Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([OH:13])=O.[CH3:14][C:15]1([CH3:29])[C:19]([CH3:21])([CH3:20])[O:18][B:17]([C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[O:16]1>>[CH3:20][C:19]1([CH3:21])[C:15]([CH3:14])([CH3:29])[O:16][B:17]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:11]([C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:2]=3[CH3:1])=[O:13])=[CH:24][CH:23]=2)[O:18]1
Reactant: Cc1c(C(=O)O)oc2ccccc12
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: Cc1c(C(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)oc2ccccc12
Yield: 55 %

Procedure:
Amide coupling of 3-methyl-benzofuran-2-carboxylic acid with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine was done according to Example 20, Step 4, to give 3-methyl-benzofuran-2-carboxylic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide in 55% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (s, 12 H) 2.6 (s, 3 H) 7.4 (m, 1 H) 7.5 (m, 1 H) 7.7 (m, 3 H) 7.8 (d, J=7.3 Hz, 1 H) 7.9 (d, J=8.6 Hz, 2 H) 10.5 (s, 1 H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:23](=[O:25])=[O:24].Cl>O.O1CCCC1>[S:13]1[C:9]([CH:8]=[CH:7][C:5]2[S:6][C:2]([C:23]([OH:25])=[O:24])=[CH:3][CH:4]=2)=[CH:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]1=2
Reactant: O=C=O
Reactant: Brc1ccc(C=Cc2cc3ccccc3s2)s1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C=Cc2cc3ccccc3s2)s1
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To a stirred, chilled (-70° C.) suspension of 2-[2-(5-bromo-2-thienyl)ethenyl]benzo[b]thiophene (15.6 g) and tetrahydrofuran (400 ml) was added n-butyl lithium (21.4 ml of a 2.5M solution in hexanes), under nitrogen over 10 mins. The solution was stirred at -70° C. for 1.5 hr, and was transferred via canula to a flask containing a suspension of dry ice (excess) and tetrahydrofuran (1000 ml). The suspension was stirred for 2 hrs and allowed to warm to room temperature overnight. The mixture was poured into water (500 ml), acidified with hydrochloric acid, and the tetrahydrofuran was removed in vacuo. The resulting suspension was filtered, and the filter cake was washed with water and dried in vacuo overnight. The filter cake was recrystallized from dimethyl sulfoxide/10% hydrochloric acid to yield 10.5 g (75%) of product, mp 236°-237° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-]>ClC(Cl)C.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)COC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 7 h
Yield: 47.3 %

Procedure:
To a solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5.0 g, 25 mmol) and rhodium(II)acetate (180 mg) in 500 ml dichloroethane at 80° C. was added (over 90 min) ethyl diazoacetate (4.2 ml, 50 mmol) in 220 ml dichloroethane. The mixture was stirred for 7 h and quenched with aqueous sodium bicarbonate (2×100 ml). The organic phase was isolated and washed with brine (2×100 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (80g) in petroleum ether:ethyl acetate (4:1) to give 3.4 g of 4-(ethoxycarbonylmethoxy)piperidine-1-carboxylic acid tert-butylester. The product was taken up in 40 ml of a 1 M lithium hydroxide solution in water:methanol (1:3) and stirred for 60 min. The mixture was concentrated in vacuo and dissolved in 20 ml of water, acidified to pH 4 with 1M aqueous hydrogen chloride and extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (10 ml), dried over magnesium sulfate and concentrated in vacuo to give 1.79 g of 4-(carboxymethoxy)piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:20]1([C:18]([NH:17][C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([O:7][C:6]4[CH:23]=[C:2]([NH:1][C:30](=[O:31])[C:29]5[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=5)[CH:3]=[CH:4][C:5]=4[CH3:24])=[N:13][N:12]3[CH:14]=2)=[O:19])[CH2:22][CH2:21]1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 72.8 %

Procedure:
Using N-[6-(5-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol), 3-(trifluoromethyl)benzoic acid (93 mg, 0.49 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (94 mg, 0.49 mmol), 1-hydroxybenzotriazole (66 mg, 0.49 mmol) and N,N-dimethylformamide (7.0 mL) as starting materials and in the same manner as in Example 318, the title compound (166 mg, 72%) was obtained as a white powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:39])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:34]1([C:30]2[CH:29]=[C:28]([C:26]3[CH2:25][C:24](=[O:39])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[CH:38]=[CH:37][N:36]=[CH:35]1
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CNc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3ccnc3)c1)=N2

Procedure:
The title compound was prepared from {2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-5-isobutylamino-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M125) (0.43 g, 0.77 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (260 mg, 76%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7]1.C(N(C(C)C)CC)(C)C.[CH3:25][C:26]1([CH3:39])[C:30]2([CH2:34][S:35](Cl)(=[O:37])=[O:36])[C:31]([CH2:33][CH:27]1[CH2:28][CH2:29]2)=[O:32]>ClCCl>[O:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7][CH:6]1[CH2:5][NH:4][CH2:3][CH2:2][NH:1][S:35]([CH2:34][C@:30]12[C:26]([CH3:25])([CH3:39])[CH:27]([CH2:28][CH2:29]1)[CH2:33][C:31]2=[O:32])(=[O:37])=[O:36]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)Cl)C(=O)C2
Reactant: NCCNCC1COc2ccccc2O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)C2CC[C@@]1(CS(=O)(=O)NCCNCC1COc3ccccc3O1)C(=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
To a solution of 2.1 g (10 mmole) of 2-{N-(2-aminoethyl)]aminomethyl-2,3-dihydrobenzodioxin and 1.3 g (10 mmole) of diisopropylethylamine in 100 ml of dichloromethane stored in an ice bath was added 2.5 g (10 mmole) (+)-10-camphorsulfonyl chloride. The mixture was allowed to stir overnight at room temperature. The reaction was next washed with saturated aqueous sodium bicarbonate, with saturated sodium chloride, dried over sodium sulfate, filtered and evaporated in vacuum. Column chromatography on 75 g of silica gel with chloroform as eluant, followed by crystallization from 100 ml of isopropanol with the addition of 5 ml of 4 N HCl/isopropyl alcohol and 300 ml of diethyl ether gave 1.2 g of the title compound as a monohydrochloride, m.p. 143°-146° C.
Reaction SMILES: CO[C:3](=[O:25])/[C:4](=[N:22]/[O:23][CH3:24])/[C:5](/[CH3:21])=[CH:6]\[CH2:7][O:8][C:9]1[CH:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:10]=1.[CH3:26][NH2:27]>C1COCC1.O>[CH3:26][NH:27][C:3](=[O:25])/[C:4](=[N:22]/[O:23][CH3:24])/[C:5](/[CH3:21])=[CH:6]\[CH2:7][O:8][C:9]1[CH:13]=[CH:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:10]=1
Reactant: CO/N=C(C(=O)OC)\C(C)=C/COc1ccn(-c2ccc(Cl)cc2)n1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C(=N/OC)/C(C)=C\COc1ccn(-c2ccc(Cl)cc2)n1

Procedure:
120 mg (0.33 mmol) (Z)-5-[1-(4-chloro-phenyl)-1H-pyrazol-3-yloxy]-2-[(E)-methoxyimino]-3-methyl-pent-3-enic acid methyl ester and 0.99 ml (1.98 mmol) of a 2-molar solution of methyl amine in THF have been stirred overnight at ambient temperature in 2.0 ml of THF and 0.5 ml of water. After removal of the solvent in vacuo the product (120 mg) was collected in quantitative yield and good purity. Melting point 129-130° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(O[K])(C)(C)C>C1(C)C=CC=CC=1.C(Cl)Cl.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]>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccccn1
Reactant: Brc1ccc2ccccc2n1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc3ccccc3n2)nc1
Yield: 45 %

Procedure:
2-Bromoquinoline, I (500 mg, 2.40 mmol), 2-aminopyridine (249 mg, 2.64 mmol), tBuOK (404 mg, 3.60 mmol), (±)-BINAP (6 mg, 0.01 mmol) and Pd2(dba)3 (5.5 mg, 0.006 mmol) were stirred in toluene (10 mL) at 90° C. under Ar(g) for 21 h. The reaction mixture was then diluted with CH2Cl2 (10 mL) and silica was added, followed by the removal of the solvent under reduced pressure. The resulting dry load material was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:1 then 100:2) to furnish II as a colourless oil (344 mg, 45%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[F:10].C([Mg]Cl)(C)C.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C.C(OCC)C>O1CCCC1>[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:3]([F:10])[CH:4]=1
Reactant: Fc1cc(Cl)c(Cl)cc1Br
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)OB(c2cc(Cl)c(Cl)cc2F)OC1(C)C
Temperature: -10 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
1-Bromo-4,5-dichloro-2-fluorobenzene (1.0 g, 4.11 mmol) was dissolved in tetrahydrofuran (THF; 20 mL) and cooled to −10° C. A 2.0M solution of isopropylmagnesium chloride (2.3 mL, 4.6 mmol) in THF was added dropwise via a syringe. The reaction mixture was stirred at −10° C. for 1 hour, allowed to warm toward 0° C. for 1 hour, then cooled to −10° C. again. A solution of 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (0.85 g, 4.56 mmol) in THF (1.0 mL) was then added dropwise and the reaction was allowed to warm to ambient temperature. The reaction mixture was then added to diethyl ether and extracted with 1N sodium hydroxide. The aqueous phases were combined, acidified to pH 3 with concentrated HCl, and extracted with dichloromethane twice. The organic phases were combined, dried, filtered and concentrated to give the title compound (0.85 g, 71% yield) that was used without further purification: 1H NMR (CDCl3): δ 7.73 (d, 1H), 7.12 (d, 1H), 1.3 (s, 12H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[C:12]([Si:16]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:17][CH:18]1[CH2:21][NH:20][CH2:19]1)([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:20]2[CH2:19][CH:18]([O:17][Si:16]([C:12]([CH3:15])([CH3:14])[CH3:13])([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](OC1CN(C(=O)Cc2ccc(Br)cc2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To 4-bromophenyl acetylchloride (300 mg, 1.28 mmol) in CH2Cl2 (5 mL) was added 3-(tert-Butyl-diphenyl-silanyloxy)-azetidine (399 mg, 1.28 mmol), DIPEA (670 μL, 3.85 mmol) and the reaction stirred at RT for 2 h. The crude material was purified by silica gel column chromatography, eluting with isohexane and increasing the polarity to 80% EtOAc/isohexane to obtain 2-(4-bromo-phenyl)-1-[3-(tert-butyl-diphenyl-silanyloxy)-azetidin-1-yl]-ethanone as a colourless glass (632 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[CH:16][C:17]=1[F:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:19][C:14]1[CH:15]=[CH:16][C:17]([F:18])=[C:12]([F:11])[CH:13]=1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: Oc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2ccc(F)c(F)c2)c(Cl)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3-chloro-4-fluorobenzaldehyde and 3,4-difluorophenol.
Reaction SMILES: [CH:1]([CH:4]1[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[CH2:6][O:5]1)=[CH:2][CH3:3].[C:12]([OH:16])(=[O:15])[CH:13]=[CH2:14]>>[C:12]([O:16][CH:2]([CH3:3])[CH2:1][CH:4]1[O:5][CH2:6][C:7]([CH3:10])([CH3:11])[CH2:8][O:9]1)(=[O:15])[CH:13]=[CH2:14]
Reactant: C=CC(=O)O
Reactant: CC=CC1OCC(C)(C)CO1
Product: C=CC(=O)OC(C)CC1OCC(C)(C)CO1

Procedure:
2-Propenyl-5,5-dimethyl-1,3-dioxane (PDD) was reacted with acrylic acid under the same conditions as the reaction with EDD (see Monomer IF).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].CC(C)([O-])C.[K+].Cl[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 13.8 %

Procedure:
To a stirred solution of 1-methoxy-2-nitrobenzene (3 g, 19.59 mmol) in dimethylformamide were added potassium tert-butoxide (8.792 g, 78.36 mmol) and ethyl 2-chloropropionate (2.5 ml, 19.59 mmol) while maintaining temperature below −30° C. The reaction mixture was stirred for 5 min at −30° C., then ethyl 2-chloropropionate (0.25 mL, 1.959 mmol) was added to mixture. The reaction mixture was stirred for 10 min at room temperature. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. Ethyl 2-(3-methoxy-4-nitrophenyl)propanoate (683 mg) was obtained as 14% yield.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)(=O)=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:21][CH2:22][CH:23]1[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CCN(Cc2ccccc2)Cc2ccccc2)CC1
Reaction time: 72 h
Yield: 67 %

Procedure:
Dibenzylamine (4.1 ml, 21.24 mmol, 1 eq) was added to a solution of tert-butyl 4-(2-(methyl-sulfonyloxy)ethyl)piperidine-1-carboxylate (6.5 g, 21.24 mmol, 1 eq) and triethylamine (3.2 ml, 23.36 mmol, 1.1 eq) in toluene (100 ml), and refluxing was carried out for 72 h. Then the reaction solution was concentrated and the residue was taken up in dichloromethane (300 ml), washed with water and sat. NaCl solution (in each case 100 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 5% ethyl acetate in hexane), a yellow solid was obtained. Yield: 67% (5.8 g, 14.21 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([OH:24])=O)[CH:20]=3)[N:15]([C:25]3[C:26]4[C@H:33]([CH3:34])[CH2:32][CH2:31][C:27]=4[N:28]=[CH:29][N:30]=3)[CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:36][NH:37][O:38][CH3:39]>>[CH3:39][O:38][N:37]([CH3:36])[C:22]([C:19]1[CH:20]=[C:21]2[C:11]3([CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]3)[CH2:14][N:15]([C:25]3[C:26]4[C@H:33]([CH3:34])[CH2:32][CH2:31][C:27]=4[N:28]=[CH:29][N:30]=3)[C:16]2=[CH:17][CH:18]=1)=[O:24]
Reactant: CNOC
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(C(=O)O)ccc43)c21
Agent: Cl
Product: CON(C)C(=O)c1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)CC1)CN2c1ncnc2c1[C@H](C)CC2

Procedure:
(R)-tert-butyl 5-(methoxy(methyl)carbamoyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate was prepared by the procedures described in Example 10, Step 5, substituting (R)-2-(1′-(tert-butoxycarbonyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-5-yl)acetic acid with (R)-1′-(tert-butoxycarbonyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-5-carboxylic acid, and substituting NH4Cl with N,O-dimethylhydroxylamine hydrochloride. LCMS (APCI+) m/z 508.3 [M+H]+; Rt=3.56 min.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[Br:8][C:9]1[CH:10]=[N:11][C:12](Cl)=[N:13][CH:14]=1>C1COCC1.O>[Br:8][C:9]1[CH:10]=[N:11][C:12]([O:7][CH2:6][CH:3]2[CH2:5][CH2:4]2)=[N:13][CH:14]=1
Reactant: Clc1ncc(Br)cn1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1cnc(OCC2CC2)nc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 94.7 %

Procedure:
A suspension of 607.92 mg (15.20 mmol) of sodium hydride in 50 mL of THF is prepared under argon. A solution of 1.10 g (15.20 mmol) of cyclopropanemethanol in 5 mL of THF is added dropwise. The mixture is stirred for 50 minutes at room temperature. 1 g (5.07 mmol) of 5-bromo-2-chloropyrimidine in 5 mL of THF is then added. The mixture is stirred at room temperature overnight. The reaction mixture is taken up in water and extracted with ethyl acetate. The organic phase is washed with aqueous NaHCO3 solution and with saturated aqueous NaCl solution, dried and evaporated to dryness to give 1.10 g of 5-bromo-2-cyclopropylmethoxypyrimidine, corresponding to the following characteristics:
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.[C@@H:18]1([NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[NH2:24].[O-]S([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.C(Cl)Cl>[NH2:24][C@@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]1[NH:25][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: CCOC(=O)c1ccc(N2CCC(=O)C2)cc1
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N2CCC(N[C@@H]3CCCC[C@H]3N)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a round bottom flask under argon was added the ethyl 4-(3-oxopyrrolidin-1-yl)benzoate (1.23 g, 5.27 mmol), (1R,2R)-cyclohexane-1,2-diamine (0.602 g, 5.27 mmol), CH2Cl2 (30 ml), solid anhydrous Na2SO4 (2.5 gm) and HOAc (1 ml). Argon was bubbled through the reaction mixture for 1 min and then the reaction was stirred under argon at rt for 1 hr. After this time, sodium triacetoxy borohydride (2.012 g, 9.49 mmol) was added to the reaction which was then stirred at rt overnight. The reaction was filtered and water (10 ml) was added to the reaction. The reaction mixture was then diluted with CH2Cl2 (100 ml). The resulting solution was washed with saturated aqueous NaHCO3 (100 ml), water (50 ml) and saturated aqueous NaCl (50 ml). The organic layer was separated, dried over MgSO4, filtered and concentrated to give the product ethyl 4-(3-((1R,2R)-2-aminocyclohexylamino)pyrrolidin-1-yl)benzoate (1 g, 3.02 mmol, 57.2% yield) as brown solid. Anal. Calcd. for C19H29N3O2 m/z 331.4, found: 332.1 (M+H)+.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH3:3].[Mg].[CH2:6]([N:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC.C1C=CC=CC=1>[CH2:6]([N:13]1[CH2:14][CH2:15][C:16]([CH2:1][CH2:2][CH3:3])([O:20][CH2:19][CH2:18][OH:17])[CH2:21][CH2:22]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(CN2CCC3(CC2)OCCO3)cc1
Reactant: CCCBr
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCCC1(OCCO)CCN(Cc2ccccc2)CC1
Yield: 50.5 %

Procedure:
A solution of 108 g of propyl bromide in 250 ml of ether was added dropwise to a refluxing mixture of 19.2 g of magnesium in 100 ml of ether and then a solution of 46.6 g of 8-benzyl-1,4-dioxa-8-aza-spiro [4,5] decane in 500 ml of benzene was added in increments. The ether was evaporated off and then cooled and hydrolyzed with a saturated aqueous ammonium chloride solution. The benzene phase was decanted and the aqueous phase was extracted with ether. The ether phase was washed with water until neutral, dried over sodium sulfate and the solvents removed under reduced pressure. The residue (B.p. = 129° C at 0.1mm/Hg) was rectified to obtain 28 g of 2-(1-benzyl-4-propyl-4-piperidyloxy)-ethanol as a yellowish oil. The product was dissolved in 250 ml of ether and 13 ml of a 5N hydrogen chloride solution in ether were added thereto. The product was vacuum filtered and crystallized from isopropanol and dried in vacuo to obtain 12.9 g of 2-(1-benzyl-4-propyl-4-piperidyloxy)-ethanol hydrochloride in the form of colorless crystals melting at 196° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:36]=[CH:37][CH:38]=1)[O:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH:27]=[C:28]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[N:29]=2)[CH:26]=1>CN(C)C=O.O1CCCC1>[CH:33]1([C:31]([NH:30][C:28]2[N:29]=[C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]4[CH:18]=[C:17]([NH:16][C:7]([C:6]5[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=5)=[O:9])[CH:38]=[CH:37][CH:36]=4)=[CH:26][N:25]3[CH:27]=2)=[O:32])[CH2:34][CH2:35]1
Reactant: Cn1nccc1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1nccc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Yield: 50.5 %

Procedure:
In the same manner as in Example 7-4 and using 1-methyl-1H-pyrazole-5-carboxylic acid (73.6 mg, 0.584 mmol), oxalyl chloride (102 μL, 1.17 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop) and N-[6-(3-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (60.0 mg, 0.195 mmol) as starting materials, the title compound (41.0 mg, 50%) was obtained as a white solid.