Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3].C1(=O)NC(=O)CC1.[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([N:29]1[CH2:34][CH2:33][N:32]([C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[NH:1][C:2](=[O:3])[CH2:4][CH2:5]3)=[O:14])[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1CCc2cc(C(=O)O)ccc2N1
Agent: O=C1CCC(=O)N1
Solvent: O
Product: O=C1CCc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
127 Milligrams of succinimide 3,4-dihydrocarbostyril-6-carboxylate and 93 mg of benzylpiperazine were dissolved in 2 ml of dimethylformaide and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture and extracted with chloroform, the chloroform layer was washed with water and a saturated sodium chloride aqueous solution. After drying the chloroform layer with anhydrous sodium sulfate, chloroform was removed by distillation under a reduced pressure, then acetone was added to the thus obtained residue to crystallize the product. Recrystallize from ethanol to obtain 130 mg of 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 198°-200° C.
Reaction SMILES: [BH4-].[Na+].C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[C:13]1([C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[OH:25][C@H:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(=O)c1ccccc1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](O)c1ccccc1
Temperature: 70 °C
Reaction time: 19 h

Procedure:
To a dispersion of 0.43 g (11.3 mmol) of sodium borohydride in THF (35 ml), there was added 1.70 g (11.3 mmol) of L-(+)-tartaric acid, and the mixture was heated under reflux for four hours in an oil bath at 70° C. with stirring. The resulting mixture was cooled in a cryostat at -20° C., a solution of 0.5 g (2.8 mmol) of ethyl phenylglyoxylate in THF (5 ml) was added dropwise over a period of ten minutes, and stirring was continued for 19 hours. The reaction mixture was treated in the same manner as in Example 6, giving 0.44 of ethyl (R)-(-)-2-hydroxy-2-phenylacetate, having a specific rotation [α]D16 of -109° (cl. 00, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18].O>CN(C=O)C>[C:17]([C:10]1[C:11]2[NH:12][C:13]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:14]=3)[C:6]=2[CH:7]=[CH:8][N:9]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc2c(c1)[nH]c1cnccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1nccc2c1[nH]c1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the product from example 12 (104 mg, 0.50 mmol) in DMF (2.0 ml) at 3° C. to 5° C. was added NaH (95%, 15 mg, 0.625 mmol). The resulting mixture was stirred for 15 min before adding acetic anhydride (0.083 ml, 0.875 mmol). The reaction was allowed to warm to RT and stirred for 3 h before pouring into with water (25 ml). The slurry was stirred for 12 h, and the product collected to give after chromatography (1:3 hexane-ethyl acetate) on silica gel 82 mg of 1-acetyl-7-chloro-β-carboline.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]I)=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([CH:21]([C:17]2[O:16][CH:20]=[CH:19][CH:18]=2)[OH:22])[CH:3]=1
Reactant: Brc1ccc(CCI)cc1
Reactant: O=Cc1ccco1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc(Br)cc1C(O)c1ccco1
Temperature: -70 °C
Reaction time: 0.67 h
Yield: 90 %

Procedure:
4-Bromo-2-iodoethyl benzene (50.0 g, 160.8 mmol) is dissolved in anhydrous tetrahydrofuran (250 ml) and cooled to −70° C. under an atmosphere of nitrogen. Isopropylmagnesium chloride (2M solution in THF, 100 ml, 200 mmol) is added dropwise with vigorous stirring over 40 minutes, maintaining the internal temp below −60° C. by external cooling. When the addition is complete, the reaction is stirred at −70° C. for 20 minutes then allowed to warm to room temperature over 1 h 20 minutes. The reaction mixture is then cooled to −70° C. and a solution of 2-furaldehyde (16 ml, 18.6 g, 190 mmol) in tetrahydrofuran (50 ml) is added dropwise over 40 minutes. On completion of the addition, the reaction is allowed to warm to room temperature and stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution (−500 ml) is added and the mixture is extracted into ethyl acetate. The organic solutions are combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is further purified by column chromatography on silica gel to give (5-bromo-2-ethylphenyl)furan-2-ylmethanol (40.7 g).
Reaction SMILES: [CH:1]([N:5]=[C:6]=[O:7])([CH2:3][CH3:4])[CH3:2].[CH3:8][CH:9]1[CH:14]([CH3:15])[CH2:13][CH2:12][CH2:11][CH:10]1[OH:16]>O>[CH3:8][CH:9]1[CH:14]([CH3:15])[CH2:13][CH2:12][CH2:11][CH:10]1[O:16][C:6](=[O:7])[NH:5][CH:1]([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)N=C=O
Reactant: CC1CCCC(O)C1C
Solvent: O
Product: CCC(C)NC(=O)OC1CCCC(C)C1C
Yield: 53 %

Procedure:
50.7 g (0.5 mol) sec.-Butyl isocyanate were placed in a 500 ml vessel at ambient temperature and 64.1 g (0.5 mol) 2,3-dimethylcyclohexanol were added. The reaction mixture was heated for 5 h to 150° C., cooled and subsequently 100 ml water were added. After refluxing for one hour the solution was cooled down, the phases separated and extracted once with MTBE (methyl tert.-butyl ether). The raw product was purified by distillation to yield 60.2 g product as a mixture of isomers with a purity of 99.6%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([CH3:22])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]2[CH:21]=[C:20]([CH3:22])[S:19][C:17]=2[N:18]=1
Reactant: Cc1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3-nitrobenzylamine with 2,4-dichloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][OH:27])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)(Cl)Cl>[C:35]([O:27][CH2:26][CH2:25][N:18]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:24]2[C:16]([C:7]2[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=2)=[N:17]1)(=[O:37])[CH3:36]
Reactant: CC(C)(C)c1cc(-c2nn(CCO)c3ncccc23)cc(C(C)(C)C)c1O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCn1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21
Yield: 86.3 %

Procedure:
To a solution of 5.2 g of the compound of Example 43 in 30 ml of chloroform is added 2.1 g of triethylamine, and the mixture is cooled and then stirred. To the reaction mixture is added dropwise 1.7 g of acetyl chloride below 0° C. over 5 minutes. After completion of the addition, the mixture is stirred at room temperature for 3 hours, and the reaction solution is washed with water, dried and concentrated. The residue is recrystallized from isopropyl alcohol to give 5 g of 1-(2-acetoxyethyl)-3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 115°-116° C.
Reaction SMILES: O[CH:2]([C:4]1[N:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)[CH3:3].S(Cl)([Cl:16])=O>ClCCl>[Cl:16][CH:2]([C:4]1[N:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)[CH3:3]
Reactant: CC(O)c1cc2c(cn1)CCCC2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(Cl)c1cc2c(cn1)CCCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
3-(1-Hydroxyethyl)-5,6,7,8-tetrahydroisoquinoline (360 mg, 2.0 mmole) was dissolved in 4 ml dichloromethane in a 25 ml one neck round bottom flask under nitrogen. The solution is cooled to 0° C., is treated dropwise with thionyl chloride (218 μl, 3.0 mmole) in 3 ml dichloromethane, and is stirred 2 h at 0° C. followed by 1.5 h at room temperature. The mixture is recooled to 0° C., is quenched with 20 ml saturated sodium bicarbonate, and the layers are separated. The aqueous layer is extracted with 4×10 ml dichloromethane and the combined organics are dried over potassium carbonate. The dried organics are concentrated in vacuo to an amber oil. The crude material is chromatographed over 30 g silica gel (230-400 mesh), eluting with 20% acetone/hexane, while collecting 5 ml fractions. Fractions 11-16 are combined and concentrated to afford 339 mg (87%) of 3-(1-chloroethyl)-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:5]=2[CH:4]=[C:3]1[C:14]([O:16][CH3:17])=[O:15].[H-].[Na+].[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]N)=[CH:24][CH:23]=1)#[N:21].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.O>[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:7]2[C:2](=[O:1])[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:5]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]2=3)=[CH:24][CH:23]=1)#[N:21]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(=O)c1cc2c([nH]c1=O)CCCCCC2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2c(n(Cc3ccc(C#N)cc3)c1=O)CCCCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under the nitrogen gas atmosphere, methyl 2-oxo-1,2,5,6,7,8,9,10-octahydro-cycloocta[b]pyridine-3-carboxylate (300 mg, 1.27 mmol) was dissolved in DMF (5 mL), sodium hydride (61 mg, 1.53 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After that, 4-cyanobenzylamine (274.9 mg, 1.40 mmol) was added, and the mixture was further stirred at room temperature for 1 hour. Subsequently, water and 5% citric acid were added to the reaction mixture, and the obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was refined with silica gel (10 g) column chromatography (ethyl acetate-hexane of 1:1 in mixing ratio), and colorless solid of methyl 1-(4-cyanobenzyl)-2-oxo-1,2,5,6,7,8,9,10-octahydro-cycloocta[b]pyridine-3-carboxylate (AA04, 100 mg, 22%, mp: 72-75° C.) and colorless solid of methyl 2-(4-cyanophenoxy)-5,6,7,8,9,10-hexahydro-cycloocta[b]pyridine-3-carboxylate (123 mg, 28%, mp: 122-123° C.) were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]4[C:24]5[CH:36]=[CH:35][CH:34]=[N:33][C:25]=5[NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:22]4=[N:21][C:20]=3[CH2:37][C:38]([OH:40])=O)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>ClCCl>[O:40]=[C:38]([NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:37][C:20]1[N:21]=[C:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[NH:26][C:25]3[N:33]=[CH:34][CH:35]=[CH:36][C:24]=3[N:23]2[C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:11][CH2:12]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(CC(=O)O)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(CC(=O)Nc4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.3 %

Procedure:
To a solution of 2-(3-(4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)phenyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)acetic acid (0.04 g, 1 eq.) in dichloromethane (2 mL) was added successively aniline (0.027 g, 4 eq.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (0.029 g, 2 eq.) and diisopropylethylamine (70 μL, 5 eq.). The reaction was stirred at room temperature for 20 hours. The reaction mixture was diluted with dichloromethane (10 mL), washed with water (2×10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by preparative HPLC (YMC PACK ODS-AM; AM12S05-1020WT; 100×20 mm ID; CAN/0.1% TFA, 30 mL/min) gave tert-butyl (1-(4-(2-(2-oxo-2-(phenylamino)ethyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.022 g, 48%). LCMS: 613 [M+H].
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([C:17]([O:19][CH3:20])=[O:18])#[C:12][C:13]([O:15][CH3:16])=[O:14]>CO>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:12](=[CH:11][C:17]([O:19][CH3:20])=[O:18])[C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: COC(=O)C=C(Nc1ccc([N+](=O)[O-])cc1)C(=O)OC
Temperature: 25 °C
Yield: 45.9 %

Procedure:
A solution of 4-nitroaniline (6.91 g, 50 mmol) and dimethyl acetylenedicarboxylate (7.82 g, 55 mmol) in methanol (100 ml) was refluxed under heating for 24.5 hr. The reaction vessel was cooled to room temperature and allowed to stand for a day. The resulting crystals were collected by filtration to give dimethyl 2-[(4-nitrophenyl)amino]-2-butenedioate (6.43 g, 46%, yellow crystals).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=5)=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][CH2:37][CH2:38][N:39]1[CH:43]=[CH:42][C:41](B2OC(C)(C)C(C)(C)O2)=[N:40]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:29][N:27]1[CH:28]=[C:24]([C:21]2[N:20]=[C:19]3[N:15]([CH2:14][CH:10]4[CH2:11][CH2:12][CH2:13][N:8]([C:5]5[N:4]=[CH:3][C:2]([C:41]6[CH:42]=[CH:43][N:39]([CH2:38][CH2:37][O:36][CH:31]7[CH2:32][CH2:33][CH2:34][CH2:35][O:30]7)[N:40]=6)=[CH:7][N:6]=5)[CH2:9]4)[N:16]=[N:17][C:18]3=[N:23][CH:22]=2)[CH:25]=[N:26]1
Reactant: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(Br)cn5)C4)c3n2)cn1
Reactant: CC1(C)OB(c2ccn(CCOC3CCCCO3)n2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(-c6ccn(CCOC7CCCCO7)n6)cn5)C4)c3n2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
1-((1-(5-bromopyrimidin-2-yl)piperidin-3-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (30 mg, 0.066 mmol), 1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (32 mg, 0.099 mmol), Pd(dppf)2Cl2(2.7 mg, 0.003 mmol), and K2CO3(28 mg, 0.20 mmol) were dissolved in dioxane (1.2 ml)+H2O (0.3 ml), and the mixture was degassed with N2(gas), followed by stirring at 80° C. for 2 hours. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (MeOH:MC=1:20), to give 6-(1-methyl-1H-pyrazol-4-yl)-1-((1-(5-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-3-yl)pyrimidin-2-yl)piperidin-3-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (28 mg, 78%).
Reaction SMILES: [C:1]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3Cl)[C@H:11](O)[C@@H:10]1O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[C:43]1([CH:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:50][NH2:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C1COCC1>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([N:8]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH:10]=[CH:11]2)=[C:19]([NH:51][CH2:50][CH:49]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[N:18]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
(1S,2R,3S,5R)-3-(di-Boc-amino)-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol (13.0 g, 27.66 mmol) is dissolved in THF (250 mL) under an atmosphere of argon. DIPEA (4.28 g, 33.19 mmol) is added followed by 2,2-diphenylethylamine (6.0 g, 30.43 mmol) and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 18 hours. The solvent is removed in vacuo and the reaction mixture is partitioned between dichloromethane (250 mL) and 0.1 M HCl (250 mL). The organic layer is washed with water (200 mL) and brine (200 mL), dried over MgSO4, filtered and the solvent is removed in vacuo to give the title compound.
Reaction SMILES: [C:1]([CH:3]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([NH:26][C:27]([NH:29][CH2:30][CH2:31][CH3:32])=[O:28])(=[O:25])=[O:24])=[CH:13][CH:12]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C([O-])([O-])=O.[K+].[K+].[C:39](Cl)(=[O:44])[CH2:40][CH2:41][CH2:42][CH3:43]>CC(C)=O>[C:1]([CH:3]([N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([NH:26][C:27]([NH:29][CH2:30][CH2:31][CH3:32])=[O:28])(=[O:25])=[O:24])=[CH:15][CH:16]=1)[C:39](=[O:44])[CH2:40][CH2:41][CH2:42][CH3:43])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCCNC(=O)NS(=O)(=O)c1ccccc1-c1ccc(CNC(C#N)C(=O)OCC)cc1
Reactant: CCCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)NCCC)cc1)C(C#N)C(=O)OCC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.7 g of the product of Stage A were dissolved in 50 ml of acetone and 0.79 g of K2CO3 and 0.45 ml of valeryl chloride were added. The mixture was stirred for 6 hours at ambient temperature and the insoluble part was filtered. The filtrate was evaporated to dryness, which after purification by chromatography (eluant: dichloromethane-ethyl acetate 4-1) yielded 295 mg of the expected product with a Rf (SiO2, dichloromethane ethyl acetate 4-1)=0.30.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([O:28][CH3:29])[C:13]([N:20]3[CH2:25][CH:24]([CH3:26])[NH:23][CH:22]([CH3:27])[CH2:21]3)=[C:14]([F:19])[CH:15]=2)[N:10]([CH2:30][C:31]([F:34])([F:33])[F:32])[CH:9]=1)=[O:7].N1C=CC=CC=1.[Cl-].[C:47]([O:52][CH2:53][CH3:54])(=[O:51])[C:48]([O-])=[O:49]>ClCCl.C(OCC)(=O)C>[CH2:53]([O:52][C:47](=[O:51])[C:48]([N:23]1[CH:22]([CH3:27])[CH2:21][N:20]([C:13]2[C:12]([O:28][CH3:29])=[C:11]3[C:16]([C:17](=[O:18])[C:8]([C:6]([NH:5][CH2:4][C:3]4[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:2]=4[Cl:1])=[O:7])=[CH:9][N:10]3[CH2:30][C:31]([F:33])([F:34])[F:32])=[CH:15][C:14]=2[F:19])[CH2:25][CH:24]1[CH3:26])=[O:49])[CH3:54]
Reactant: COc1c(N2CC(C)NC(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(CC(F)(F)F)c12
Reactant: CCOC(=O)C(=O)[O-]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)N1C(C)CN(c2c(F)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4Cl)cn(CC(F)(F)F)c3c2OC)CC1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
200 mg of the compound from Example 37A are dissolved in 3 ml of dichloromethane and 0.26 ml of pyridine and 71 μl of ethyl oxalate chloride are then added. The mixture is stirred at RT for 3 h. For the work-up, the mixture is diluted with ethyl acetate, and extracted by shaking twice with water, once with a saturated sodium hydrogen carbonate solution and once with a saturated sodium chloride solution. The organic phase is dried over sodium sulfate, concentrated in vacuo, and dried under high vacuum. 220 mg of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C:10](=O)[CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]([NH2:27])[CH3:26])=[CH:21][C:20]=1[O:28][CH3:29]>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]([NH:27][CH:10]2[CH2:11][CH2:12][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([C:14]([F:17])([F:16])[F:15])[CH:4]=3)[CH2:9]2)[CH3:26])=[CH:21][C:20]=1[O:28][CH3:29]
Reactant: COc1cc([C@@H](C)N)ccc1F
Reactant: O=C1CC[C@H](c2ccc(O)c(C(F)(F)F)c2)C1
Product: COc1cc([C@@H](C)NC2CC[C@H](c3ccc(O)c(C(F)(F)F)c3)C2)ccc1F

Procedure:
General procedure A was followed using (S)-3-(4-hydroxy-3-trifluoromethyl-phenyl)-cyclopentanone (Preparation 10) as the ketone and (R)-1-(4-fluoro-3-methoxyphenyl)-ethylamine as the amine. 1H NMR (300 MHz, DMSO) δ 10.22 (bs, 1H), 7.39-7.20 (m, 2H), 7.19-7.04 (m, 2H), 6.96-6.84 (m, 2H), 3.82 (s, 3H), 3.73 (q, 1H), 3.26-2.79 (m, 2H), 2.24-1.27 (m, 7H), 1.23 (d, 3H).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[CH3:7][N:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:18].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Br:1][CH:2]([CH3:6])[C:3]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[N:8]([CH3:7])[CH2:17]2)=[O:4]
Reactant: CN1Cc2ccccc2NC1=O
Reactant: CC(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Br)C(=O)c1ccc2c(c1)CN(C)C(=O)N2

Procedure:
2-Bromopropionyl bromide (71.02 g) is added dropwise to a stirred mixture of 3,4-dihydro-3-methyl-2(1H)quinazolinone (26.75 g) and anhydrous aluminum chloride (54.98 g) in carbon disulfide (350 ml). The reaction mixture is stirred under reflux for 5 hrs., the carbon disulfide decanted, and the residue treated with HCl (6N). The resulting solid is filtered, and washed with water and dried in vacuo to obtain 6-(2-bromopropionyl)-3,4,dihydro-3-methyl-2(1H)-quinazolinone which is used in the next step.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[Cl:31])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.[F:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1B(O)O.[F-].[Cs+].C(N(CC)CC)C>CC(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:31][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][C:14]1[CH:32]=[CH:33][C:11]([C:9](=[O:10])[NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([C:38]4[CH:37]=[CH:36][C:35]([F:34])=[CH:40][C:39]=4[F:41])[N:7]=3)=[CH:12][CH:13]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(Br)n4)cc3)c(Cl)cc21
Reactant: OB(O)c1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(F)cc5F)n4)cc3)c(Cl)cc21
Temperature: 105 °C
Yield: 70.6 %

Procedure:
Ethyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (Example 52, Step A, 40 mg, 0.0752 mmol), 2,4-difluorophenylboronic acid (15.4 mg, 0.0978 mmol), and cesium fluoride (29.7 mg, 0.196 mmol) in i-PrOH (1 ml) were sparged with argon for 2 minutes in a vial. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (3.09 mg, 0.00376 mmol) and triethylamine (15.7 μl, 0.113 mmol) were added and the vial capped. The reaction was heated to 105° C. for 90 minutes. The reaction was applied directly to a silica gel column and eluted with 20 to 80% ethyl acetate/hexanes gradient to provide the title compound (30 mg, 0.0531 mmol, 70.6% yield) as a white foam.