Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH:10]([OH:16])[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:23][C:24]([C:34]([F:37])([F:36])[F:35])=[CH:25][C@@H:26]1[C@H:28]([C:29](Cl)=[O:30])[C:27]1([CH3:33])[CH3:32]>C1(C)C=CC=CC=1>[Cl:23][C:24]([C:34]([F:35])([F:36])[F:37])=[CH:25][C@@H:26]1[C@H:28]([C:29]([O:16][CH:10]2[CH2:9][C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11]2)=[O:30])[C:27]1([CH3:33])[CH3:32]
Reactant: OC1Cc2cccc(-c3ccccc3)c2C1
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OC1Cc2cccc(-c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
A stirred solution of 0.25 g (0.0012 mole) of 4-phenyl-2-indanol and 0.11 g (0.0014 mole) of pyridine in 10 ml of toluene was cooled to 5° C., and a solution of 0.28 g (0.0011 mole) of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride, prepared in accordance with Example 8, in 5 ml of toluene was added portionwise. Upon complete addition the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to a residual oil. The oil was placed on a silica gel pad, and the product was eluted with 50 ml of 1:1 hexane:toluene. The eluate was concentrated under reduced pressure at 100°-115° C./0.02 mm using a Kugelrohr distilling system to give 0.12 g of 4-phenyl-2-indanyl cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](I)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].B1([C:21]2[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=2)OCCCO1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[Cl:1][C:2]1[N:10]=[C:9]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)n1cnc2c(Cl)nc(I)nc21
Reactant: c1cncc(B2OCCCO2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)n1cnc2c(Cl)nc(-c3cccnc3)nc21
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A round-bottom flask was charged with 6-chloro-2-iodo-9-isopropyl-9H-purine (1.2 g, 3.7 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (0.91 g, 5.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (430 mg, 0.37 mmol). To this mixture was added toluene (60 ml), ethanol (6 ml) and aqueous sodium carbonate solution (2M, 15 ml). The flask was sealed and the reaction mixture was stirred at 80° C. for 4 h. Water was added to the cooled mixture, which was extracted with ethyl acetate (50 ml×3). The organic fractions were combined, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel, eluting with 30 to 70% EtOAc in hexane to afford the title compound as a solid. 1H NMR (400 MHz, CD3OD) δ 9.60 (d, 1H), 8.90-8.87 (m, 1H), 8.68 (s, 1H), 8.67 (d, 1H), 7.63-7.60 (m, 1H), 5.12-5.05 (m, 1H), 1.74 (d, 6H). MS m/z 274.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[CH2:16](OC(C1NC2C(C=1)=CC=CC=2)=O)C>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:16])[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: CCOC(=O)c1cc2cc(F)ccc2n1C
Yield: 100 %

Procedure:
According to the procedure of Preparation 1(a), except substituting ethyl 5-fluoro-indole-2-carboxylate for the ethyl-indole-2-carboxylate, the title compound (3.3 g, 100%) was prepared as a white solid: MS (ES) m/e 222 (M+H)+.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]([OH:6])[CH3:5].[CH:7](=O)[CH2:8][CH:9]([CH3:11])[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(NCC)C>ClCCl>[CH2:8]([CH:7]1[S:1][CH2:2][CH2:3][CH:4]([CH3:5])[O:6]1)[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)CC=O
Reactant: CC(O)CCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCNCC
Product: CC(C)CC1OC(C)CCS1

Procedure:
75 ml of dichloromethane is placed into a 100 ml round-bottom flask. To the dichloromethane is added 5.3 grams (0.05 moles) of 4-mercapto-2-butanol. 4.74 grams (0.055 moles) of isovaleraldehyde is then added followed by 0.1 grams of p-toluene sulfonic acid. Boiling chips are added to the flask. A Dean-Starke distilling receiver is placed on the flask, and a reflux condenser is placed on the receiver. The flask is then heated slowly until reflux occurs, and then the temperature is increased for a more vigorous reflux. The reflux lasts for a period of 2 hours before water of reaction ceases to be formed. The reaction mass is then cooled and neutralized with diethyl amine to a pH of about 8. The reaction mass is filtered through fluted filter paper, and the dichloromethane solvent is removed by means of rotary evaporation. 8.8 grams of crude product are recovered after the rotary evaporation operation. The crude product is then distilled by means of vacuum distillation yielding the following 3 fractions:
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH:9]([CH2:29][OH:30])[CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[C:15]([NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:16].[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([O:43][CH2:44][CH3:45])[C:41]=1[F:42])[CH:37]=O)[CH3:32].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([O:43][CH2:44][CH3:45])[C:41]=1[F:42])[CH2:37][N:21]1[CH2:22][CH2:23][CH:18]([NH:17][C:15](=[O:16])[C:14]2[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=[C:12]([O:11][CH2:10][CH:9]([OH:8])[CH2:29][OH:30])[CH:13]=2)[CH2:19][CH2:20]1)[CH3:32]
Reactant: COc1cc(OCC(O)CO)cc(C(=O)NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCC(O)CO)c3)CC2)cc(OCC)c1F

Procedure:
In analogy to the procedure described in example 50k), crude rac-3-(2,3-dihydroxy-propoxy)-5-methoxy-N-piperidin-4-yl-benzamide trifluoroacetate (example 175b) was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless amorphous solid. MS: 521.4 (MH+).
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:11]=1)[C:4]([O:6]CC)=[O:5])[CH3:2].[OH-].[Na+].[ClH:33]>CO>[ClH:33].[CH2:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][NH:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=2)[CH:11]=1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(CNCc2ccc(C(F)(F)F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(Cc1ccc(OC)c(CNCc2ccc(C(F)(F)F)cc2)c1)C(=O)O
Temperature: 60 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
A mixture of ethyl 2-ethyl-3-[3-[4-(trifluoromethyl)benzylaminomethyl]-4-methoxyphenyl]propanoate (90.2 mg, 0.213 mmol), methanol (2 mL) and 2.5 mol/L aqueous solution of sodium hydroxide (2 mL) was stirred for 5 hours under heating at 60° C. After cooling, ice water (20 mL) was added and the mixture was made acidic with 1 mol/L hydrochloric acid, which was then saturated with sodium chloride and extracted with ethyl acetate. The extracte was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=10:1 v/v) to afford 78.0 mg (85%) of the title compound as a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][C:11]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=3)=[C:12]([CH3:14])[N:13]=2)[CH:5]=[N:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[S:10][C:9]([NH:8][C:6]3[N:7]=[C:2]([N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)[CH:3]=[N:4][CH:5]=3)=[N:13][C:12]=2[CH3:14])=[CH:16][C:17]=1[C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:22]
Reactant: CN1CCNCC1
Reactant: Cc1nc(Nc2cncc(Cl)n2)sc1-c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Product: Cc1nc(Nc2cncc(N3CCN(C)CC3)n2)sc1-c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1

Procedure:
The titled compound is prepared from (6-chloro-pyrazin-2-yl)-[5-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-amine (65) and 1-methyl piperazine following the procedure described in Example 13.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19](=[S:21])[NH2:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:23]([C:29](=O)[CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CCO>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]3[S:21][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:29]([CH3:30])[N:20]=3)=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cccc2c(C(N)=S)cn(CC3CCCCC3)c12
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)nc1C
Temperature: 0 °C
Yield: 61 %

Procedure:
To a solution of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbothioic acid amide (604 mg, 2.00 mmol) in EtOH (5.0 ml) was added ethyl 2-chloro-3-oxobutanoate (0.332 ml, 2.40 mmol). The mixture was refluxed for 1 h. After cooling to 0° C., the precipitate was collected by filtration to afford 1-cyclohexylmethyl-3-(5-ethoxycarbonyl-4-methylthiazol-2-yl)-7-methoxy-1H-indole (505 mg, 1.22 mmol).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][O:9][CH:8]=1.[CH3:12][C:13]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:16]=2[O:15][N:14]=1.[Cl-].[NH4+]>CCCCCC.CCOCC>[O:9]1[CH:10]=[CH:11][C:7]([C:21]2([OH:22])[C:16]3[O:15][N:14]=[C:13]([CH3:12])[C:17]=3[CH2:18][CH2:19][CH2:20]2)=[CH:8]1
Reactant: Brc1ccoc1
Reactant: Cc1noc2c1CCCC2=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1noc2c1CCCC2(O)c1ccoc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
To a solution of 4 ml (0.04 mol) of 10M n-butyllithium in hexane cooled to -78° C. was added 3.59 ml (0.04 mol) of 3-bromofuran in 100 ml of ether and the mixture was stirred for 10 min. To the above cooled solution was added 5.49 g (0.036 mol) 4,5,6,7-tetrahydro-3-methyl-benzisoxazol-7-one and the mixture was allowed to warm to room temperature, and then stirred for 1 h. To the mixture was added saturated ammonium chloride solution and the resulting mixture was extracted with ethyl acetate (3×100 ml), and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 7.6 g (96%) of 7-(3-furyl)-3-methyl-4,5,6,7-tetrahydrobenzisoxazol-7-ol, as a brown oil.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:37]=[CH:36][C:22]([C:23]([NH:25][CH2:26][C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=4)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][NH:39][CH3:40].C(Cl)CCl>ClCCl>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:26][C:27]4[CH:35]=[CH:34][C:30]([C:31]([N:39]([CH3:40])[CH3:38])=[O:33])=[CH:29][CH:28]=4)=[O:24])=[CH:36][CH:37]=3)(=[O:17])=[O:18])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(CNC(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)cc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C)C(=O)c1ccc(CNC(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)cc1
Yield: 15.2 %

Procedure:
Combine 4-{[4-(3-Phenyl-indole-1-sulfonyl)-benzoylamino]-methyl}-benzoic acid (0.489 mmole) with dimethylamine (0.587 mmole), and EDC (0.733 mmole) in 5 ml of dichloromethane and stir for 15 hrs. Dilute □eaction and wash with 1 N HCl. Dry organic layer over MgSO4 and concentrate. Purify the residue via column chromatography with a mixture of ethyl acetate and dichloromethane to isolate 0.040 g (15.2%) of the title compound: MSES+ 537.95; MSES− 536.08.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58]1[CH:63]=[CH:62][N:61]=[C:60]([N:64]2[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[CH2:66][CH2:65]2)[CH:59]=1.C(NC(C)C)(C)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([N:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58]1[CH:63]=[CH:62][N:61]=[C:60]([N:64]2[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[CH2:66][CH2:65]2)[CH:59]=1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: c1ccc2c(c1)CCN2c1cc([C@@H]2CCCN2)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ccnc(N2CCc3ccccc32)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of (S)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (99 mg, 0.39 mmol), HOBt (57 mg, 0.42 mmol) and HBTU (160 mg, 0.42 mmol) in DMF (10 mL) is stirred at room temperature for 30 min. Then a solution of 1-((S)-4-pyrrolidin-2-yl-pyridin-2-yl)-2,3-dihydro-1H-indole (6) in DMF (10 mL) is added, followed by diisopropylamine (226 mg, 1.75 mmol). After stirring at room temperature for 2 h, the reaction mixture is diluted with water and extracted with EtOAc. The combined organic layers are washed with water, sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by flash chromatography on silica gel (EtOAc/Hexane: 5%˜40%) to give ((S)-1-Cyclohexyl-2-{(S)-2-[2-(2,3-dihydro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester as white solid (120 mg, 68%). M/Z=505.3 [M+1]
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]4[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:9]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[CH:38][C:5]=2[N:4]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:20]1[CH2:19][CH:18]([C:13]2[N:14]([CH3:17])[C:15]3[C:11]([N:12]=2)=[C:10]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[N:9]=[C:8]([N:7]2[C:6]4[CH:35]=[CH:36][CH:37]=[CH:38][C:5]=4[N:4]=[C:3]2[CH2:1][CH3:2])[N:16]=3)[CH2:21]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CNC3)n(C)c2n1
Reaction time: 2.5 h
Yield: 85 %

Procedure:
To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]azetidine-1-carboxylic acid tert-butyl ester 678 (325 mg, 0.63 mmol) in DCM (4 mL) was added TFA (2 mL). The resulting mixture was stirred for 2.5 h at r.t then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-20%) affording 680 as a cream foam (224 mg, 85%). LCMS (method I): RT 2.30 min, [M+H]+ 419.1. 1H NMR (CDCl3, 400 MHz): δ 8.00-8.00 (1 H, m), 7.75-7.74 (1 H, m), 7.26 (2 H, s), 4.34-4.32 (7 H, m), 3.89-3.88 (6 H, m), 3.71-3.69 (3 H, m), 3.35-3.34 (2 H, m), 1.44-1.43 (3 H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]#[N:33])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][O:27][CH2:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]#[N:33])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][O:27][CH2:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CCCOC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2CCCOC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
451 mg (purity 82%, 0.78 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-3-yl)propanoate (mixture of racemic diastereomers) were hydrolysed with TFA according to General Method 6A. Yield: 440 mg (purity 82%, quant.)
Reaction SMILES: Cl.[C:2]12([CH2:12][CH2:13][NH2:14])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:25])=[C:20]([CH:24]=1)[C:21](O)=[O:22]>>[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:25])=[C:20]([CH:24]=1)[C:21]([NH:14][CH2:13][CH2:12][C:2]12[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2)=[O:22]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: NCCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Product: Nc1ccc(Cl)c(C(=O)NCCC23CC4CC(CC(C4)C2)C3)c1
Yield: 58 %

Procedure:
Prepared according to the method of Example 14 from 1-adamantaneethylamine hydrochloride (0.105 g) and 5-amino-2-chlorobenzoic acid (0.132 g) and purified by supercritical fluid chromatography eluting with CO2 in ethanol to give the title compound as a white foam (0.094 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.[BH4-].[Na+].O>C(O)C>[OH:1][C@@H:2]1[CH2:5][C@H:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1
Reactant: CCOC(=O)C1CC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@H]1C[C@@H](O)C1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To a cooled (-30° C.) solution of ethyl 3-oxocyclobutanecarboxylate (J. Org. Chem. 1988, 53, 3481) (18.1 g, 130 mmol) in ethanol (100 ml) was added NaBH4 (4.92 g, 130 mmol) in small potions over 0.25 h. The reaction mixture was stirred at -30° C. for 0.5 h and then at room temperature for 0.5 h. The reaction mixture was poured into water (200 ml) and extracted with ether (500 ml). The organic phase was washed with brine (200 ml), dried (MgSO4) and concentrated. The residue was distilled to afford 15.1 g (81%) of ethyl cis-3-hydroxycyclobutanecarboxylate as a colorless oil: bp 86°-88° C. (1 mmHg); 1H NMR δ4.24 (m, 3H), 2.66-2.52 (m, 3H), 2.28-2,09 (m, 2H), 2.03 (br s, 1H), 1.26 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][OH:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Se](=O)=O>O1CCOCC1.ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH:11]=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccnc(CO)c1
Agent: O=[Se]=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)c1ccnc(C=O)c1
Temperature: 82.5 °C
Yield: 95.8 %

Procedure:
4-t-Butyl-2-hydroxymethyl-pyridine (4.13 g, 25 mmole) is dissolved in 75 ml dioxane in a 200 ml one neck round bottom flask under nitrogen. The solution is treated with selenium dioxide (1.53 g, 13.75 mmole) and the reaction is warmed to 80-85° C. for 1 h. The mixture is cooled, diluted with dichloromethane, and is filtered through celite. The filter cake is washed well with dichloromethane and the filtrate is concentrated to an amber oil. The crude oil is passed through a 50 g plug of silica gel (230-400 mesh), eluting with 20% acetone/hexane, while collecting 100 ml fractions. Fractions 1-3 are combined and concentrated to give 3.91 g (96%) of 4-t-Butyl-2-pyridine-carboxaldehyde as a light amber oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N+:6]([O-:20])=[CH:7]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cccc2cnccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: [O-][n+]1ccc2c(Br)cccc2c1
Reaction time: 8 h
Yield: 75.9 %

Procedure:
A mixture of 5-bromoisoquinoline (0.83 g, 3.0 mmol), MCPBA (1.84 g, 8 mmol) and NaHCO3 (0.672 g, 8 mmol) in CH2Cl2 (10 mL) and H2O (5 mL) was stirred overnight. The solvents were removed, and the residue was purified by silica gel column chromatography eluting with EtOAc to give 0.51 g of the title compound. MS (APCI) m/e 225 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=O.[NH:18]=[N+]=[N-].S(=O)(=O)(O)O>C1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:18]
Reactant: O=Cc1ccc(C2CCCc3cncn32)cc1
Reactant: [N-]=[N+]=N
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: N#Cc1ccc(C2CCCc3cncn32)cc1
Reaction time: 2 h

Procedure:
A solution of 2.01 g of 5-(p-formylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and 0.96 g of hydrazoic acid in 30 ml benzene is maintained by external cooling at room temperature, while 0.8 ml of concentrated sulfuric acid is added dropwise. The reaction mixture is stirred for 2 h and neutralized. The organic phase is separated, dried over sodium sulfate and evaporated to yield an oil which is chromatographed on silica gel with ethyl acetate to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH2:4]O.[ClH:14]>>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH2:4][Cl:14]
Reactant: Nc1cccc(C(F)(F)F)c1CO
Reactant: Cl
Product: Nc1cccc(C(F)(F)F)c1CCl
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To 4.06 g (7.8 mmole) of 2-amino-6-trifluoromethylbenzyl alcohol in a pressure bottle was added 60 ml of concentrated hydrochloric acid, the bottled stoppered and immersed in an oil bath maintained at 100°. The mixture was stirred for 1.5 hr., cooled and the precipitate filtered under suction. The colorless solid was washed with water and dried under high vacuum, yielding 3.28 g (75% yield) of a colorless solid; mp 155-161°. The sample was used as such without further purification.
Reaction SMILES: [Mg].[CH2:2]([O:4][CH:5]([O:10][CH2:11][CH3:12])[CH2:6][C:7]([OH:9])=O)[CH3:3].C(N1[CH:24]=[CH:23]N=C1)(N1C=CN=C1)=O>O1CCCC1>[CH2:11]([O:10][CH:5]([O:4][CH2:2][CH3:3])[CH2:6][C:7](=[O:9])[CH2:6][C:5]([O:10][CH2:23][CH3:24])=[O:4])[CH3:12]
Reactant: CCOC(CC(=O)O)OCC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(OCC)OCC
Temperature: 80 °C
Reaction time: 72 h

Procedure:
To a solution of 16 mL of 3-ethoxy-3-oxomalonic acid (135 mmol) in 40 mL of tetrahydrofuran there are added, under argon, 21.9 g of powdered magnesium (90.4 mmol). The mixture obtained is then heated at 80° C. for 7 hours. After returning to ambient temperature, this mixture is transferred by cannula to a solution of 10 g of the compound obtained in Step A (61.7 mmol) in 64 mL of tetrahydrofuran to which there has previously been added, in portions, 11 g of carbonyldiimidazole (66 mmol). The reaction mixture is stirred for 3 days at ambient temperature. After concentration, the residue is taken up in a mixture of ethyl acetate and aqueous sodium hydrogen sulphate (NaHSO4) solution. The mixture is stirred vigorously until no more gas is evolved. After separation of the phases, the organic phase is washed successively with water, saturated aqueous NaHCO3 solution and finally brine. After drying over MgSO4 and concentrating to dryness, the title product is obtained in the form of an oil which is used in the next Step without being otherwise purified.