Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12]O)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][Cl:18])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(CO)NC(=O)c1cccnc1Cl
Reactant: O=S(Cl)Cl
Product: CC(C)(CCl)NC(=O)c1cccnc1Cl
Temperature: 0 °C

Procedure:
76.8 g (0.336 mole) of 2-chloro 3-(1,1-dimethyl-2-hydroxy-ethyl)aminocarbonyl pyridine are placed in a reaction vessel immersed in a cooling bath (ice+water). 244 ml (3.36 moles) of thionyl chloride are then added so as to maintain the temperature below 20° C.
Reaction SMILES: C([Li])(C)(C)C.[O:6]1[C@H:8]2[C@:9]3([CH2:25][CH2:24][C@H:23]4[C@@H:14]([CH2:15][CH2:16][C:17]5[CH:18]=[C:19]([O:26][CH3:27])[CH:20]=[CH:21][C:22]=54)[C@@H:12]3[CH2:13][C@@H:7]12)[CH2:10][CH3:11].O>CCCCC.CCOCC>[CH3:27][O:26][C:19]1[CH:20]=[CH:21][C:22]2[C@@H:23]3[C@H:14]([C@H:12]4[C@@:9]([CH2:25][CH2:24]3)([CH2:10][CH3:11])[C@H:8]([OH:6])[CH:7]=[CH:13]4)[CH2:15][CH2:16][C:17]=2[CH:18]=1
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1C[C@H]1O[C@H]12
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCCCC
Solvent: CCOCC
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1C=C[C@H]2O
Reaction time: 1 h

Procedure:
At 0° C. and under argon, 4 ml. of a 2-molar tert.-butyllithium solution in pentane is added to 450 mg. of 16α,17α-epoxy-3-methoxy-18-methyl-1,3,5(10)-estratriene in 12 ml. of ether. After 1 hour, the solution is diluted with ether, gently mixed with water, washed neutral, and dried over sodium sulfate. After purifying the crude product by preparative layer chromatography (system: hexane/ethyl acetate = 7 : 3), 140 mg. of 3-methoxy-18-methyl-1,3,5(10),15-estratetraen-17α-ol is obtained as an oily product. [α]D 20 = -105°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10](Cl)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br-].[S:24]1[CH:28]=[CH:27][N:26]=[C:25]1[Zn+]>>[C:1]([O:5][C:6](=[O:22])[N:7]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10]([C:25]2[S:24][CH:28]=[CH:27][N:26]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(Cl)n1
Reactant: [Zn+]c1nccs1
Agent: [Br-]
Product: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(-c2nccs2)n1

Procedure:
Was prepared according to Example 5 from (4-chloro-phenyl)-(6-chloro-pyrazin-2-yl)-carbamic acid tert-butyl ester and 2-thiazolylzinc bromide.
Reaction SMILES: C(N[C@H](C1C=CC=CC=1)C)CC=C.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Br:21].[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.[Cu-]=O>[Br:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([O:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:15]=1
Reactant: Brc1ccccc1Br
Reactant: Oc1ccccc1
Agent: O=[Cu-]
Agent: C=CCCN[C@@H](C)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: Brc1cccc(Oc2ccccc2)c1
Temperature: 195 °C
Yield: 53 %

Procedure:
1-Bromo-3-phenoxy-benzene (A) A mixture of dibromobenzene (3 g, 12.75 mmol), phenol (1 g, 10.6 mmol), copper(I) oxide (152 mgs, 1 mmol), and cesium carbonate (3.46 g, 10.6 mmol) in 8 mL of NMP is heated at 195° C. for 20 minutes in a microwave. The heterogeneous mixture is filtered through a bed of Celite and the residue is washed with EtOAc (1×20 mL). The filtrate is diluted with 1N NaOH (200 mL) and extracted with EtOAc (3×100 mL). The organics were combined, dried over Na2SO4, filtered and concentrated under reduced pressures to give crude product as a yellow oil which is purified by column chromatography (100% hexanes) to give 1-bromo-3-phenoxy-benzene as a colorless oil (1.4 g, 53%). LCMS m/z 250 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:7]=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[N:7]=[N:6][N:5]([CH2:1][CH2:2][C:3]#[C:4][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:9]=1
Reactant: Brc1ccccn1
Reactant: C#CCCn1cc(-c2ccccc2Cl)nn1
Product: Clc1ccccc1-c1cn(CCC#Cc2ccccn2)nn1
Yield: 34.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 1-(but-3-ynyl)-4-(2-chlorophenyl)-1H-1,2,3-triazole (200 mg, 0.86 mmol, Example 259(B)) and 2-bromopyridine (150 mg, 0.95 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 93.4 mg (0.30 mmol, 35%) of 2-(4(4-(2-chlorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[C:25]([C:27]([N:29]2[CH2:35][CH2:34][CH2:33][CH2:32][C:31]3[CH:36]=[CH:37][CH:38]=[CH:39][C:30]2=3)=[O:28])[CH:24]=[CH:23][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[F:18])[N:11]([CH2:19][CH2:20][OH:21])[C:10](=[O:22])[CH2:9]1)=[O:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH3:1][C:2]1[CH:26]=[C:25]([C:27]([N:29]2[CH2:35][CH2:34][CH2:33][CH2:32][C:31]3[CH:36]=[CH:37][CH:38]=[CH:39][C:30]2=3)=[O:28])[CH:24]=[CH:23][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[F:18])[N:11]([CH2:19][CH:20]=[O:21])[C:10](=[O:22])[CH2:9]1)=[O:7]
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(CCO)c2cccc(F)c21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(CC=O)c2cccc(F)c21
Reaction time: 2 h

Procedure:
To a solution of 8-fluoro-4-(2-hydroxyethyl)-3-oxo-3,4-dihydro-2H-quinoxaline-1-carboxylic acid 2-methyl-4-(2,3,4,5-tetrahydrobenzo[b]azepine-1-carbonyl)benzylamide from Example 9 (105 mg, 0.20 mmol) in dichloromethane (5 ml) was added Dess-Martin periodinane (100 mg, 0.24 mg). The mixture was stirred for 2 h and evaporated. The residue was taken up in chloroform and water and separated. The organic layer was dried and evaporated. The residue was purified by flash chromatography on silica (eluant methanol:dichloromethane 4:96) to give a white solid; yield 73 mg, 69%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8](=[CH:13]N(C)C)[C:7](=O)[C:6]=2[CH:18]=1.Cl.[C:20]([NH2:23])(=[NH:22])[CH3:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8]3[CH:13]=[N:22][C:20]([CH3:21])=[N:23][C:7]=3[C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Cl)cc2C1=O
Reactant: CC(=N)N
Agent: Cl
Product: Cc1ncc2c(n1)-c1cc(Cl)ccc1NC(=O)C2
Yield: 58 %

Procedure:
Analogous to Scheme 1, from 7-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and acetamidine hydrochloride. Yield: 58%.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CC(O)C.C1COCC1>[CH3:7][NH:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:7][N:6]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:5][CH2:4]1
Reactant: Clc1ccncc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CNCCC1CCN(c2ccncc2)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
(2.00 g, 8.76 mmol), 4-chloropyridine hydrochloride (1.31 g, 8.76 mmol) and TEA (2.44 ml, 17.55 mmol) were in i-PrOH (10 ml) and heated in the microwave for 2 h at 120° C. The solvent was removed under vacuum. The product was purified by column chromatography (silica gel, DCM/(7 M NH3 in MeOH, 99:1→98:2→95:5). 2. The reaction was performed under an argon atmosphere. The amine from stage 1 (1.87 g, 4.56 mmol) was dissolved in dry THF (75 ml) and cooled to 0° C. A solution of LAH (2.4 M in THF, 7.6 ml, 18.25 mmol) was added dropwise. On completion of the addition the mixture was heated to 60° C. After a reaction time of 4.5 h the mixture was cooled to RT and stirred overnight at RT. Na2SO4.10H2O was added to the reaction solution until no further H2 evolution could be detected. The viscous solution was dried by adding Na2SO4 and filtered after approximately 30 min. The residue was rewashed with THF. The combined filtrates were concentrated to dryness and the crude product obtained was purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)([OH:15])[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)([OH:15])[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(O)(c2cccc(F)c2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(O)(c4cccc(F)c4)C3)CC2)cc1
Yield: 66.9 %

Procedure:
The title compound (D161) (64.7 mg) was prepared according to the experimental procedure described in Description 146 (reaction time 1 h) starting from 5-chloro-2-(3-(3-fluorophenyl)-3-hydroxyazetidin-1-yl)nicotinic acid (D111) (63 mg, 0.195 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (44.4 mg, 0.195 mmol).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH2:24]([N:26]([CH2:43][CH3:44])[CH2:27][CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)[CH3:25].C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C.O>[CH2:43]([N:26]([CH2:24][CH3:25])[CH2:27][CH2:28][N:29]1[CH:33]=[C:32]([C:2]2[CH:23]=[CH:22][C:5]3[C:6]4[N:7]([CH:11]=[C:12]([C:14]5[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=5)[N:13]=4)[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[CH:31]=[N:30]1)[CH3:44]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CCN(CC)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN(CC)CCn1cc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1
Reaction time: 0.17 h
Yield: 32.8 %

Procedure:
A 5 mL microwave vial was charged with 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (347 mg, 0.928 mmol), N,N-diethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanamine (340 mg, 1.16 mmol), 2 M potassium carbonate in water (0.9 mL, 2 mmol), and acetonitrile (1.52 g, 37.1 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride (45.4 mg, 0.056 mmol) was added prior to sealing the vial. The reaction was placed on the microwave at 140° C. for 10 minutes. The cooled reaction mixture was diluted with ethyl acetate and water and partitioned. The organic layer was washed with brine and, dried over sodium sulfate, concentrated in vacuo and purified by HPLC to give 222 (140 mg, 33% yield, M+1 461.6)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:6]([C:15](=[O:17])[CH3:16])[CH:5]=[C:4]([Cl:18])[C:3]=1[CH3:19].Cl[CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25].CC(C)([O-])C.[K+]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:15]([C:6]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:2]([N:1]2[CH2:21][CH2:22][CH2:23][C:24]2=[O:25])[C:3]([CH3:19])=[C:4]([Cl:18])[CH:5]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)c1cc(Cl)c(C)c(N)c1-c1cccc(F)c1
Reactant: O=C(Cl)CCCCl
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c(C)c(N2CCCC2=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
To a mixture of 1-(6-amino-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone (100 mg, 0.4 mmol) and 4-dimethylaminopyridine (52.8 mg, 0.432 mmol) in tetrahydrofuran (1 mL) was added 4-chlorobutanoyl chloride (0.044 mL, 0.40 mmol). The reaction was stirred at room temperature for 1 hour. Potassium tert-butoxide (1.0 M) in tetrahydrofuran (0.79 mL, 0.79 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours, then quenched with aq. ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried and evaporated. The resulting residue was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, to give the product (40 mg, 30%). LCMS calculated for C19H18ClFNO2 (M+H)+: m/z=346.1. found: 346.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C.C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:5]([CH:4]=1)[NH2:6]
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(N)c1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1ccc([N+](=O)[O-])c(N)c1
Temperature: 5 °C

Procedure:
A solution of 3-methoxyaniline (2.21 g) in acetic acid (3 ml) and acetic anhydride (10 ml) was stirred at room temperature for 1 hour. The solution was cooled to 5° C. and 60% nitric acid (1 ml) was added dropwise with stirring. When the cooling bath was removed, whereupon the solution temperature rose to 60° C. The solution was allowed to cool down to room temperature, poured into ice-water (100 ml) and neutralized with sodium hydroxide. The separated crystals were collected by suction and washed with water. To the crystals was added 4N hydrochloric acid (45 ml) and the mixture was refluxed for 2 hours. The reaction mixture was alkalized with sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: chloroform) to give 0.67 g of 5-methoxy-2-nitroaniline.
Reaction SMILES: [CH2:1]([N:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]C1C(=O)C(Br)=CC(Br)(Br)C=1>ClCCl>[CH2:1]([N:8]([C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)c1ccccc1
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Solvent: ClCCl
Product: CN(Cc1ccccc1)c1ccc(Br)cc1
Reaction time: 20 h
Yield: 56.7 %

Procedure:
N-benzyl-N-phenyl-N-methylamine (4.41 g, 0.0224 mol) was dissolved in anhydrous dichloromethane (150 mL) and 2,4,4,6-tetrabromocyclohexadiene-1-one(9.16 g, 0.0224 mol) was added in 10 equal portions over a 30 min. period. Stirring was continued at ambient temperature for 20 hours. The organic phase was successively washed with 0.5N solution of sodium hydroxide in water (100 mL), 1N solution of sodium hydroxide in water (100 mL), water (120 mL) and brine (120 mL). The organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (1:99) as mobile phase to yield N-benzyl-N-(4-bromophenyl)-N-methylamine (3.52 g, 0.0127 mol) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]2[N:7]([C:10]3[CH:11]=[C:12]([NH:24]C(=O)C)[CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=4[F:23])[CH:15]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].[OH-:30].[K+]>C(O)C>[NH2:24][C:12]1[CH:11]=[C:10]([N:7]2[C:6]3[CH:28]=[CH:29][C:3]([C:1]([NH2:2])=[O:30])=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:13]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(C#N)ccc32)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: NC(=O)c1ccc2c(c1)ncn2-c1cc(N)cc(-c2ccc(F)cc2F)c1
Temperature: 85 °C
Yield: 71 %

Procedure:
To a solution of N-(5-(5-cyano-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide (0.5 g, 1.28 mmol, 1 eq.) in ethanol (10 ml) was added 20% aqueous solution of potassium hydroxide (0.721 g, 12.88 mmol, 10 eq.) and the mixture was heated at 85° C. for 5 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford title product in 71% yield (0.32 g). LC-MS (ESI): Calculated mass: 364.11; Observed mass: 365.1 [M+H]+ (rt: 0.59 min).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:16]=[C:15]([NH:17][C:18]([C:20]3([C:23]4[CH:33]=[CH:32][C:26]5[O:27][C:28]([F:31])([F:30])[O:29][C:25]=5[CH:24]=4)[CH2:22][CH2:21]3)=[O:19])[CH:14]=[CH:13][C:12]=2[CH3:34])=[CH:5]1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37].C(N(CC)CC)C>CN(C)C=O>[F:30][C:28]1([F:31])[O:27][C:26]2[CH:32]=[CH:33][C:23]([C:20]3([C:18]([NH:17][C:15]4[N:16]=[C:11]([C:6]5[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH2:3][CH2:2][NH:1][C:36](=[O:37])[O:38][CH2:39][CH3:40])[CH:5]=5)[C:12]([CH3:34])=[CH:13][CH:14]=4)=[O:19])[CH2:22][CH2:21]3)=[CH:24][C:25]=2[O:29]1
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)n(CCN)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)NCCn1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)ccc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
To a flask containing N-(6-(1-(2-aminoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (36 mg, 0.08 mmol), ethyl chloroformate (10 mg, 0.09 mmol), and triethylamine (32 μL, 0.23 mmol) was added N,N-dimethyl formamide (1 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and purified by reverse-phase preparative liquid chromatography to give the product (11 mg, 25%). ESI-MS m/z calc. 540.18. found 541.7 (M+1)+. Retention time 1.72 minutes.
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)=[CH:10][CH2:9][C:8]=2[C:7]([O:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].C([OH:27])C>[Pd]>[CH3:23][CH:22]([CH3:24])[CH2:21][CH2:20][O:19][C:7]1[C:8]2[C:9](=[O:27])[CH:10]=[C:11]([C:14]3[NH:15][N:16]=[N:17][N:18]=3)[O:12][C:13]=2[C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: C=CCc1ccc(OCCC(C)C)c2c1OC(c1nnn[nH]1)=CC2
Reactant: CCO
Agent: [Pd]
Product: CCCc1ccc(OCCC(C)C)c2c(=O)cc(-c3nnn[nH]3)oc12

Procedure:
A solution of 1.0 parts of 5-[8-allyl-5-(3-methyl-n-butoxy)-4H-1-benzopyran-2-yl]tetrazole in 19 parts of ethanol was hydrogenated overnight at room temperature and pressure using 0.02 parts of 5% palladium on charcoal as catalyst. The reaction mixture was filtered and the solvent removed by evaporation. Cystallisation of the residue from ethanol gave 0.52 parts of 5-[5-(3-methyl-n-butoxy)-8-n-propyl-4-oxo-4H-1-benzopyran-2-yl]tetrazole, m.p. 202°-204° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3Cl)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[CH2:39][NH2:40])=[CH:34][CH:33]=1>>[C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3[NH:40][CH2:39][CH:38]([C:35]2[CH:34]=[CH:33][C:32]([CH3:31])=[CH:37][CH:36]=2)[C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: Cc1ccc(C(CN)c2ccc(C)cc2)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(C)cc4)c4ccc(C)cc4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The compound was prepared from (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (Preparation 45) and 2,2-bis(4-methylphenyl)ethanamine (J. Med. Chem., 1969, 12 (1), 9) using a similar method to that of Preparation 64.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7](Cl)[CH:6]=1)=[O:4].Cl.[NH2:18][C@H:19]1[CH2:23][CH2:22][N:21]([C:24](=[O:37])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[CH2:20]1.C(N(CC)CC)C.C(O)(C)C>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:16])[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24](=[O:37])[CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:30][CH:31]=3)[CH2:20]2)[CH:6]=1)=[O:4]
Reactant: N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: CN(C)C(=O)c1cc(Cl)nc2ccccc12
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN(C)C(=O)c1cc(N[C@H]2CCN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C2)nc2ccccc12
Temperature: 130 °C
Yield: 18.5 %

Procedure:
A mixture of 2-chloroquinoline-4-carboxylic acid dimethylamide (0.20 g), 1-((S)-3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (0.13 g), triethylamine (95 mg), and isopropanol (0.85 mL) was heated at 130° C. in a microwave reaction apparatus for 1.5 h. The reaction mixture was diluted with chloroform, washed with 1 M aqueous sodium hydroxide, and then dried with anhydrous magnesium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=1:3−ethyl acetate) to obtain 2-((S)-1-(2-(4-trifluoromethoxyphenyl)ethanoyl)pyrrolidin-3-ylamino)quinoline-4-carboxylic acid dimethylamide (36 mg). (2) 2-((S)-1-(2-(4-Trifluoromethoxyphenyl)ethanoyl)pyrrolidin-3-ylamino)quinoline-4-carboxylic acid dimethylamide (36 mg) was dissolved in ethyl acetate, followed by addition of a solution (0.046 mL) of 4 M HCl in ethyl acetate. The mixture was concentrated under reduced pressure, and then the resulting residue was solidified with a mixed solvent of diisopropyl ether and chloroform to obtain the title compound (21 mg).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]2[CH2:13][CH2:14][C@@:15]3([CH:19]=[CH:18][CH2:17][O:16]3)[C@:9]1([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:10][C@H:11]2[S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:36]1[C:44]2[O:43][CH:42]([CH3:45])[CH2:41][C:40]=2[CH:39]=[C:38]([O:46][C:47]([F:50])([F:49])[F:48])[CH:37]=1.[Cl-].[Li+].C([O-])=O.[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O.O>[CH2:1]([N:8]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]3([CH2:19][C@@H:18]([C:36]4[C:44]5[O:43][CH:42]([CH3:45])[CH2:41][C:40]=5[CH:39]=[C:38]([O:46][C:47]([F:49])([F:48])[F:50])[CH:37]=4)[CH2:17][O:16]3)[C@:9]1([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:10][CH:11]2[S:20]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:21])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1Cc2cc(OC(F)(F)F)cc(I)c2O1
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@@]21C=CCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CC1Cc2cc(OC(F)(F)F)cc([C@H]3CO[C@]4(CC[C@@H]5C(S(=O)(=O)c6ccccc6)C[C@]4(c4ccccc4)N5Cc4ccccc4)C3)c2O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.2 %

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-1-phenyl-6-phenylsulphonylspiro[8-azabicyclo[3.2.1]octane-2,2′(5′H)-furan] (Description 15; 500 mg, 1.05 mmol), 2,3-dihydro-7-iodo-2-methyl-5-trifluoromethoxybenzofuran (Description 22; 1.11 g, 3.22 mmol), tetra-n-butylammonium chloride (310 mg, 0.96 mmol), lithium chloride (640 mg, 1.48 mmol), potassium formate (420 mg, 5 mmol), palladium(II) acetate (47 mg, 0.21 mmol), water (0.2 ml) and N,N-dimethylformamide (5 ml) was stirred at +65° C. for 24 hours. An additional batch of 2,3-dihydro-7-iodo-2-methyl-5-trifluoromethoxybenzofuran (0.7 g, 2.0 mmol) and palladium(II) acetate (22 mg, 0.1 mmol) was added and the reaction mixture was stirred at +65° C. for 48 hours. The mixture was cooled to room temperature, quenched with saturated aqueous NaHCO3 and extracted into diethyl ether. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-45%) to give the title compound (320 mg, 44%) as a 1:1 mixture of epimers.