Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27]CC3C=CC(OC)=CC=3OC)[CH:22]=2)=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.CCOCC>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=2)=[O:20])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2cc(C(=O)NCC3CCN(C(=O)OCc4ccccc4)CC3)ccn2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Nc1cc(C(=O)NCC2CCN(C(=O)OCc3ccccc3)CC2)ccn1
Reaction time: 0.5 h

Procedure:
4-({[2-(2,4-Dimethoxy-benzylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid benzyl ester (EXAMPLE 171) (124 mg) in dichloromethane (5 mL) was treated with trifluoroacetic acid (0.5 mL). After 30 min, the reaction mixture was partitioned between EtOAc and dilute sodium bicarbonate solution. The organic layer was washed with brine, dried and the solvent evaporated to give the crude product which was stirred with ether (3mL) and filtered to give the 4-{[(2-amino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.Cl[CH:33]([F:35])[F:34]>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=1)[C:10]([O:17][CH:33]([F:35])[F:34])=[N:11]2
Reactant: COC(=O)COc1ccc(F)c2[nH]c(=O)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Reactant: FC(F)Cl
Product: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(-n4cccn4)cc3)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 10c using [8-fluoro-4-methyl-2-oxo-3-(4-pyrazol-1-ylbenzyl)-1,2-dihydroquinolin-5-yloxy]acetic acid methyl ester and chlorodifluoromethane.
Reaction SMILES: [N:1]([CH2:4][C:5]1([CH3:23])[NH:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:6]1=[O:22])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH2:4][C:5]1([CH3:23])[NH:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:6]1=[O:22]
Reactant: CC1(CN=[N+]=[N-])NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(CN)NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=O

Procedure:
5-Azidomethyl-3-(4-chloro-3-trifluoromethyl-phenyl)-5-methyl-imidazolidine-2,4-dione (500 mg, 1.45 mmoL), Ph3P (380 mg, 1.45 mmoL) in THF (5 mL) and water (1 mL) was heated to reflux for 4 hrs. The solid was filtered through a pad of Celite. The Celite was washed with ethyl acetate. The combined filtrate was concentrated to give a colorless oil, which was used without further purification.
Reaction SMILES: [C:1]([N:4]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27](OCC)=[O:28])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:32])[CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C[N:47](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl-].[NH4+]>CO.CN(C=O)C>[C:1]([N:4]([C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH2:47])=[O:28])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:32])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CCCCC(N)=O)cc2)c2ccccc21
Temperature: 40 °C
Reaction time: 18 h

Procedure:
Ethyl 5-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)pentanoate (0.135 g, 0.25 mmol) was hydrolyzed to the acid by dissolving in 6 ml methanol and potassium carbonate (0.2 g in 4 ml water) was added. The mixture was heated to 40° C. for 24 hours and methanol was removed in vacuo. The mixture was acidified to form a white precipitate. The solid was filtered to give the acid. To a solution of the acid in DMF (10 mL) at room temperature was added HATU (0.143 g, 0.375 mmol), DIEA (0.18 mL, 1 mmol), HOBt (0.057 g, 0.375 mmol), and ammonium chloride (0.027 g, 0.5 mmol) was added. The mixture was stirred for 18 hours and concentrated. The residue was dissolved in CH2Cl2 and washed with water. The organic layer was concentrated and purified by silica gel chromatography (87% CH2Cl2/13% methanol) to afford 5-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)pentanamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:24])[N:3]=1.B([C:28]1[CH:39]=[CH:38][C:31]([CH2:32][C@@H:33]([C:35]([OH:37])=[O:36])[NH2:34])=[CH:30][CH:29]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:34][CH:33]([CH2:32][C:31]1[CH:38]=[CH:39][C:28]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:23])([F:22])[F:21])[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:24])[N:3]=2)=[CH:29][CH:30]=1)[C:35]([OH:37])=[O:36]
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: Nc1nc(Cl)cc(OC(c2ccccc2C(F)(F)F)C(F)(F)F)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Nc1nc(OC(c2ccccc2C(F)(F)F)C(F)(F)F)cc(-c2ccc(CC(N)C(=O)O)cc2)n1
Temperature: 150 °C
Yield: 11.2 %

Procedure:
In a microwave vial, 4-chloro-2-amino-6-[1-(2-trifluoromethylphenyl)-2,2,2-trifluoro-ethoxy]-pyrimidine (33 mg, 0.1 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol) and 1 ml of acetonitrile, 0.7 ml of water. 0.3 ml of 1N aqueous sodium carbonate was added to above solution followed by 5 mole percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and then was purified by Prep-LC to give 5.6 mg of 2-amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(2-trifluoromethylphenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (400 MHz, CD3OD) δ 7.96 (m, 3H), 7.80 (d, J=8.06 Hz, 1H), 7.74 (t, J=7.91 Hz 1H), 7.63 (t, J=8.06 Hz, 1H), 7.41 (d, J=8.3 Hz, 2H), 7.21 (m, 1H), 6.69 (s, 1H), 3.87 (m, 1H), 3.34 (m, 1H), 3.08 (m, 1H).
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[C:8](=[O:20])[CH2:9][C@@H:10]([O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:11]=1)=[O:5])C.[OH-].[Na+]>P([O-])([O-])([O-])=O>[OH:5][C:4]([CH2:6][C:7]1[C:8](=[O:20])[CH2:9][C@@H:10]([O:12][Si:13]([CH2:16][CH3:17])([CH2:18][CH3:19])[CH2:14][CH3:15])[CH:11]=1)=[O:3]
Reactant: CCOC(=O)CC1=C[C@H](O[Si](CC)(CC)CC)CC1=O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: CC[Si](CC)(CC)O[C@H]1C=C(CC(=O)O)C(=O)C1
Temperature: 25 °C
Yield: 66.2 %

Procedure:
20 g of (R)-2-ethoxycarbonylmethyl-4-triethylsilyloxy-2-cyclopenten-1-one obtained from Example 35 and 2 g of Candida antarcitica lipase were suspended in 200 ml of phosphate buffer (10 mM, pH 6.5-7.5) and stirred at room temperature. The pH of the solution was maintained by 1N sodium hydroxide solution and finally adjusted to 7.0 upon completion of the reaction and the Lipase was removed by filtration. The reaction mixture was extracted with 100 ml of ethyl acetate twice. The pH of the aqueous layer was further adjusted to 6.0 using a saturated sodium hydrogensulfate solution. The aqueous layer was extracted twice again using 100 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain (R)-2-hydroxycarbonylmethyl-4-triethylsiloxy-2-cyclopenten-1-one (12 g, 65% yield). [α]D: +19.8° (c 1.0, CH3CN);
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15](Cl)=[O:16])[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[N:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][NH:20][C:15]([C:12]2[CH:13]=[C:14]3[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]3[CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:10][CH:11]=2)=[O:16])=[CH:24][CH:25]=1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)Cl)ccc12
Reactant: NCCc1ccncc1
Product: CCc1nn(C2CCCC2)c2cc(C(=O)NCCc3ccncc3)ccc12
Yield: 34.2 %

Procedure:
This compound was prepared according to the method of Example 15, using 78 mg (0.282 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl chloride and 36 μL (0.295 mmol, 1.05 equiv) 4-(2-aminoethyl)pyridine as starting materials, to give 35 mg (35%) of white crystals: mp 123-126° C.; Anal. calcd for C22H26N4O.¼H2O: C, 72.01; H, 7.28; N, 15.27. Found: C, 71.77; H, 7.45; N, 15.23.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][CH:3]=1.C=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Pd](Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: C=Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Product: Clc1ccc(C=Cc2ccccc2)cc1
Yield: 43.3 %

Procedure:
The procedure described in Example 1 is followed, except that 17.5 g (0.1 mol) of 4-chlorobenzoyl chloride, 13.02 g (0.125 mol) of styrene, 35.37 g (0.1 mol) of tri-2-ethylhexylamine and 0.1773 g (0.01 mol) of palladium chloride are used. After a reaction time of 4 hours at 120° C., 9.3 g (0.0433 mol) of 4-chlorostilbene, corresponding to a yield of 43.3% of theory, are obtained in the form of white flakes; melting point 129°-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][C:31]=5F)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[N:51]1([CH2:57][CH2:58][OH:59])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>>[CH3:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:50][CH:49]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:54]6[CH2:55][CH2:56][N:51]([CH2:57][CH2:58][OH:59])[CH2:52][CH2:53]6)=[O:36])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:42][CH:43]=1
Reactant: OCCN1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(CCO)CC4)cc3)cn2)cc1
Yield: 103.6 %

Procedure:
Using 4-(4-{2-[Bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (70.4 mg, 0.104 mmol) obtained in Step A in Example 1-D-21 and 1-piperazineethanol (25.5 μl, 0.208 mmol) instead of 1-pyridine-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, to obtain a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone as a yellow solid (83.2 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-145) as a yellow powder (24.5 mg, 43%).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[S:10][C:9](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[CH:8][CH:7]=1.[N-:16]=[N+:17]=[N-:18].[Na+].O1CCOCC1>C(Cl)(Cl)Cl.O>[Br:5][C:6]1[S:10][C:9](/[CH:11]=[CH:12]/[C:13]([N:16]=[N+:17]=[N-:18])=[O:15])=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)/C=C/c1ccc(Br)s1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: [N-]=[N+]=NC(=O)/C=C/c1ccc(Br)s1
Temperature: 75 °C
Reaction time: 0.17 h

Procedure:
Thionyl chloride (1.04 mL) was added to a solution of (2E)-3-(5-bromothien-2-yl) acrylic acid (1.04 g, 4.46 mmol) in chloroform (20 mL) and the mixture was refluxed for 2 h at 75° C. and than used in the next step. The above solution was added drop wise to a stirred suspension of sodium azide (0.58 g, 8.93 mmol), dioxane (3 mL) and water (3 mL) in an ice bath. After 10 min a precipitate appeared which was filtered off and washed with water. The residue was dissolved in dichloromethane, dried with MgSO4, filtered and the solvent was removed to afford: 0.96 g (83.4%). 1H NMR (270 MHz CH3OH-d4) δ ppm 6.20 (d, J=15.57 Hz, 1H) 7.15-7.25 (m, 2H) 7.80 (d, J=15.57 Hz, 1H); MS 258.1 (M−H)+; Purity (HPLC) 65%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12](OCC)=[O:13])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1.[NH3:22]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([NH2:22])=[O:13])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1
Reactant: N
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(N)=O)C1
Reaction time: 0.08 h

Procedure:
Ethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate (0.1 g, 0.35 mmol) was taken in 4 ml aqueous ammonia and heated at 120 deg C. for 5 min in microwave. The solid product precipitated out after the reaction was filtered through a Buchner funnel and washed with 10% sodium bicarbonate (10 ml×2) followed by demineralised water (10 ml×2) wash. Product was vacuum dried and was taken in 5 ml ethanolic HCl, stirred for 15 min, concentrated in vacuo to afford 38 mg of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetamide as hydrochloride salt. 1H NMR (DMSO)HCl Salt 10.38 (bs, 1H), 7.67 (s, 1H), 7.58 (s, 1H), 7.43 (d, 1H), 7.38 (s, 1H), 7.18 (d, 1H), 4.79 (d, 2H), 4.62 (d, 1H), 4.21-4.31 (m, 1H), 3.68-3.81 (m, 1H), 3.42-3.53 (m, 1H), 3.04-3.14 (m, 2H), 2.96 (s, 3H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:16][OH:17])=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:18][CH3:19])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>C(Cl)Cl>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:16][O:17][S:28]([CH3:27])(=[O:30])=[O:29])=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:18][CH3:19])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: CCc1[nH]n(C2CCCC2)c2nc(CO)nc(=O)c1-2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(COS(C)(=O)=O)nc(=O)c1-2
Reaction time: 1 h

Procedure:
To a mixture of 1-cyclopentyl-3-ethyl-6-(hydroxymethyl)pyrazolo[3,4-d]pyrimidin-4-one (1.0 g, 3.8 mmol), CH2Cl2 (25 mL) and triethylamine (0.77 g, 7.6 mmol) at -50° C. was added methanesulfonyl chloride (0.44 g, 3.8 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred for 1 hour, CH2Cl2 and water were added and the organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo to afford 1.28 g of crude product. The crude product was combined with that from a similar experimental run and the mixture was recrystallized from ether (2×) to afford 1-cyclopentyl-3-ethyl-6-(methylsulfonyloxymethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 138°-140° C.
Reaction SMILES: Br.Br.[N:3]1([CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[N:3]1([CH2:8][C:9]2([C:29](=[O:30])[CH2:28][C:23]3[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=3)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: Oc1ccc2c(c1)C(CN1CCCC1)NCC2
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Cl)c(Cl)c1)C1(CN2CCCC2)NCCc2ccc(O)cc21

Procedure:
Prepared as Ex. No. 5, from 3 g (7.61 mmoles) of 1-(pyrrolidin-1-yl)methyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide, 1.9 g (9.31 mmoles) of 3,4-dichlorophenylacetic acid, 2.3 ml (16.36 mmoles) of triethylamine and 3.2 g (15.61 mmoles) of dicyclohexylcarbodiimide in 110 ml of dry chloroform.
Reaction SMILES: C1(C[N:8](CC2C=CC=CC=2)[CH2:9][C@@H:10]([C:12]2[CH:13]=[CH:14][C:15]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=2)[OH:11])C=CC=CC=1.[H][H]>CCOC(C)=O.CCO.[Pd].[OH-].[OH-].[Pd+2]>[NH2:8][CH2:9][C@@H:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=1)[OH:11]
Reactant: C[Si](C)(C)CCOCOc1ccc([C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)cc1NC=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[Si](C)(C)CCOCOc1ccc([C@@H](O)CN)cc1NC=O
Yield: 89.7 %

Procedure:
A solution of {5[(1R)-2-[bis(phenylmethyl)amino]-1-hydroxyethyl}-2-[({[2-(trimethylsilyl)ethyl]oxy}methyl)oxy]phenyl}formamide (90 mg) in EtOAc (8 ml) and EtOH (8 ml) was hydrogenated over 10% palladium on carbon (40 mg) and 20% palladium hydroxide on carbon (20 mg). When hydrogen uptake had ceased the mixture was filtered through celite and the solvent evaporated in vacuo to give the title compound (52 mg). LCMS RT=2.31 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:18][N:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)(O)[O-].[Na+].[I-].[K+]>CN(C)C=O>[CH3:20][N:19]([CH3:21])[CH2:18][C:12]1([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)=[CH:7][CH:8]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: CN(C)CC1(c2ccc(OCCCCl)cc2)CCOCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CC1(c2ccc(OCCCN3CCN(C)CC3)cc2)CCOCC1
Yield: 38.8 %

Procedure:
A mixture of 1-{4-[4-(3-chloropropoxy)phenyl]tetrahydro-2H-pyran-4-yl}-N,N-dimethylmethanamine (200 mg, 0.7 mmol), N-methyl piperazine (87 μl, 0.79 mmol), solid sodium bicarbonate (66 mg, 0.79 mmol) and a catalytic amount of potassium iodide was heated at 50° C. in N,N-dimethylformamide (2 ml) for 18 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (2×75 ml) and water (20 ml). The organic layers were combined, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4 by volume) to provide the title compound (102 mg, 39%). 1H NMR (400 MHz, CDCl3) δ 1.84-1.91 (m, 2H), 1.95-1.99 (m, 8H), 2.07-2.11 (m, 2H), 2.30 (s, 3H), 2.40 (s, 2H), 2.42-2.59 (m, 10H), 3.54 (t, 2H), 3.72-3.78 (m, 2H), 4.00 (t, 2H), 6.86 (d, 2H), 7.20 (d, 2H). HRMS ESI+ m/z 376.2951 [MH]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[N:10]1.[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH3:18])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[N:10]1
Reactant: COCCOCCO
Reactant: COC(=O)c1ccn(-c2ccc(O)cc2O)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOCCOc1ccc(-n2ccc(C(=O)OC)n2)c(O)c1
Reaction time: 8 h

Procedure:
To a solution of methyl 1-(2,4-dihydroxyphenyl)-1H-pyrazole-3-carboxylate 3 (200 mg, 0.855 mmol, 1.00 equiv) in THF (5 mL), 2-(2-methoxyethoxy)ethanol (103 mg, 0.855 mmol, 1.00 equiv) was added Ph3P (223 mg, 0.855 mmol, 1.00 equiv), and DEAD (149 mg, 0.855 mmol, 1.00 equiv) at 0° C. The resulting solution was stirred overnight. The solvent was concentrated under vacuum, the residue was applied onto a silica gel column and eluted with PE/EA (1/1). This resulted in 70 mg (50%) of methyl 1-(2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-1H-pyrazole-3-carboxylate 4 as a green oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:13])=[C:5]([CH3:12])[C:6]=1[C:7](OCC)=[O:8].[CH:14]([NH2:16])=O>>[OH:8][C:7]1[C:6]2[C:5]([CH3:12])=[C:4]([CH3:13])[S:3][C:2]=2[N:1]=[CH:14][N:16]=1
Reactant: NC=O
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Product: Cc1sc2ncnc(O)c2c1C

Procedure:
Using ethyl 2-amino-4,5-dimethylthiophene-3-carboxylate (500 mg, 2.5 mmol) and formamide (5 ml), a similar procedure to a) in Production Example 208 was carried out to obtain 4-hydroxy-5,6-dimethylthieno[2,3-d]pyrimidine (380 mg, 2.1 mmol) having the following physical properties:
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:30])[CH:11]=[C:12]([C:27]([OH:29])=[O:28])[N:13]([CH2:24][CH2:25]O)[C:14]=1[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[OH:16])C1C=CC=CC=1>CO.[Pd]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH:15]([OH:16])[C:14]2[N:13]3[C:12]([C:27](=[O:28])[O:29][CH2:25][CH2:24]3)=[CH:11][C:10](=[O:30])[C:9]=2[OH:8])=[CH:18][CH:19]=1
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)c(C(O)c2ccc(F)cc2)n1CCO
Agent: [Pd]
Solvent: CO
Product: O=C1OCCn2c1cc(=O)c(O)c2C(O)c1ccc(F)cc1

Procedure:
0.266 g of 5-benzyloxy-6-[(4-fluoro-phenyl)-hydroxy-methyl]-1-(2-hydroxy-ethyl)-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid are dissolved in 20 ml of methanol and hydrogenated at room temperature over 0.05 g of palladium on carbon (5%) until 1 mol of H2 per mol of starting material has been taken up. The catalyst is removed by filtration and the flitrate is concentrated to dryness by evaporation using a rotary evaporator. Recrystallisation from methanol yields 6-[(4-fluoro-phenyl)-hydroxy-methyl]-7-hydroxy-3,4-dihydro-pyrido[2,1-c]-[1,4]oxazine-1,8-dione in the form of colourless crystals. M.p.: 221°-225° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]([OH:13])[CH3:12])[C:9]#[N:10])=[CH:4][CH:3]=1.[CH3:14][C:15](C)=[O:16]>CCCCCC>[C:15]([O:13][CH:11]([CH3:12])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]#[N:10])(=[O:16])[CH3:14]
Reactant: CC(C)=O
Reactant: CC(O)C(C#N)c1ccc(Cl)cc1
Solvent: CCCCCC
Product: CC(=O)OC(C)C(C#N)c1ccc(Cl)cc1
Yield: 85 %

Procedure:
This ester was prepared using the procedure described in Example 5, except 2-(4-chlorophenyl)-3-hydroxybutanenitrile was used in place of 2-(2-chloro-5-(difluoromethoxy)phenyl)-3-hydroxypropanenitrile. The preparation of 2-(4-chlorophenyl)-3-hydroxybutanenitrile is described in Example 17. The recovered ester product was a mixture of diastereoisomers (85% yield), Rf 0.29 and 0.35 (silica gel, acetone:hexane=1:3).
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:20])[CH2:12][CH2:11]3)[CH2:8]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C)C=O>[N:21]([CH2:6][CH:7]1[O:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:20])[CH2:12][CH2:11]3)[CH2:8]1)=[N+:22]=[N-:23]
Reactant: CS(=O)(=O)OCC1Cc2c(ccc3c2CCC(=O)N3)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1Cc2c(ccc3c2CCC(=O)N3)O1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
The compound obtained in Example 160 (0.691 g, 2.32 mmol) and sodium azide (1.51 g) were suspended in dimethylformamide (14 ml) and stirred at 120° C. for 2 hours. The suspension was cooled and poured into water, followed by extraction with chloroform. The chloroform phase was washed with water and dried over sodium sulfate. When the solvent was distilled off under reduced pressure, 0.553 g of the pale yellow crystals of the title compound was obtained (97.4%, mp.: 157°-158° C.).