)C(=O)C)=O)C=C>>[NH2:7][CH2:6][CH:5]([CH2:14][NH2:15])[CH:2]([OH:1])[CH2:3][CH3:4]
Reactant: C=CCOC(=O)NCC(CNC(=O)OCC=C)C(=O)CC
Agent: C=CCOC(=O)NCC(CNC(=O)OCC=C)C(C)=O
Product: CCC(O)C(CN)CN

Procedure:
2-(1-Oxopropyl)-1,3-bis(allyloxycarbonylamino)propane (1.1 g) was 1-allyloxycarbonylamino-2-(N-allyloxycarbonylaminomethyl)butan-3-one was obtained from 1-amino-2-aminomethyl-3-hydroxypentane in substantially the same manner as those of Preparations 5 and 7.
Reaction SMILES: [CH2:1]([O:3][C:4]1[S:5][C:6]([C:10]#[N:11])=[C:7]([OH:9])[N:8]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[P:18](Cl)([O:22][CH3:23])([O:20][CH3:21])=[O:19]>CC(C)=O>[CH2:1]([O:3][C:4]1[S:5][C:6]([C:10]#[N:11])=[C:7]([O:9][P:18]([O:22][CH3:23])([O:20][CH3:21])=[O:19])[N:8]=1)[CH3:2]
Reactant: CCOc1nc(O)c(C#N)s1
Reactant: COP(=O)(Cl)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1nc(OP(=O)(OC)OC)c(C#N)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.5 %

Procedure:
A mixture of 17 g of 2-ethoxy-4hydroxy-5-cyano-thiazole, 14 g of potassium carbonate, 13 g of O,O-dimethyl chlorophosphate and 150 ml of acetone was stirred for 3 hours at room temperature and the mixture was concentrated to dryness. The residue was added to an aqueous sodium chloride solution which was then extracted with ethyl ether. The ether extracts were washed with an aqueous 2% sodium hydroxide solution, dried and evaporated to dryness to obtain 14.4 g of 2-ethoxy-4-dimethoxyphosphoryloxy-5-cyano-thiazole as an oil with a refractive index n D 23 = 1.5056.
Reaction SMILES: N12CCCN=C1CC[CH2:4][CH2:3][CH2:2]2.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:19][CH:20]([OH:39])/[CH:21]=[CH:22]/[C@H:23]2[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[N:24]2[CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][C:36]([OH:38])=[O:37])[CH:16]=[CH:17][CH:18]=1.IC(C)C>CC(C)=O>[CH:3]([O:37][C:36](=[O:38])[CH2:35][O:34][CH2:33][CH2:32][CH2:31][CH2:30][N:24]1[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C@@H:23]1/[CH:22]=[CH:21]/[CH:20]([OH:39])[CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=1)([CH3:4])[CH3:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Solvent: CC(C)=O
Solvent: CC(C)I
Product: CC(C)OC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Reaction time: 0.08 h
Yield: 49.9 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 16 μL, 0.11 mmol) was added to a solution of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-hydroxy-but-1-enyl]-6-oxo-piperidin-1-yl}-butoxy)-acetic acid (29 mg, 0.071 mmol) in acetone (0.5 mL). After 5 min, 2-iodopropane (35 μL, 0.35 mmol) was added. After 17 h, the reaction mixture was concentrated in vacuo, EtOAc (15 mL) was added and the resultant mixture was washed with 0.5 M aqueous HCl (5 mL), saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic phase was then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2<5% MeOH/CH2Cl2, gradient) afforded 16 mg (50%) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.COC[O:11][C:12]1[CH:39]=[CH:38][C:37]([CH2:40][N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:36][C:13]=1[C:14]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])=[O:15].C(Cl)[Cl:48]>>[ClH:48].[OH:11][C:12]1[CH:39]=[CH:38][C:37]([CH2:40][N:41]2[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]2)=[CH:36][C:13]=1[C:14]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:26][C:18]=1[C:19]([OH:21])=[O:20])=[O:15]
Reactant: ClCCl
Reactant: COCOc1ccc(CN2CCCCC2)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(CN2CCCCC2)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under ice-cooling, trifluoroacetic acid (1.0 mL) was added to a methylene chloride (2.0 mL) solution of the obtained tert-butyl 2-(2-(methoxymethoxy)-5-((piperidin-1-yl)methyl)benzamido)-4-phenylbenzoate (0.080 g), followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and ethyl acetate was added to the obtained residue. The solid substance was collected by filtration. Ethyl acetate (1.0 mL) and a 4.0 mol/L hydrogen chloride-dioxane solution (0.20 mL) were added to the obtained solid substance, followed by stirring at room temperature for 3 hours. The solid substance was collected from the reaction mixture by filtration to obtain 0.020 g of 2-(2-hydroxy-5-((piperidin-1-yl)methyl)benzamido)-4-phenylbenzoic acid hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[O:16][CH3:17])[CH:3]=1.[CH:18](OC)(OC)OC.Cl.[OH-].[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C.O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:18])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[O:16][CH3:17])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1cc(Cl)nnc1N
Reactant: COC(OC)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CNc1nnc(Cl)cc1-c1ccc(F)cc1OC
Temperature: 0 °C

Procedure:
To a solution of 6-chloro-4-(4-fluoro-2-methoxy-phenyl)-pyridazin-3-ylamine (300 mg, 1.18 mmol) in trimethyl orthoformate (1.00 g, 1.04 mL, 9.46 mmol) were added 2-3 drops of trifluoroacetic acid. The reaction mixture was stirred at reflux for 2 hours and then concentrated under vacuum. The residue was dissolved in 5 mL toluene and concentrated again under vacuum. This was repeated for three times to completely remove all volatiles. The residue was dissolved in tetrahydrofuran (3 mL) and borane tetrahydrofuran complex (1M solution, 2.96 mL, 2.96 mmol) was added in portions at 0° C. The reaction mixture was stirred at 90° C. for 2 hours and the resulting brown solution was cooled down to 0° C. and 25% aqueous hydrochloric acid (1 mL) was added slowly. The mixture was stirred at 90° C. for 1 hour and then poured on 30 mL water and 30 mL ethyl acetate. Aqueous sodium hydroxide solution (25%, 2 mL) was added and the layers were separated. The aqueous layer was extracted a second time with 30 mL ethyl acetate. The organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100). Light yellow solid (119 mg, 37.6%). MS (ESI+): m/z=268.065 ([M+H]+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[I:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=NN1CCC[C@H]1COC)[CH2:19][CH2:18][CH2:17]2.I[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].N.[O:41]1CCCC1>O>[CH2:34]([C@@H:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([I:13])[CH:15]=2)[C:20]1=[O:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: C1CCOC1
Reactant: COC[C@@H]1CCCN1N=C1CCCc2cc(I)ccc21
Reactant: CCCCCCI
Agent: N
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Product: CCCCCC[C@@H]1CCc2cc(I)ccc2C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of diisopropylamine (19.43 mL, 136 mmol) in anhydrous tetrahydrofuran (250 mL) was added butyl lithium solution (2.5 M in hexanes, 39.4 mL, 98 mmol) dropwise at 0° C. under nitrogen. The resulting solution was stirred at the same temperature for 15 min before a solution of (S)—N-(6-iodo-3,4-dihydronaphthalen-1(2H)-ylidene)-2-(methoxymethyl)pyrrolidin-1-amine (I-8B, 29.1 g, 76 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise. The reaction solution was stirred at 0° C. for 2 h. A solution of 1-iodohexane (22.35 mL, 151 mmol) in tetrahydrofuran (50 mL) was added dropwise at −78° C. and the mixture was stirred at the same temperature for 2 h. The temperature was raised to room temperature over 1.5 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) and water (50 mL). The mixture was extracted with hexanes (200 mL) and ethyl acetate (3×50 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil. The oil was dissolved in THF (200 mL). A solution of cupric chloride, dihydrate (52 g) in water (220 mL) was added at 0° C. dropwise and the mixture was vigorously stirred at room temperature overnight. Aqueous ammonia solution was added to raise the pH to approximately 9. The mixture was extracted with hexane (100 mL) and diethyl ether (2×100 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated. Flash chromatography purification (330 g silica gel column, gradient elution from 0 to 15% EtOAc in hexanes) afforded (R)-2-hexyl-6-iodo-3,4-dihydronaphthalen-1(2H)-one (21.6 g, 60.6 mmol) as a white solid containing some of the (S) isomer, which was removed in the subsequent step. LC/MS M+1=357.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)COc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
A mixture of 3-nitrophenol (6.95 g), ethyl bromoacetate (8.35 g) and potassium carbonate (6.9 g) in dry NHP (50 ml) was stirred at room temperature for 48 hours. The reaction mixture was partitioned between water (300 ml) and diethyl ether (75 ml). The organic layer was separated, washed with water, brine and dried (MgSO4). The residue was filtered through silica and eluted with a 3:2 mixture of hexane and ethyl acetate to give ethyl 3-nitrophenoxyacetate as a viscous oil in 98% yield;
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.C(N(CC)CC)C.[Cl:33][CH2:34][C:35](Cl)=[O:36]>ClCCl>[Cl:33][CH2:34][C:35]([NH:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12)=[O:36]
Reactant: O=C(Cl)CCl
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(=O)CCl)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.4 %

Procedure:
To a round bottom flask charged with 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 1J, 47.2 mg, 0.139 mmol) was added dichloromethane (697 μL) and triethylamine (35.0 μL, 0.251 mmol). Chloroacetyl chloride (12.20 μL, 0.153 mmol) was added dropwise. The reaction mixture was stirred at rt for 16 h. Additional chloroacetyl chloride (12.20 μL, 0.153 mmol) was added. The reaction mixture was diluted with dichloromethane. The organics were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 4-(2-Chloroacetamido)-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (58.5 mg, 101% yield) was isolated as an orange paste. Material was used in subsequent reactions with no further purification.