Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([CH:6]1[C:14](=[O:15])[C:13]2[CH:12]=[N:11][CH:10]=[CH:9][C:8]=2[C:7]1=[O:16])=[O:5])C.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:24][C:4]([CH:6]2[C:14](=[O:15])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7]2=[O:16])=[O:5])[CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C1C(=O)c2ccncc2C1=O
Reactant: Nc1cccc(Cl)c1
Product: O=C(Nc1cccc(Cl)c1)C1C(=O)c2ccncc2C1=O

Procedure:
In a similar manner to Example 1a, 5,7-dioxo-6,7-dihydro-5H-[2]pyrindine-6-carboxylic acid (3-chloro-phenyl)-amide was obtained starting from 5,7-dioxo-6,7-dihydro-5H-[2]pyrindine-6-carboxylic acid ethyl ester and 3-chloro-phenylamine. The desired product was obtained as a brownish orange powder. ESI−MS: m/z 301 (MH+); 1H-NMR (DMSO-d6): δ6.96-7.00 (1H, m), 7.27-7.29 (2H, m), 7.35 (1H, dd, J=1.3 Hz, 4.6 Hz), 7.98-7.99 (1H, m), 8.53 (1H, d, J=1.0 Hz), 8.74 (1H, d, J=4.6 Hz), 10.92 (1H, brs).
Reaction SMILES: F[C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[N:7]([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:28]=[C:29]([O:31][C@H:32]2[CH2:36][CH2:35][O:34][CH2:33]2)[CH:30]=1)[C:18]([NH:20][C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=1)=[O:19]>>[CH3:10][N:7]1[C:6](=[O:11])[C:5]2[CH:12]=[CH:13][C:2]([O:14][C:15]3[CH:16]=[C:17]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:18]([NH:20][C:21]3[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=3)=[O:19])=[CH:3][C:4]=2[O:9][CH2:8]1
Reactant: CN1COc2cc(F)ccc2C1=O
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCOC3)c2)cn1
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc4c(c3)OCN(C)C4=O)cc(O[C@H]3CCOC3)c2)cn1

Procedure:
The preparations of 7-fluoro-3-methyl-2,3-dihydro-4H-1,3-benzoxazin-4-one and 3-hydroxy-N-(5-methylpyrazin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide were described earlier.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>ClCCl>[C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:15](=[O:16])[N:14]([CH3:13])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Oc1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(OC(C)(C)C)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-tert-butoxy-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad12/25, flash 12, dichloromethane) followed by a recrystallization from ethanol (41%, crystals). HPLC-MS m/z=300.3 (M+1), Rt: 4.7 min.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=O.COC1C=CC(/C=[C:38]2/[C:39]([NH:41][C:42]([S:44]/2)=[NH:43])=[O:40])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[NH2:43][C:42]1[S:44]/[C:38](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])/[C:39](=[O:40])[N:41]=1
Reactant: COCCOCCOc1c(C#N)cnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCCOCCOc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12
Temperature: 130 °C
Reaction time: 12 h
Yield: 23.9 %

Procedure:
The suspension of 6-formyl-4-[2-(2-methoxy-ethoxy)-ethoxy]-quinoline-3-carbonitrile (example 28b, 50 mg, 0.17 mmol), pseudothiohydantoin (19.3 mg, 0.17 mmol), and sodium acetate (55 mg, 0.68 mmol) in acetic acid (180 uL) was stirred at 130° C. for 12 h. After cooling to room temperature, water was added. The solid was collected by filtration, washed with water and dried. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-7% methanol in methylene chloride in 30 min) afforded 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-[2-(2-methoxy-ethoxy)-ethoxy]-quinoline-3-carbonitrile (16.2 mg, 24%) as a slight yellow solid. LC-MS m/e 399 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][C:10]#[N:11].C(C1CCCC([Cl:22])C1=O)(C)(C)C>>[Cl:22][CH:7]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:8][CH2:9][C:10]#[N:11])[C:2]1=[O:1]
Reactant: N#CCCC1CCCCC1=O
Reactant: CC(C)(C)C1CCCC(Cl)C1=O
Product: N#CCCC1CCCC(Cl)C1=O

Procedure:
The chlorination of 2-oxo-1-cyclohexanepropionitrile takes place in a manner similar to that described above for the preparation of 2-tert-butyl-6-chloro-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C@@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.O[CH2:21]N1C2C=CC=CC=2N=N1.[BH4-].[Na+]>CCO.CN(C=O)C>[CH3:21][NH:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C@@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2
Reactant: OCn1nnc2ccccc21
Reactant: Nc1ccc2c(c1)C[C@]1(C2)C(=O)Nc2ncccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CNc1ccc2c(c1)C[C@]1(C2)C(=O)Nc2ncccc21
Temperature: 70 °C

Procedure:
A mixture of (S)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (154 mg, 0.613 mmol, described in Intermediate 3) and 1-(hydroxymethyl)benzotriazole (93 mg, 0.625 mmol) in EtOH (2 mL) and DMF (0.2 mL) was heated at reflux for 4 h, then concentrated to dryness under reduced pressure. The residue was resuspended in THF (3 mL) and sodium borohydride (40 mg, 1.05 mmol) was added. The resulting mixture was heated to 70° C. for 6 h then quenched with H2O (50 mL) and extracted with EtOAc (50 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 80:20, to give the title compound, which was of sufficient purity for use in the next step. MS: m/z=266 (M+1).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15].Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:15][CH:14]([CH3:16])[C:13]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 48370 %

Procedure:
With ice-cooling, a solution of 73.0 g (0.985 mol) of tert-butanol, 190 g (1.877 mol) of triethylamine and 0.573 g (0.0047 mol) of DMAP in 750 ml of dichloromethane is treated with a solution of 100 g (0.939 mmol) of isobutyryl chloride in 150 ml of dichloromethane, and the mixture is then stirred overnight. 500 ml of 2 M hydrochloric acid are then added, the aqueous phase is extracted with dichloromethane and the combined organic phases are washed with water, sat. NaHCO3 solution and sat. NaCl solution, dried over sodium sulphate and concentrated. Distillative purification of the crude product gives 65.5 g (48%) of tert-butyl 2-methylpropionate.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccccn3)nc(NCCc3ccc4c(c3)OCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=2)[C:9]1=[O:30].C(O)C.[Cl-].[NH4+]>[Fe].O>[NH2:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][N:10]1[C:11]2[C:12](=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[N:8]([C@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]2[CH3:1])[C:9]1=[O:30]
Reactant: C[C@@H]1CCCC[C@@H]1n1c(=O)n(Cc2cccc([N+](=O)[O-])c2)c2cnc3[nH]ccc3c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C[C@@H]1CCCC[C@@H]1n1c(=O)n(Cc2cccc(N)c2)c2cnc3[nH]ccc3c21
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of rel-1-[(1S,2R)-2-methylcyclohexyl]-3-(3-nitrobenzyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (150 mg) in a mixed solution of ethanol (1.5 mL) and water (0.45 mL) were added iron powder (62 mg) and ammonium chloride (10 mg). The solution was refluxed for 3 hours. After cooling to ambient temperature, the precipitate was filtered through a pad of Celite. After concentration under reduced pressure, the residue was extracted with chloroform and washed with water and dried over MgSO4. Concentration under reduced pressure to give 3-(3-aminobenzyl)-1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]-pyridin-2(1H)-one (139 mg) as a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:23])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH:32]1[CH2:34][CH2:33]1.O>CN(C)C=O>[CH:32]1([CH2:31][N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[CH:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:23])[CH2:5][CH2:6]2)[CH2:34][CH2:33]1
Reactant: BrCC1CC1
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(CC2CC2)CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 98.5 %

Procedure:
To a solution of 200 mg (0.65 mmol) of 3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 5 ml of N,N-dimethylformamide (DMF), 270 mg (1.95 mmol) of potassium carbonate and 176 mg (1.30 mmol) of bromomethylcyclopropane were added at room temperature subsequently and stirred at about 50° C. for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to afford a residue, which was purified by silica gel column chromatography (chloroform—10% methanol/chloroform) to give 231 mg (0.64 mmol) of the title compound as colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1.Cl.[OH-].[Na+]>O.C(O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:7]=[C:2]([NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH:3]=2)[CH2:15][CH2:16]1
Reactant: COc1cccc(N)c1
Reactant: Clc1cc(N2CCOCC2)nc(-c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc(Nc2cc(N3CCOCC3)nc(-c3ccccc3)n2)c1
Yield: 9.1 %

Procedure:
A mixture of 4-(6-chloro-2-phenyl-4-pyrimidyl)morpholine (50 mg, 0.181 mmol), m-anisidine (20 μl, 0.181 mmol) and aqueous 2N HCl (150 μl) in water:ethanol (1:1, 10 ml) was refluxed for 5 days. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10–12. The mixture was extracted with ethyl acetate (50 ml), which was washed with water (2×25 ml), aqueous saturated NaCl, and dried over anhydrous sodium sulfate. The ethyl acetate solution was concentrated in vacuo and isolated as a yellow solid (6 mg, 9%). 1H NMR (CDCl3): 8.40–8.37 (m, 2H), 7.46–7.43 (m, 3H), 7.31–7.25 (m, 2H), 7.00 (t, J=2.3 Hz, 1H), 6.91 (dd, J=1.7, 8.0 Hz, 1H), 6.70–6.67 (m, 2H), 3.83 (s, 3H), 3.81–3.63 (m, 8H).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:26]([O:28][CH3:29])=[O:27])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][CH:19]=[CH:18][C:17]4[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:30].[Na+].OO>C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:26]([O:28][CH3:29])=[O:27])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][CH2:19][CH:18]([OH:30])[C:17]4[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC=Cc1ccccc1-3
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCCC(O)c1ccccc1-3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
BH3Me2S (1.6 eq, 2M solution in THF) was added to a 0.2M solution of methyl 14-cyclohexyl-7,8-dihydroindolo[2,1-a][2]benzazocine-11-carboxylate in THF, and the mixture was stirred for 2 h at RT. 3M aq NaOH (3 eq) and 35% H2O2 (3 eq) were added at 0° C., and stirring was continued overnight at RT. After dilution with sat NaHCO3 the aq. phase was extracted with EtOAc, the organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give mainly methyl 14-cyclohexyl-5-hydroxy-5,6,7,8-tetrahydroindolo[2,1-a][2]benzazocine-11-carboxylate (with traces of its regioisomer methyl 14-cyclohexyl-6-hydroxy-5,6,7,8-tetrahydroindolo[2,1-a][2]benzazocine-11-carboxylate).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]([NH:8][CH2:9][CH2:10][SH:11])=[N:6][S:5](=[O:13])(=[O:12])[N:4]=1.[CH3:14][N:15]([CH2:17][C:18]1[O:22][C:21]([CH2:23]O)=[CH:20][CH:19]=1)[CH3:16]>Cl>[CH3:14][N:15]([CH2:17][C:18]1[O:22][C:21]([CH2:23][S:11][CH2:10][CH2:9][NH:8][C:7]2[C:3]([NH:2][CH3:1])=[N:4][S:5](=[O:13])(=[O:12])[N:6]=2)=[CH:20][CH:19]=1)[CH3:16]
Reactant: CNC1=NS(=O)(=O)N=C1NCCS
Reactant: CN(C)Cc1ccc(CO)o1
Agent: Cl
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A mixture containing 3-methylamino-4-(2-mercaptoethylamino)-1,2,5-thiadiazole 1,1-dioxide (1.0 g; 4.5 mmoles) [prepared in Step A] and 5-dimethylaminomethyl-2-furanmethanol (0.82 g; 4.5 mmoles) [prepared according to the procedure in J. Chem. Soc., 4728 (1958)] in 20 ml of concentrated hydrochloric acid was stirred in an ice-water bath for 2 hours and then allowed to stand at 0° for 64 hours. The reaction mixture was stirred at ambient temperature for 23 hours, evaporated without heating under reduced pressure and the residue partitioned between water and methylene chloride. The aqueous phase was made basic with sodium bicarbonate and extracted with methylene chloride. The combined organic phase was washed with saturated brine solution, dried and evaporated under reduced pressure. The residue was placed on 25 g of silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fraction was evaporated and the product crystallized from methanol. Recrystallization from methanol yielded the title compound, mp 92°-96°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([Cl:18])[C:13]([CH3:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:26])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([Cl:18])[C:13]([CH2:17][Br:26])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc2c(ccn2C(=O)OC(C)(C)C)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CBr)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
To a stirred solution of 314 (38.1 g, 0.143 mol) in CCl4 (300 mL) at 80° C. was added NBS (30.6 g, 0.172 mol) followed by AIBN (1.2 g, 7.31 mmol), and the reaction mixture was stirred at 80° C. overnight. The cooled reaction mixture was diluted with EtOAc, and the organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (2 to 20% EtOAc) to afford 16.1 g (33%) of tert-butyl-5-(bromomethyl)-4-chloro-1H-indole-1-carboxylate (316) as a white solid: NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 6.71 (d, J=3.8 Hz, 1H), 4.75 (s, 2H), 1.67 (s, 9H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]([C:14]([O:16]CC)=O)=[CH:7]2.[CH3:19][N:20]1C2C(=CC=CC=2)C=C1C(OCC)=O>>[CH3:19][NH:20][C:14]([C:8]1[N:9]([CH3:13])[C:10]2[C:6]([CH:7]=1)=[CH:5][C:4]([F:3])=[CH:12][CH:11]=2)=[O:16]
Reactant: CCOC(=O)c1cc2ccccc2n1C
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1C
Agent: [Na+]
Agent: [OH-]
Product: CNC(=O)c1cc2cc(F)ccc2n1C
Yield: 68 %

Procedure:
According to the procedure of Preparation 1 (b), except substituting ethyl 5-fluoro-1-methyl-1H-indole-2-carboxylate for the ethyl 1-methyl-1H-indole-2-carboxylate, the title compound (2.1 g, 68%) was prepared as a white solid: MS (ES) m/e 207 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[Cl:8][C:4]1[N:3]=[C:2]([NH:15][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: NC1CCCCC1
Product: Clc1cncc(NC2CCCCC2)n1

Procedure:
Was prepared according to Example 1 from 2,6-dichloropyrazine and cyclohexylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=[C:9]2[C:17](N(OC)C)=[O:18])[CH:5]=[CH:6][CH:7]=1.[CH3:23][Mg]Br.CCOCC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=[C:9]2[C:17](=[O:18])[CH3:23])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc2cccnc2n1-c1cccc(F)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cc2cccnc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a mixture of 1-(3-fluorophenyl)-N-methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (0.35 g, 1.2 mmol) in tetrahydrofuran (10 mL) was added 3.0 M methylmagnesium bromide in ether (3.1 mL, 9.4 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl solution and then extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated to give the desired product (0.24 g, 81%). The crude product was used directly in next step. LCMS calculated for C15H12FN2O(M+H)+: m/z=255.1. Found: 255.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#N)=[C:10]([CH3:16])[CH:9]=2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C[OH:28].Cl>C1(C)C=CC=CC=1.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:28])=[C:10]([CH3:16])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cc1cc(-c2ccc(O)cc2)ccc1C#N
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(O)cc2)ccc1C=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
A solution of 4′-hydroxy-3-methyl[1,1′-biphenyl]-4-carbonitrile (500 mg, 2.39 mmol) in dry toluene was cooled to −78° C. and diisobutylaluminum hydride (4.0 mL of 1.5 M solution in toluene, 5.98 mmol) was added all at once. The reaction mixture was allowed to warm to room temperature over a period of 3.5 h. Methanol (1.2 mL) was added followed by water (1.2 mL) at 0° C. and the mixture was stirred at room temperature for 20 min. 1 N HCl solution was added with stirring until pH<7. The mixture was extracted with ethyl acetate (3×), washed with brine, dried over sodium sulfate, filtered, and the solvent evaporated. Purification by silica chromatography (15%-25% ethyl acetate-hexane) to yield 459 mg (91%) of the title compound as a white solid: mp 161-162° C.; 1H NMR (DMSO-d6): δ 2.67 (3H, s), 6.88 (2H, d, J=8.41 Hz), 7.59-7.65 (4H, m), 7.85 (1H,d, J=8.03 Hz), 9.78 (1H, s), 10.22 (1H, s); IR 1680 cm−1; MS (ESI) m/z 211 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH3:17])([C:14](O)=[O:15])[N:9]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Br:26][C:27]1[CH:36]=[C:35]2[C:30]([CH:31]=[CH:32][C:33]([C@H:37]([NH2:39])[CH3:38])=[N:34]2)=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:14](=[O:15])[NH:39][C@@H:37]([C:33]2[CH:32]=[CH:31][C:30]3[C:35](=[CH:36][C:27]([Br:26])=[CH:28][CH:29]=3)[N:34]=2)[CH3:38])([CH3:17])[N:9]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(C)(C(=O)O)N1C(=O)OC(C)(C)C
Reactant: C[C@@H](N)c1ccc2ccc(Br)cc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C)c1ccc2ccc(Br)cc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
To a solution of 3-methyl-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-methyl ester (1.62 g, 4.52 mmol) in tetrahydrofuran/water/methanol (50 mL, 5:1:1) at 0° C. was added lithium hydroxide hydrate (2.2 g, 52.3 mmol). The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 1 h. The reaction mixture was heated at 40° C. for 19 h then cooled to room temperature and the solvent was evaporated. The residue was partitioned between ethyl acetate and water and the mixture was acidified to pH 5 with hydrochloric acid (1 M). The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The residue was dissolved in toluene and the solvent was evaporated to give 3-methyl-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester as a yellow oil (1.47 g, 95%). LCMS (m/z) 343.1 [M−H], Tr=2.36 min. To a solution of 3-methyl-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester (1.37 g, 4.0 mmol) in dichloromethane (30 mL) at 0° C. was added (R)-1-(7-bromo-quinolin-2-yl)-ethylamine hydrochloride (1.30 g, 4.5 mmol) and N,N-diisopropylethylamine (2.8 mL, 16.0 mmol) followed by (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate (1.81 g, 4.76 mmol). The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 2 h. The reaction mixture was diluted with dichloromethane and washed with water. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were passed through a hydrophobic frit and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with a gradient of iso-hexanes/ethyl acetate 20:1 to 0:1 to afford the title compound (929 mg, 40%) as a yellow foam and as a mixture of diastereoisomers. LCMS (m/z) 577.3, 579.2 [M+H], Tr=3.72 min.