Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:32]2[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=2[O:34][C:35]=1[CH3:36])=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:32]4[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=4[O:34][C:35]=3[CH3:36])=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: Cc1oc2ccccc2c1C(=O)CCCCCBr
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2c(C)oc3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(2-methyl-3-benzo[b]furyl)-1-hexanone were reacted and treated in the same manner as in Example 172 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(2-methyl-3-benzo[b]furyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH:4]([OH:6])[CH3:5].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:18]([CH3:20])[CH3:19])=[C:16]=[O:17])=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH:18]([CH:15]([C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=1)[C:16]([O:6][CH:4]([CH3:5])[CH2:3][N:2]([CH3:7])[CH3:1])=[O:17])([CH3:20])[CH3:19]
Reactant: CC(O)CN(C)C
Reactant: CC(C)C(=C=O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CC(CN(C)C)OC(=O)C(c1ccc(Cl)cc1)C(C)C
Reaction time: 1.25 h

Procedure:
A 1 dram vial fitted with a septum cap was charged with 0.69 g of toluene followed by 1.08 g of optically-active 1-(dimethylamino)-2-propanol. The resulting mixture was chilled with ice and then 0.196 g of (4-chlorophenyl)isopropylketene was injected. The reaction temperature rose slowly to 30° C. The color discharged after 1.25 hours at room temperature. The reaction product was separated by gas liquid chromatography to give the desired product in a diastereomer ratio of 25.6% of isomer pair 1 and 74.4% of isomer pair 2.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([CH:26]([CH3:28])[CH3:27])[C:10]3[N:15]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([O:23]C)=[C:18]([CH3:25])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([CH:26]([CH3:27])[CH3:28])[C:10]3[N:15]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH3:25])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: COc1c(C)cc(-c2nc3c(C(C)C)nc(Cc4ccc(Cl)cc4)nc3o2)cc1C
Agent: BrB(Br)Br
Product: Cc1cc(-c2nc3c(C(C)C)nc(Cc4ccc(Cl)cc4)nc3o2)cc(C)c1O
Yield: 70 %

Procedure:
Analogously to example 1 (e), the reaction of 170 mg of 5-(4-chlorobenzyl)-7-isopropyl-2-(4-methoxy-3,5-dimethylphenyl)oxazolo[5,4-d]pyrimidine with boron tribromide gave 115 mg (70%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH2:24]Cl)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:35]=[C:32]([CH:33]=O)[C:31]([OH:36])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[O:36][C:31]4[CH:30]=[CH:29][C:28]([Cl:27])=[CH:35][C:32]=4[CH:33]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)CCl)CC2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3cc4cc(Cl)ccc4o3)CC2=O)CC1
Temperature: 100 °C
Reaction time: 48 h
Yield: 9.1 %

Procedure:
A mixture of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-(chloromethanesulfonyl)-2-piperazinone (2.47 g), 5-chlorosalicylaldehyde (917 mg), potassium carbonate (810 mg) and DMF (30 ml) was stirred at 100° C. for 2 days, and the reaction solution was concentrated. To the residue was added water, and the mixture was extracted with ethyl acetate, washed with water and brine, dried and concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:4) to give colorless solid of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-(5-chlorobenzofuran-2-sulfonyl)-2-piperazinone (272 mg).
Reaction SMILES: [C:1]([CH2:6][CH:7]([CH:9]1[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]1=[O:17])[CH3:8])([O:3][CH2:4][CH3:5])=[O:2].[CH2:18](Br)[CH:19]=[CH2:20]>>[CH2:20]([C:9]1([CH:7]([CH3:8])[CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]1=[O:17])[CH:19]=[CH2:18]
Reactant: CCOC(=O)CC(C)C1C(=O)NC(=O)NC1=O
Reactant: C=CCBr
Product: C=CCC1(C(C)CC(=O)OCC)C(=O)NC(=O)NC1=O

Procedure:
5-(β-Carboethoxy-α-methyl-ethyl)-barbituric acid was treated with allyl bromide at 50° C. to afford 5-allyl-5-(β-carboethoxy-α-methyl-ethyl)-barbituric acid, m.p. 114°. Alkaline saponification of this compound afforded 5-allyl-5-(β-carboxy-α-methyl-ethyl)-barbituric acid, which was recrystallized from water, m.p. 200°.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].BrN1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.Cl.[C:35]([O:39][C:40](=[O:44])[CH2:41][NH:42][CH3:43])([CH3:38])([CH3:37])[CH3:36].C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOC(C)=O.O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH2:1][N:42]([CH3:43])[CH2:41][C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:44])=[C:3]([C:10]([F:11])([F:12])[F:13])[CH:4]=1)#[N:7]
Reactant: Cc1ccc(C#N)cc1C(F)(F)F
Reactant: CNCC(=O)OC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1C(F)(F)F
Temperature: 70 °C
Yield: 58.2 %

Procedure:
A solution of 4-methyl-3-(trifluoromethyl)benzonitrile (1.85 g, 10 mmol), N-bromosuccinimide (2.14 g, 12.0 mmol) and AIBN (0.033 g, 0.2 mmol) in ACN (40 mL) was heated under reflux for 18 hours. The reaction mixture was diluted with EtOAc and water. The suspension was filtered and the filtrate was separated. The organic phase was washed with brine, dried (MgSO4) and concentrated under vacuum. The residue was purified by flash chromatography (silica, iso-hexane/EtOAc). The material was treated with sarcosine tert-butyl ester hydrochloride (0.516 g, 2.84 mmol) and K2CO3 (0.980 g, 7.1 mmol) in ACN (10 mL). The mixture was heated at 70° C. for 18 hours. The solvent was evaporated under vacuum. The residue was dissolved in a mixture of DCM and water and then poured through a hydrophobic frit. The solvent was evaporated under vacuum. The residue was purified by flash chromatography (silica, iso-hexane/EtOAc) to afford the title compound (0.543 g, 70%). 1H NMR (CDCl3, 400 MHz) δ δ 8.15 (1H, d, J=8.2 Hz), 7.90 (1H, s), 7.83 (1H, d, J=8.2 Hz), 3.90 (2H, s), 3.26 (2H, s), 2.37 (3H, s), 1.48 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:17][OH:18])=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:6]=1.C(OCC)(=O)C.CCCCCCC>ClCCl>[CH3:1][C:2]1[S:3][C:4]([CH:17]=[O:18])=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:6]=1
Reactant: COC(=O)CCCCCCc1nc(C)sc1CO
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)CCCCCCc1nc(C)sc1C=O
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
The solution of 2.8 g of crude 2-methyl-4-(6-carbomethoxyhexyl)-5-hydroxymethyl thiazole (XII, R1 = CH3) in 25 ml of dichloromethane was dropwise added to the solution of 16 g of chromium trioxide-dipyiridine complex in 320 ml of dichloromethane. Stirring of the reaction mixture was continued for 30 minutes, then the reaction mixture was filtered and the filtrate was evaporated in vacuo. After purifying the crude product obtained as evaporation residue, by preparative thin layer chromatography using a silica gel layer as adsorbent and a mixture of 50 % ethyl acetate and 50 % of n-heptane as running solvent, 2.15 g of 2-methyl-4-(6-carbomethoxyhexyl)-thiazole-5-carbaldehyde (XIII, R1 = CH3) were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS([CH2:29][CH2:30][O:31][CH2:32][CH:33]=[CH2:34])(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.ClCCl>CC(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([C:16]2[N:17]([CH2:29][CH2:30][O:31][CH2:32][CH:33]=[CH2:34])[C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCOCCS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: C=CCOCCn1c(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (1.87 g, 5.68 mmol), allyl methanesulfonylethyl ether (1.83 g, 10.1 mmol), and potassium carbonate (1.60 g, 11.5 mmol) in acetone (21 mL) and water (7 mL). Heat to reflux. After 18 hours, concentrate the reaction mixture in vacuo to remove most of the acetone. Partition the concentrated reaction mixture between ethyl acetate and water. Separate the aqueous layer and extract three times with ethyl acetate. Extract the combined organic layers with saturated aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 15% ethyl acetate/dichloromethane to give 1-(t-butoxycarbonyl)-4-(1-(2-allyloxyethyl)-1H-benzimidazole-2-carbonyl)piperidine: Rf=0.48 (silica gel, 20% ethyl acetate/dichloromethane).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[CH2:24][CH:25]([OH:28])[CH2:26][OH:27])=[CH:11][CH:10]=1)C1C=CC=CC=1>[C].[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[CH2:24][CH:25]([OH:28])[CH2:26][OH:27])=[CH:11][CH:10]=1
Reactant: OCC(O)Cc1nccn1CCCCc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Product: OCC(O)Cc1nccn1CCCCc1ccc(O)cc1
Yield: 98.6 %

Procedure:
Using 3-{1-[4-(4-benzyloxyphenyl)butyl]-1H-imidazol-2-yl}-1,2-propanediol (1.22 g) and 10% palladium carbon (0.18 g), the same reaction as Reference Example 11-(v) was carried out to yield the titled compound (0.918 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16]2)[CH3:14])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>[N:9]1[C:10]2[C:5](=[CH:4][C:3]([C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[C:4]([O:12][C@@H:13]([C@H:15]4[CH2:19][NH:18][C:17](=[O:20])[CH2:16]4)[CH3:14])[CH:3]=3)=[CH:2][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C[C@@H](Oc1cc(Br)cc2ncccc12)[C@H]1CNC(=O)C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(-c2ccc3ncccc3c2)cc2ncccc12)[C@H]1CNC(=O)C1
Yield: 131.1 %

Procedure:
40 mg Example 27, 31 mg quinoline-6-boronic acidboronic acid, 14 mg tetrakis-(triphenylphosphin)-palladium(0), 120 μL 2N aqueous sodium carbonate and 0.5 mL dioxan were heated in the microwave (MW) for 15 min at 140° C. The mixture was purified with HPLC (XbridgeC18, MeOH/water, TFA) and the desired fractions lyophilized to yield 30 mg (75%) of Example 29 as yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][CH:10]=[O:11])=[CH:4][N:3]=1.[BH4-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][OH:11])=[CH:6][N:7]=1
Reactant: Cc1ncc(C=CC=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ncc(C=CCO)cn1
Reaction time: 0.08 h

Procedure:
To a suspension of 4-2 (0.5 g, 3.7 mmol) in MeOH (5 mL) and THF (15 mL) at −78° C. was added sodium borohydride (0.042 g, 1.11 mmol) in one portion. After 5 minutes, the cooling bath was removed, and the mixture allowed to warm and stir for 10 minutes. Concentrated HCl (0.3 mL) was added dropwise, and the volume of the mixture reduced to 2 mL by evaporation. Following the addition of sat. NaHCO3 (10 mL), the mixture was extracted with chloroform, the organics dried over MgSO4, and the solvents evaporated to give alcohol 4-3 as a white solid.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[CH3:20][N:21]1[CH:25]=[CH:24][N:23]=[C:22]1[N:26]1[C:30]2=[N:31][CH:32]=[N:33][C:34](OC3C=CC=CC=3)=[C:29]2[CH:28]=[N:27]1>C1COCC1>[CH:17]([O:16][CH2:15][C@H:4]([O:3][C:34]1[N:33]=[CH:32][N:31]=[C:30]2[N:26]([C:22]3[N:21]([CH3:20])[CH:25]=[CH:24][N:23]=3)[N:27]=[CH:28][C:29]=12)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6])([CH3:19])[CH3:18]
Reactant: Cc1ccc(NC(=O)[C@@H](O)COC(C)C)nc1
Reactant: Cn1ccnc1-n1ncc2c(Oc3ccccc3)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](COC(C)C)Oc2ncnc3c2cnn3-c2nccn2C)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% in oil) (28.8 mg, 0.72 mmol) was added to (S)-2-hydroxy-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate C7) (143 mg, 0.60 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 1-(1-methyl-1H-imidazol-2-yl)-4-phenoxy-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AV1) (193 mg, 0.66 mmol) in THF (1 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with 1M citric (2 mL), extracted with EtOAc, the organic layer was washed with water ×2 and brine, dried (MgSO4), filtered and evaporated to afford orange oil. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents to afford the product (90 mg, 34.4%, 100% ee). 1H NMR (400 MHz, CDCl3) δ 1.18 (6H, t), 2.29 (3H, s), 3.65 (3H, s), 3.67-3.76 (1H, m), 4.08 (2H, d), 6.01 (1H, t), 7.01 (1H, d), 7.17 (1H, d), 7.49-7.55 (1H, m), 8.06-8.14 (2H, m), 8.42 (1H, s), 8.65 (1H, s), 8.68 (1H, s); m/z (ES+) (M+H)+=437.51; HPLC tR=1.89 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH3:30][CH:31]([CH3:34])[CH2:32][OH:33]>O1CCOCC1.CN(C=O)C>[CH2:32]([O:33][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[CH:31]([CH3:34])[CH3:30]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OCC(C)C)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and 2-methyl-propanol in dioxane and DMF. ES-MS m/e (%): 443 (M+H+, 100).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:5]=2[C:6]=1[CH3:7].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:12][C:9]1[CH:10]=[CH:11][C:4]2[S:3][C:2]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]([CH3:7])[C:5]=2[CH:8]=1
Reactant: C1COCCN1
Reactant: Cc1c(Br)sc2ccc(Cl)cc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCOCC2)sc2ccc(Cl)cc12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 2-bromo-5-chloro-3-methylbenzothiophene (523 mg, 2 mmol), morpholine (210 uL, 2.4 mmol), Pd2dba3 (37 mg, 0.04 mmol), BINAP (62 mg, 0.1 mmol), and sodium tert-butoxide (270 mg, 2.8 mmol) in toluene (5 mL) was stirred at 80° C. for 18 hours. The reaction mixture was purified by flash column chromatography on silica gel with 20% ethyl acetate/hexanes to provide the desired product. MS (ESI(+)) m/e 268 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)[C:5]([Cl:24])=[CH:4][N:3]=1.Cl.[CH3:26][N:27]1[C:35]([CH3:36])=[C:34]2[C:29]([CH:30]=[C:31]([NH2:37])[CH:32]=[CH:33]2)=[N:28]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:24][C:5]1[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)=[N:7][C:2]([NH:37][C:31]2[CH:32]=[CH:33][C:34]3[C:29]([CH:30]=2)=[N:28][N:27]([CH3:26])[C:35]=3[CH3:36])=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3Cl)CC2C1
Reactant: Cc1c2ccc(N)cc2nn1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1c2ccc(Nc3ncc(Cl)c(NC4CC5CN(C(=O)OC(C)(C)C)CC5C4)n3)cc2nn1C
Temperature: 150 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
To a suspension of tert-butyl 5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (621.8 mg, 1.666 mmol) and 2,3-dimethylindazol-6-amine hydrochloride (999.6 mg, 5.057 mmol) in n-BuOH (6 mL) was added DIPEA (1.10 g, 8.43 mmol). The reaction mixture was stirred at 150° C. under microwave for 2 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=2/1) to give the title compound as a pale brown solid (452.1 mg, 54.5%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: CCS(=O)(=O)Cl
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(C2CC(C)(C)c3cc(C(F)(F)F)ccc3N2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.47 mmol) in pyridine (74 mg, 0.94 mmol) and dichloromethane (2 mL) at 0° C. was added dropwise a solution of ethanesulfonyl chloride (90 mg, 0.70 mol) in dichloromethane (1 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford ethanesulfonic acid [3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide (143 mg, 74.1%) as a white solid. MS (ESI+APCI) M+1=413.1.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2[CH:13]=[CH:14][CH:15]=CC=2N=N1.[NH2:25][C:26]1[N:34]=[C:33]([C:35]([OH:37])=O)[N:32]=[C:31]2[C:27]=1[NH:28][C:29](=[O:45])[N:30]2[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(C(C)C)CC)(C)C.NCC1CC1>CC(N(C)C)=O>[CH:13]1([CH2:12][NH:8][C:35]([C:33]2[N:32]=[C:31]3[C:27]([NH:28][C:29](=[O:45])[N:30]3[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:26]([NH2:25])[N:34]=2)=[O:37])[CH2:15][CH2:14]1
Reactant: Nc1nc(C(=O)O)nc2c1[nH]c(=O)n2Cc1ccccc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Nc1nc(C(=O)NCC2CC2)nc2c1[nH]c(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (48.1 g, 126.8 mmol) was added to a solution of the product of Preparation 12, 6-amino-9-benzyl-8-oxo-8,9-dihydro-7H-purine-2-carboxylic acid (32.88 g, 115.3 mmol) and diisopropylethylamine (40.2 ml, 230.6 mmol) in dimethylacetamide (250 ml) and the reaction mixture stirred at room temperature for 1 hour. Aminomethylcyclopropane (12.5 ml, 144.1 mmol) was added and the reaction mixture stirred at room temperature for a further 20 hours. The reaction mixture was concentrated in vacuo and water added. The resultant precipitate was collected by filtration, azeotroped with toluene and triturated with methanol to yield the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C:21](=[O:24])[CH2:22]Cl)[C@@H:5]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:6]([NH:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1)=[O:7].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH:15]1([CH2:14][C@H:5]([N:4]2[CH2:3][CH2:2][NH:1][CH2:22][C:21]2=[O:24])[C:6]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[O:7])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NCCN(C(=O)CCl)[C@@H](CC1CCCCC1)C(=O)Nc1nccs1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1CCNCC1=O
Yield: 90.1 %

Procedure:
A solution of compound 12E (1.12 g, 2.5 mmol) and DIEA (1.4 ml, 8 mmol) in DMF (15 ml) was maintained at ambient temperature for 30 minutes. Reaction mixture was diluted with water (150 ml) and extracted with EtOAc (2×150 ml). Organic layer was washed with 5% aq. sodium bicarbonate (100 ml) and brine (100 ml), dried over anh. MgSO4 and evaporated in vacuum to provide target product (758 mg, 90%) as light yellow oil. LC-MS [M+H] 337.2 (C16H24N4O2S+H, requires 337.46).
Reaction SMILES: C(S)C.C[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1>CN(C)C=O>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1
Reactant: COc1ccc(C(CC(=O)O)CC(=O)O)cc1
Solvent: CCS
Solvent: CN(C)C=O
Product: O=C(O)CC(CC(=O)O)c1ccc(O)cc1
Temperature: 165 °C
Reaction time: 0.25 h
Yield: 81.5 %

Procedure:
To a stirred suspension of 57% sodium hydride-paraffin (6.45 g), in dry dimethylformamide (70 ml) is slowly added ethanethiol (11.89 ml) in dry dimethylformamide (20 ml). After stirring the resultant slurry for 15 minutes, a solution of 3-(4-methoxyphenyl)glutaric acid (3.0 g) in dry dimethylformamide (20 ml) is added. The slurry is heated in a bath at 165° C. for 5.0 hours and most of the solvent is removed by distillation in vacuo. The residue is diluted with water, acidified with concentrated hydrochloric acid and extracted twice with ether (the extracts are discarded). The solution is saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate solution is washed once with brine, dried and the residue crystallized from chloroform-hexane to afford 2.3 g of 3-(4-hydroxyphenyl)-glutaric acid, melting point 168°-170° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[C:4]#[CH:5].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].CO>C(OCC)C>[CH2:3]([O:6][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]#[CH:5]
Reactant: CCOC(=O)CBr
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: C#CCOCC(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.4 %

Procedure:
To an anhydrous solution containing 5.1 g of 55% oily sodium hydride in 120 ml of diethyl ether were added 24 ml of an anhydrous diethyl ether solution containing 5.6 g of propargyl alcohol. The mixture was stirred at room temperature for 1.5 hours, after which 20.9 g of ethyl bromoacetate were added dropwise. The mixture was allowed to stand overnight, after which the excess sodium hydride was decomposed with methanol. After separating off the precipitate produced, the filtrate was distilled to give 10 g of ethyl α-propargyloxyacetate, boiling at 52°-60° C./4-7 mmHg.