Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]([CH3:16])[C:12]([O:14]C)=[O:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl>[OH-].[Na+].CO.CS(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]([CH3:16])[C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)C(C)C(c1ccccc1)c1ccc2[nH]ncc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: CC(C(=O)O)C(c1ccccc1)c1ccc2[nH]ncc2c1
Yield: 82 %

Procedure:
Each diastereomer of methyl 3-(1H-indazol-5-yl)-2-methyl-3-phenylpropanoate was heated to 100° C. overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidified to pH 5 with HCl and extracted 2×EtOAc. The organic layers were washed with water×2, dried over MgSO4, filtered, concentrated in vacuo, and purified by HPLC to give 27 mg (82% yield, 2 steps) and 35 mg of the diastereomers of acid 3-(1H-indazol-5-yl)-2-methyl-3-phenylpropanoic acid. MS found: (M+H)+=281.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH:10]([N:13]=[C:14]=[O:15])([CH3:12])[CH3:11].Cl>CN(C)C1C=CN=CC=1.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14](=[O:15])[NH:13][CH:10]([CH3:12])[CH3:11])=[C:4]([F:9])[CH:3]=1
Reactant: CC(C)N=C=O
Reactant: Oc1ccc(Cl)cc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)NC(=O)Oc1ccc(Cl)cc1F
Temperature: 60 °C
Yield: 91.4 %

Procedure:
To 5 g (34 mmol) 4-Chloro-2-fluorophenol and 416 mg (3.41 mmol) 4-dimethylaminopyridine in 18 ml THF are added 3.7 ml (37.5 mmol) isopropyl isocyanate and the mixture is heated for 20 hours at 60° C. After cooling down to room temperature 2 M HCl is added and the aqueous phase is extracted with diethyl ether. The combined organic phases are washed with brine, dried over sodium sulfate and evaporated to yield 7.2 g isopropylcarbamic acid 4-chloro-2-fluorophenyl ester as the crude product. To 7.2 g (31 mmol) isopropylcarbamic acid 4-chloro-2-fluorophenyl ester and 5.1 ml tetramethylene diamine in 300 ml diethyl ether are added 5.9 ml (32.5 mmol) (trimethylsilyl)(trifluoromethan)sulfonate at room temperature. After 30 minutes the mixture is cooled to −70° C., 10.2 ml tetramethylene diamine and 27 ml of a 2.5 M n-BuLi solution are added successively. After one hour at −70° 24 ml DMF in are added at −70° C. and the mixture is stirred another hour at −70° C. 130 ml ethanol and 36 ml of a 2 M aqueous NaOH are added and the reaction is warmed to ambient temperature over 18 hours. The reaction mixture is set acidic by addition of 100 ml 2 M aqueous HCl and partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, the combined organic phases are washed with brine, dried over sodium sulphate and evaporated. The crude product is purified by chromatography on silica gel to yield 1.1 g 5-chloro-3-fluoro-2-hydroxybenzaldehyde. 1.1 g (6.1 mmol) 5-chloro-3-fluoro-2-hydroxybenzaldehyde and 1.56 g (11.3 mmol) potassium carbonate are stirred vigorously in 11 ml DMF while 0.7 ml methyliodide are added. Stirring is continued for 18 hours and water is added. The aqueous phase is extracted with diethyl ether, the combined organic phases are dried over sodium sulfate and evaporated. The crude product is purified by chromatography on silica gel (ethyl acetate in hexane 0 to 10%) to yield 570 mg 5-chloro-3-fluoro-2-methoxybenzaldehyde. 1H-NMR (CDCl3); δ=4.10 (d, 3H), 7.35 (dd, 1H), 7.59 (m, 1H), 10.35 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][C:8]([N:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:11])=[O:9].[N:30]#[C:31]Br>C(O)C>[NH2:30][C:31]1[N:5]([CH2:6][CH2:7][C:8]([N:10]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH3:11])=[O:9])[CH2:4][C:3]2[C:2](=[CH:21][CH:20]=[C:19]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=2)[N:1]=1
Reactant: CN(C(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1N)C1CCCCC1
Reactant: N#CBr
Solvent: CCO
Product: CN(C(=O)CCN1Cc2cc(C(=O)c3ccccc3)ccc2N=C1N)C1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 3-(2-amino-5-benzoyl-benzylamino)-N-cyclohexyl-N-methyl-propionamide (0.017) prepared as described in Example 3 in ethanol (250 mL) was stirred at room temperature and cyanogen bromide (0.027 mol) was added. The reaction mixture was stirred and refluxed for 3 hours, then cooled. The solvent was evaporated and the residue was crystallized from CH3CN. The precipitate was filtered off and dried to yield the title compound as a residue.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Br[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.C(OCC)(=O)C>C1COCC1>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][O:3][CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)=[CH:20][CH:21]=1)#[N:24]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc(C#N)cc2)CC1
Temperature: 25 °C

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil; 490 mg, 12.2 mmol) in THF (10 mL) was added a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.46 g, 12.2 mmol) in THF (2 mL) at rt. The reaction mixture was stirred at rt for several minutes and then heated to reflux for 15 min. After cooling to rt 4-(bromomethyl)benzonitrile (2.00 g, 10.2 mmol) was added, and the reaction mixture was stirred at rt over night. Ethyl acetate was added and the mixture was washed with water. The organic layer was dried with anhydrous magnesium sulfate and filtered. The solvent was removed and the crude product was used as such for Step 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:12])[C:6]([NH2:13])=[N:5]2.[C:14](OC(=O)CC)(=O)[CH2:15][CH3:16]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[NH:12][C:14]([CH2:15][CH3:16])=[N:13][C:6]1=[N:5]2
Reactant: Nc1nc2ccc(Cl)cc2nc1N
Reactant: CCC(=O)OC(=O)CC
Solvent: C1CCOC1
Product: CCc1nc2nc3cc(Cl)ccc3nc2[nH]1

Procedure:
Four parts of 6-chloro-2,3-diaminoquinoxaline was combined with 3 parts of propionic anhydride in 2 parts of tetrahydrofuran. The mixture was heated for three hours during which time a thick slurry formed. The solid was collected from the hot mixture by filtration and washed twice with two parts of tetrahydrofuran. The gray solid was air-dried to give four parts of 6-chloro-2-ethyl-1H-imidazo[4,5-b]quinoxaline, m.p. 298°-300°.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[CH:21]([N-]C(C)C)(C)[CH3:22].[Li+].C(I)C.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C:6]([CH2:21][CH3:22])([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CC[C@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1(CC)C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
(7S)-2-Chloro-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one 41f (148 mg, 0.50 mmol) was dissolved in 20 mL of tetrahydrofuran. The reaction solution was cooled down to −78° C. followed by the addition of lithium diisopropylamide (0.5 mL, 1 mmol), stirred for 30 minutes, then added with ethyl iodide (156 mg, 1 mmol) and stirred for another 4 hours. The reaction mixture was added with 50 mL of saturated ammonium chloride solution, concentrated under reduced pressure and and extracted with dichloromethane (100 mL×2). The combined organic phase was washed with water (20 mL) and saturated sodium chloride solution (20 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system B to obtain the title compound 2-chloro-8-cyclopentyl-7,7-diethyl-5-methyl-pteridin-6-one 42a (100 mg, yield: 62.0%) as a yellow solid.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].C([O:20][C@H:21]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C@@H:23]([CH2:24][CH2:25][C@:26]3([CH3:49])[C@@H:35]2[CH2:34][CH2:33][C@H:32]2[C@@:27]3([CH3:48])[CH2:28][CH2:29][C@@:30]3([CH:46]=O)[CH2:42][CH2:41][C:40]([CH:43]([CH3:45])[CH3:44])=[C:31]32)[C:22]1([CH3:51])[CH3:50])(=O)C>CN(C)C=O.O1CCCC1>[OH:20][C@H:21]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C@@H:23]([CH2:24][CH2:25][C@:26]3([CH3:49])[C@@H:35]2[CH2:34][CH2:33][C@H:32]2[C@@:27]3([CH3:48])[CH2:28][CH2:29][C@@:30]3(/[CH:46]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:42][CH2:41][C:40]([CH:43]([CH3:44])[CH3:45])=[C:31]32)[C:22]1([CH3:50])[CH3:51]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)CC[C@]5(C=O)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/[C@]12CCC(C(C)C)=C1[C@H]1CC[C@@H]3[C@@]4(C)CC[C@H](O)C(C)(C)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a suspension of ethyl 2-(diethoxyphosphoryl)acetate (7.80 g, 34.8 mmol) in anhydrous N,N-Dimethylformamide (DMF) (20 ml) and Tetrahydrofuran (THF) (10 ml) stirred under nitrogen at 0° C. was added NaH (1.288 g, 32.2 mmol) dropwise during 5 min and stirred for 10 mins. The solution was warmed to rt and stirred for 30 mins before (3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-formyl-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (4.2 g, 8.70 mmol) was added to above mixture. After sitting overnight, the reaction was quenched by water and washed with saturated NaHCO3, water and brine. The organic fraction was dried over sodium sulfate, filtered and concentrated to give a residue, which was purified on a silica gel column (petrol ether/EtOAc=10:1) to obtain the pure product (E)-ethyl 3-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)acrylate (3.1 g, 69%) as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.01-6.84 (m, 2H), 5.64 (d, J=16.1 Hz, 1H), 4.20 (q, J=7.3 Hz, 2H), 3.26-3.07 (m, 3H), 2.40-2.11 (m, 5H), 2.08-1.91 (m, 2H), 1.89-0.61 (m, 43H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[C:4]2[CH:14]=[C:15]([C:17]([OH:19])=O)[S:16][C:3]1=2.O=S(Cl)Cl.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.Cl.N1CCOCC1>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[C:4]2[CH:14]=[C:15]([C:17]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:19])[S:16][C:3]1=2
Reactant: Cn1c2ccc([N+](=O)[O-])cc2c2cc(C(=O)O)sc21
Reactant: C1COCCN1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cn1c2ccc([N+](=O)[O-])cc2c2cc(C(=O)N3CCOCC3)sc21
Reaction time: 1 h

Procedure:
280 mg of (68) was added to 25 ml of THF, 0.5 ml of SOCl2 was added, and the reaction left with stirring for 1 hour. 1 ml of morpholine was added in portions, and stirring continued . The precipitated morpholine hydrochloride was filtrered off, and the solvent evaporated. The residue was purified by column chromatography on silica gel, using MeOH in CH2Cl2, 1+9 as the eluent. MeOH was added to the pooled fractions to precipitate the product, giving after filtration and drying 50 mg of (69). M.p. 250°-2° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH2:16]([O:23][CH2:24][CH2:25][C@H:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:27](O)=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:34]([O:33][C:31](=[O:32])[NH:30][C@H:26]([C:27](=[O:28])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:25][CH2:24][O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)Nc1ccc(F)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
A mixture of 4-fluoro-N2-phenylbenzene-1,2-diamine (614 mg, 3.04 mmol), (S)-4-benzyloxy-2-tertbutoxycarbonylaminobutyric acid (1.0 g, 3.3 mmol), HOAt (0.450 g, 3.3 mmol), 4-methylmorpholine (0.7 mL, 6.7 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.63 g, 3.3 mmol) in DCM (15 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford the title compound as a yellow oil (1.22 g, 82%). LCMS (Method J): RT 4.17 min [M+H]+ 494.1.
Reaction SMILES: [N:1]([C@H:4]([CH3:31])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[C:13]2[C:16](=[O:28])[CH:17]=[C:18]([CH3:27])[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[N:11]([CH3:29])[C:10]1=[O:30])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][C@H:4]([CH3:31])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[C:13]2[C:16](=[O:28])[CH:17]=[C:18]([CH3:27])[N:19]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:12]=2[N:11]([CH3:29])[C:10]1=[O:30]
Reactant: Cc1cc(=O)c2c(=O)n(CCCC[C@@H](C)N=[N+]=[N-])c(=O)n(C)c2n1Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(=O)c2c(=O)n(CCCC[C@@H](C)N)c(=O)n(C)c2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.4 %

Procedure:
A mixture of (R)-3-(5-azidohexyl)-8-benzyl-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (380 mg, 0.90 mmol), triphenylphosphine (260 mg, 0.99 mmol), water (0.1 ml) and tetrahydrofuran (15 ml) was stirred at room temperature for 18 hours followed by heating at 500 C for 4 hours. Another portion of triphenylphosphine (100 mg) was added and the mixture was heated at 65° C. for 18 hours. After concentration under reduced pressure, the residue was treated with 1.0 M aqueous hydrochloric acid (10 ml) and ethyl acetate (10 ml), followed by extraction of the organic layer with 1.0 M aqueous hydrochloric acid (2×10 ml). The combined aqueous layers were made slightly basic (pH˜8) by addition of aqueous potassium hydroxide solution and extracted with ethyl acetate (2×20 ml). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to afford (R)-3-(5-aminohexyl)-8-benzyl-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (155 mg, 43% yield) as a beige powder. 1H NMR (300 MHz, CDCl3) δ 1.05 (d, 3H), 1.39 (broad s, 4H), 1.66 (m, 2H), 1.90 (broad s, 1H), 2.45 (s, 3H), 2.81 (broad s, 1H), 3.61 (s, 3H), 4.00 (t, 2H), 5.25 (s, 2H), 6.51 (s, 1H), 7.25-7.55 (m, 5H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][OH:15])=[C:4]([NH2:16])[N:3]=1.[NH3:17]>>[NH2:17][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][OH:15])=[C:4]([NH2:16])[N:3]=1
Reactant: N
Reactant: Nc1nc(Cl)nc2c1ncn2COCCO
Product: Nc1nc(N)c2ncn(COCCO)c2n1
Temperature: 120 °C
Yield: 12 %

Procedure:
A mixture of 2-chloro-9-(2-hydroxyethoxymethyl)adenine (4.4 g) and liquid ammonia (40 ml) was heated at 120° C. in a bomb for 19 hours. The reaction mixture was removed from the bomb and excess ammonia removed in vacuo. The residue was partitioned between ether and water and the aqueous layer washed twice more with ether and once with chloroform. The aqueous solution was then treated with an excess of a strongly basic ion exchange resin to convert the ammonium chloride to ammonia and evaporated to dryness in vacuo. The residue was dissolved in a minimal amount of ethanol, Florisil (Registered Trade Mark) (10 g) added, and the mixture evaporated in dryness. The residue was transferred to a prepared column of Florisil in chloroform and eluted with 5% methanol/95% chloroform (v/v). Fractions (30 ml) were collected and examined by TLC (silica gel plates developed in 10% methanol/90% chloroform) for the presence of product. The first 40 fractions contained starting material but no product and were discarded. Succeeding fractions which were found to contain the desired product were combined and evaporated to dryness. The residue was recrystallized from ethanol (with activated charcoal treatment) and from n-propanol to give 2-amino-9-(2-hydroxyethoxymethyl) adenine (0.5 g, 12% of theoretical), m.p. 183°-184° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[CH3:11]CCCCC.C[Si](C=[N+]=[N-])(C)C>ClCCl.CO>[NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1
Reactant: NC1CCC(C(=O)O)CC1
Reactant: CCCCCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CCC(N)CC1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of 4-amino-1-cyclohexanecarboxylic acid (500 mg) in dichloromethane (20 mL) and methanol (10 mL) was added 10% hexane solution of trimethylsilyldiazomethane (638 mg), and the mixture was stirred for 21 hours at ambient temperature. The mixture was evaporated in vacuo to give methyl 4-amino-1-cyclohexanecarboxylate as a colorless oil (544 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([N:8]2[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:6]3[C:10]([C:2]([F:1])=[CH:3][CH:4]=[CH:5]3)=[N:9]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2c3cccc(F)c3nn2C2CCCC2)cc1
Yield: 5.7 %

Procedure:
Prepared according to Example 116 from 7-fluoro-3-(4-methoxyphenyl)-1H-indazole (0.75 g, 3.1 mmol), sodium hydride (60% in oil, 0.124 g, 3.1 mmol) and cyclopentylbromide (0.36 mL, 3.3 mmol) to give the title compound (0.055 g) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@@H:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:3]1.[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:2]12([O:18][CH2:17][CH2:16][O:1]1)[C:11]1[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:5][C@@H:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:3]2
Reactant: OCCO
Reactant: COC(=O)[C@H]1CC(=O)c2ccccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COC(=O)[C@@H]1Cc2ccccc2C2(C1)OCCO2
Reaction time: 20 h
Yield: 85.9 %

Procedure:
To the stirred solution of (R)-methyl 4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (4.5 g, 22.03 mmol) in benzene (40 mL), ethane-1,2-diol (3.69 mL, 66.1 mmol) and a catalytic amount of p-toluenesulfonic acid was added. The reaction mixture was heated to reflux temperature and further maintained for 20 hours. After 20 hours, the reaction mixture was allowed to RT, concentrated under vacuum to yield 12 g of crude compound. Crude material was purified by flash chromatography (Biotage) using 7% ethyl acetate:hexane get title compound (4.7 g) m/z 248.6.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)=O)=[N+:2]=[N-:3].[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[BH3-]C#N.[Na+]>>[N:1]([CH2:4][CH:5]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)[NH:25][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[N+:2]=[N-:3]
Reactant: COc1cc(C(=O)CN=[N+]=[N-])cc(OC)c1OC
Reactant: NC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1cc(C(CN=[N+]=[N-])NC2CCCCC2)cc(OC)c1OC

Procedure:
In a manner similar to Preparation 21 react 2-azido-1-(3,4,5-trimethoxyphenyl)ethanone with cyclohexanamine and NaCNBH3 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[C:38]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][CH:24]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:32])[CH2:3][CH2:4]2)=[O:9])[CH:37]=[CH:36][N:35]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccnc(Cl)c1)N1CCC(N2CCCC2)CC1
Yield: 17 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 169), 2-chloropyridine-4-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a yellow oil (17%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17]#[N:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:16][C:17]#[N:18]
Reactant: Sc1ccccc1Br
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCSc1ccccc1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.4 %

Procedure:
A mixture of 2-bromobenzenethiol (6.3 mL, 53 mmol), K2CO3 (13.8 g, 100 mmol) and 2-chloroacetonitrile (3.2 mL, 50 mmol) in DMF (50 mL) was stirred at 25° C. for 6 h, poured into water (700 mL), and extracted with petroleum ether (300 mL) followed by DCM (2×200 mL). The combined DCM extracts were concentrated to dryness, and re-dissolved in petroleum ether/ethyl acetate (10:1, 600 mL). The organic solution was washed with water (250 mL) and brine (250 mL), dried over Na2SO4, filtered and concentrated to dryness to give the title compound (11 g, 85%). 1H NMR (300 MHz, CDCl3) δ 7.67 (dd, J=7.8, 1.5, 1H), 7.60 (dd, J=7.8, 1.5, 1H), 7.41 (m, 1H), 7.25 (m, 1H), 3.68 (s, 2H).