Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]2([O:24][CH3:25])[CH2:22][CH2:21][O:20][CH:19]2[CH3:23])[CH:5]=[C:6]([CH:17]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][CH:9]=1.Cl.[NH2:27][OH:28]>>[F:1][C:2]1[CH:3]=[C:4]([C:18]2([O:24][CH3:25])[CH2:22][CH2:21][O:20][CH:19]2[CH3:23])[CH:5]=[C:6]([CH:17]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11](/[C:14](=[N:27]/[OH:28])/[CH3:15])=[CH:10][CH:9]=1
Reactant: NO
Reactant: COC1(c2cc(F)cc(Oc3ccc(C(C)=O)cc3)c2)CCOC1C
Agent: Cl
Product: COC1(c2cc(F)cc(Oc3ccc(/C(C)=N/O)cc3)c2)CCOC1C
Yield: 42 %

Procedure:
Using an analogous procedure to that described in Example 66, 4'-{5-fluoro-3-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]phenoxy}acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-{5-fluoro-3-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]phenoxy}acetophenone oxime in 42% yield, m.p. 126°-127° C.
Reaction SMILES: [Br:1]Br.Cl.[C:4]1([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:16]1[S:15][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:13][C:12]=1[CH2:11][CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1sc(C2CCNCC2)nc1CCc1ccccc1
Reaction time: 0.5 h

Procedure:
At 0° C., bromine (123 mg) is added dropwise to a solution of 4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 200 mg) in acetic acid (2 ml). The mixture is stirred for 30 min, and saturated sodium bicarbonate solution is then added. The aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are dried over anhydrous sodium carbonate, concentrated under reduced pressure and purified chromatographically. This gives 4-[5-bromo-4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidine (127 mg).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[C@H:15](O)[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:22])[CH2:3]1.[O:23]=[O:24]>>[O:23]([C@:4]12[CH2:3][C@@H:2]([OH:1])[CH2:19][CH2:18][C@:17]1([CH3:20])[C@@H:16]1[C@H:7]([C@H:8]3[C@@:12]([CH2:14][CH2:15]1)([CH3:13])[C:11](=[O:22])[CH2:10][CH2:9]3)[CH:6]=[CH:5]2)[OH:24]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2[C@H](O)C[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=O
Product: C[C@]12CC[C@H]3[C@@H](C=C[C@@]4(OO)C[C@@H](O)CC[C@]34C)[C@@H]1CCC2=O

Procedure:
3β-Hydroxyandrost-5-en-17-one (DHEA) 1 reacts with singlet oxygen to yield 5α-hydroperoxy-3β-hydroxy-androst-6-en-17-one 2. This hydroperoxide undergoes a rearrangement when in chloroform solution to yield 7α-hydroperoxy-3β-hydroxyandrost-5-en-17-one, 3. Treatment of the hydroperoxide with zinc and acetic acid yields 3β,7α-dihydroxy-androst-5-en-17-one, 4. ##STR35##
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[N:13]([CH2:17]/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C@@H:27]([CH3:36])[C:28](N4CCOCC4)=[O:29])[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[OH-:37].[Li+]>O1CCCC1.CO.O>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[N:13]([CH2:17]/[CH:18]=[CH:19]/[C:20]3[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=3)[O:26][C@@H:27]([CH3:36])[C:28]([OH:37])=[O:29])[CH:14]=[CH:15][CH:16]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: [OH-]
Reactant: CCc1cccc(NC(=O)c2cccn2C/C=C/c2cccc(O[C@@H](C)C(=O)N3CCOCC3)c2)c1
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCc1cccc(NC(=O)c2cccn2C/C=C/c2cccc(O[C@@H](C)C(=O)O)c2)c1
Yield: 88 %

Procedure:
A mixture of N-(3-ethylphenyl)-1-[(2E)-3-(3-{[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]oxy}phenyl)prop-2-enyl]-1H-pyrrole-2-carboxamide (348 mg, 0.714 mmol) in tetrahydrofuran (4 ml), methanol (4 ml) and an aqueous 1N lithium hydroxide (6 ml) was stirred for 6 hours at 50° C. The reaction mixture was diluted with water, washed with diethyl ether. The aqueous layer was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed to give the subject compound (264 mg, 88%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([O:25][CH3:26])[NH:22][N:21]=2)[CH:16]=[C:15]([Cl:27])[N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:27][C:15]1[N:14]=[C:13]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([O:25][CH3:26])[NH:22][N:21]=2)[CH:16]=1
Reactant: COc1cc(Nc2cc(Cl)nc(Cl)n2)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2cc(Cl)nc(N[C@@H](C)c3ncc(F)cn3)n2)n[nH]1
Temperature: 105 °C
Yield: 52.3 %

Procedure:
A mixture of (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 512 mg), 2,6-dichloro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 42, 682 mg) and DIPEA (1.16 ml) in n-BuOH (13 ml) was heated at 105° C. over night. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound as solid (500 mg). 1H NMR δ 8.92 (s, 2H) 5.95 (s, 1H) 5.18 (s, 1H) 3.77 (s, 3H) 1.49 (d, 3H); m/z 366.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][S:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.O.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25]Cl>CCOCC.CCCCCC>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][CH:10]1[S:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]1=2
Reactant: CN(C)CCCl
Reactant: c1ccc2c(c1)CSc1ccccc1S2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: CN(C)CCC1Sc2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.40 g of 11H-dibenzo(b,e)-1,4-dithiepin (K. Sindelar, M. Protiva and M. Hrubantova, Czech. 202.239) in 50 ml of ether was treated dropwise over 20 minutes of 15% n-butyllithium solution in hexane in a nitrogen atmosphere. The mixture was stirred for 30 minutes at room temperature and then treated with external cooling with ice and water and with 10 ml of 2-dimethylaminoethyl chloride, added dropwise. Then, the mixture was stirred for another 2 hours at room temperature. It was then washed with water and the basic product extracted into a mild excess of 1:1 dilute hydrochloric acid. The acid aqueous layer was separated, made alkaline with aqueous ammonia and the base extracted with ether. The extract was dried with potassium carbonate and evaporated. The remaining oily base was dissolved in 7 ml of acetone and treated with a solution of 1.81 g of oxalic acid in 5 ml of acetone. The crystalline hydrogen oxalate (5.31 g) separated, was filtered with suction and purified by recrystallization from aqueous ethanol, m.p. 195°-197° C.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]\[S:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:7][CH:8]=1)(O)=[O:2].C(C(C(C(O)=O)O)O)(O)=O.[OH:41][CH:42]1[CH2:45][NH:44][CH2:43]1>>[OH:41][CH:42]1[CH2:45][N:44]([C:1]([C:4]2[N:5]=[C:6](/[CH:9]=[CH:10]\[S:11][C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:7][CH:8]=2)=[O:2])[CH2:43]1
Reactant: O=C(O)c1csc(/C=C\SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: OC1CNC1
Agent: O=C(O)C(O)C(O)C(=O)O
Product: O=C(c1csc(/C=C\SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)N1CC(O)C1
Yield: 79.7 %

Procedure:
In the same manner as in step c) in Example 3, 1.169 g of the title compound was prepared from 1.300 g of 4-carboxy-2-((Z)-2-tritylthioethen-1-yl)thiazole and 1.028 g of 3-hydroxyazetidine tartrate.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].Cl[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1.O>CS(C)=O>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[CH2:14][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6]
Reactant: O=C1NCCN1
Reactant: ClCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1NCCN1Cc1ccc2ccccc2c1
Reaction time: 1.8 h
Yield: 56 %

Procedure:
A 21.5g (0.25 mole) portion of 2-imidazolidinone in 250 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of K2CO3, 20 g (0.12 mole) of KI and 44.3 g (0.25 mole) of 2-(chloromethyl)-naphthalene. The reaction mixture was heated to 105° over 0.3 hours, held at 105°-110° for 1.8 hours and poured with rapid stirring into 1.5 l of water. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 500 ml of water, dried over MgSO4 overnight and filtered. The filtrate was concentrated to dryness to give 31.5 g (56%) of a light yellow solid, m.p. 102 soften, 120°-138°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[OH:32])[C:6]([NH:8][NH:9][C:10]([C:12]1[O:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])=[O:7])#[N:2].C1(=O)O[CH2:36][CH2:35][O:34]1>[I-].C([N+](CC)(CC)CC)C.CN(C=O)C>[OH:34][CH2:35][CH2:36][O:32][C:31]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][NH:9][C:10]([C:12]2[O:13][CH:14]=[C:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:11])=[O:7])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: O=C1OCCO1
Reactant: N#Cc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1O
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1OCCO
Temperature: 100 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
A mixture of the compound of Example 18 (0.42 g), ethylene carbonate (0.088 g), tetraethylammonium iodide (0.026 g) and DMF (10 ml) was stirred at 100° C. for 2 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 50%→90% ethyl acetate/hexane gradient), thereby giving 0.26 g of the desired compound. HPLC retention time: 6.31 minutes.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1(C)C(C)(C)OB([C:33]2[O:37][CH:36]=[N:35][CH:34]=2)O1.O.[F-].[K+].[Br-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.[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>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14]([C:33]3[O:37][CH:36]=[N:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Reactant: CC1(C)OB(c2cnco2)OC1(C)C
Agent: [Pd]
Agent: [Br-]
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2cnco2)c1OC
Temperature: 125 °C
Yield: 77.2 %

Procedure:
A mixture of ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 61, 0.1 g), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (0.071 g), tetrakis-(triphenylphosphine) palladium (0.028 g), potassium fluoride monohydrate (0.102 g) and sodium bromide (0.045 g) in toluene (2 ml) was heated in a sealed tube under nitrogen at 125° C. for 18 hours. The mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give ethyl 6-(benzenesulphonylmethyl)-2-methoxy-3-(oxazol-5-yl)benzoate (0.075 g) as a yellow gum.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([NH:21][C:22](=[O:24])[CH3:23])[CH2:9][C@@H:8]1[CH:25]1[CH2:27][CH2:26]1)=[O:6])([CH3:3])[CH3:2].[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:33]Br.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=2)[C@H:10]([N:21]([C:22](=[O:24])[CH3:23])[CH2:33][C:32]2[CH:35]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:37]=[C:30]([C:29]([F:28])([F:42])[F:43])[CH:31]=2)[CH2:9][C@@H:8]1[CH:25]1[CH2:26][CH2:27]1)=[O:6])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC(=O)N[C@@H]1C[C@H](C2CC2)N(C(=O)OC(C)C)c2ccc(C(F)(F)F)nc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)N(C(=O)OC(C)C)c2ccc(C(F)(F)F)nc21
Yield: 35 %

Procedure:
Prepare the title compound by essentially following the procedure described in Example 49, Step 2, by replacing (+/−)-N-(1-cyclopently-6-methoxy-2-methyl-1,2,3,4-tetrahydro-[1,5]napthyridin-4-yl)-acetamide, with (+/−)-cis-4-acetylamino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (0.075 g, 0.019 mmol), and using 3,5-bis trifluoromethyl benzyl bromide and lithium hexamethyldisilazide. Purify by silica gel column chromatography (gradient eluent, neat ethyl acetate) to afford the title compound (0.042 g, 35%). MS (ES+): 612 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][N:10]=2)[C:5]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]2)=[C:6]([C:13]#[N:14])[C:7]1=[O:12])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(Cl)cnc2[nH]c1=O
Reactant: BrCc1ccccc1
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(Cl)cnc2n(Cc2ccccc2)c1=O

Procedure:
This compound was prepared from 6-chloro-2-oxo-4-[4-(furan-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (101) and benzyl bromide according to General Procedure B. Yield 223 mg (31%), MP 196° C.; 1H-NMR (DMSO-d6): δ 3.75 (m, 4H), 3.94 (m, 4H), 5.51 (s, 2H), 6.66 (dd, J=1.6, 3.6 Hz, 1H), 7.09 (d, J=3.2 Hz, 1H), 7.22-7.28 (m, 5H), 7.89 (d, J=1.6 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 8.76 (d, J=2.4 Hz, 1H); EIMS: 474 (M+1). Anal. (C25H20ClN5O3) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1.C(O)(=O)C.[N:23]1([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C([BH3-])#N.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][CH:15]([N:26]3[CH2:25][CH2:24][N:23]([C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])[CH2:28][CH2:27]3)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=C1CCC(C(=O)NCc2nccnc2Cl)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(NCc1nccnc1Cl)C1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.6 %

Procedure:
N-((3-chloropyrazin-2-yl)methyl)-4-oxocyclohexanecarboxamide (3.7 mmol, 1 g) was dissolved in dichloromethane (10 mL) and acetic acid (0.1 mL) was added. To this solution benzyl 1-piperazinecarboxylate (11.2 mmol, 2.16 mL) and sodium cyanoborohydride (7.47 mmol, 0.47 g) were added subsequently. The mixture was stirred overnight at room temperature. Reaction was quenched with an aqueous sodium hydrogencarbonate solution and extracted twice with dichloromethane. The combined organic layers were dried over phase separation filter, concentrated under reduced pressure and purified using column chromatography (silica gel; dichloromethane/methanol) to yield 2.35 g of the title compound as a mixture of cis and trans isomers which was used in the next step without further purification.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)([O-:3])=O.[C:13]([O:17][C:18]([N:20]1[CH2:23][CH2:22][C@H:21]1[CH2:24][O:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([C:32]#[CH:33])[CH:31]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(N=C=O)C=CC=CC=1.C(N(CC)CC)C>C1C=CC=CC=1.O>[C:13]([O:17][C:18]([N:20]1[CH2:23][CH2:22][C@H:21]1[CH2:24][O:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([C:32]2[O:3][N:1]=[C:4]([CH2:5][O:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)[CH:33]=2)[CH:31]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: C#Cc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Reactant: O=[N+]([O-])CCOC1CCCCO1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C=Nc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cc(COC3CCCCO3)no2)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 82.7 %

Procedure:
To a solution of 1-nitro-2-(tetrahydro-2H-pyran-2-yloxy)ethane (Basra, S. K.; Drew, M. G. B.; Mann, J.; Kane, P. D. J. Chem. Soc., Perkin Trans. 1, 2000, 3592-3598) (0.53 mL, 3.4 mmol, 3.0 equiv.) and 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-ethynylpyridine (330 mg, 1.14 mmol) in dry benzene (11 mL) were added phenyl isocyanate (0.37 mL, 3.4 mmol, 3.0 equiv.) and triethylamine (0.70 mL, 5.0 mmol, 4.4 equiv.). The reaction mixture was stirred at 60° C. for 24 h, then diluted with water, stirred vigorously for 2 h, and extracted with CH2Cl2. The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by CC on SiO2 with EtOAc/hexane 1:1 to give the isoxazole (420 mg, 82%). 1H NMR (CDCl3, 400 MHz) δ 8.64 (br s, 1H), 8.41 (br s, 1H), 7.64 (s, 1H), 6.71 (s, 1H), 4.86 (d, 1H, J=12.0 Hz), 4.77 (t, 1H, J=4.0 Hz), 4.68 (d, 1H, J=12.0 Hz), 4.55 (m, 1H), 4.41 (m, 1H), 4.21 (dd, 1H, J=8.0, 4.0 Hz), 3.91 (t, 3H, J=8.0 Hz), 3.59 (m, 1H), 2.38 (m, 2H), 1.78 (m, 2H), 1.58 (m, 4H), 1.42 (s, 9H).
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([CH:13]([CH3:15])[CH3:14])[C:11]2[N:10]=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:26](O)=[O:27])=[C:21]4[C:25]=3[O:24][CH2:23][CH2:22]4)[N:8]=[CH:7][C:6]=2[N:5]([CH3:29])[C:4]1=[O:30])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:62][CH2:63][C@H:64]([OH:73])[CH2:65][N:66]1[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:1]([C@H:3]1[N:12]([CH:13]([CH3:14])[CH3:15])[C:11]2[N:10]=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:26]([NH:62][CH2:63][C@H:64]([OH:73])[CH2:65][N:66]4[CH2:67][CH2:68][N:69]([CH3:72])[CH2:70][CH2:71]4)=[O:27])=[C:21]4[C:25]=3[O:24][CH2:23][CH2:22]4)[N:8]=[CH:7][C:6]=2[N:5]([CH3:29])[C:4]1=[O:30])[CH3:2]
Reactant: CN1CCN(C[C@@H](O)CN)CC1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@H](O)CN4CCN(C)CC4)c4c3OCC4)nc2N1C(C)C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
7-[[(7R)-7-Ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 22f (150 mg, 0.36 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (117 mg, 0.36 mmol) were dissolved in 30 mL of anhydrous dichloromethane followed by the addition of diisopropylethylamine (0.1 mL, 0.8 mmol) and (2S)-1-amino-3-(4-methylpiperazin-1-yl)propan-2-ol 21c (63 mg, 0.36 mmol) successively. The reaction solution was stirred for 2 hours. The resulting solution was added with 20 mL of saturated sodium carbonate solution and extracted with dichloromethane (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-[(2S)-2-hydroxy-3-(4-methylpiperazin-1-yl)propyl]-2,3-dihydrobenzofuran-4-carboxamide 32 (40 mg, yield: 20.0%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1CCN2C(=NCCC2)CC1>O>[N:12]1([C:2]2[C:6]3[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=3[O:4][N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: Cc1ccc2onc(Cl)c2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Cc1ccc2onc(N3CCNCC3)c2c1
Yield: 79.7 %

Procedure:
3-Chloro-5-methyl-1,2-benzisoxazole (2.17 g, 12.93 mmol) was stirred together with piperazine (10.0 g, 116.1 mmol) and DBU (diazabicycloundecene; 2.0 g 13.14 mmol) in a melt at 120° C. for 4 h, after which the reaction was complete according to TLC. After cooling, the mixture was added to water, and the aqueous phase was extracted 3 times with dichloromethane, and the organic phases were washed with water, dried over magnesium sulfate and concentrated in vacuo. This resulted in 2.24 g of 3-piperazin-1-yl-5-methyl-1,2-benzisoxazole (yield: 80%) being obtained as a slightly impure solid product which was purified by chromatography.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[O:12][CH2:13][C@H:14]([OH:16])[CH3:15]>C(O)C.[Pd]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[O:12][CH2:13][C@H:14]([OH:16])[CH3:15]
Reactant: C[C@@H](O)COc1c([N+](=O)[O-])ccc(F)c1F
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](O)COc1c(N)ccc(F)c1F
Yield: 91.4 %

Procedure:
To a solution of 3.1 g of 2,3-difluoro-6-nitro-{[(R)-2-hydroxypropyl]oxy}benzene (VIIIR, Xa=Xb=F) in 50 ml of ethanol was added 500 mg of 5% palladium on charcoal. Catalytic reduction was performed under atmospheric pressure at room temperature. When the absorption of hydrogen ceased, the catalyst was removed by filtration and the solvent was removed from the filtrate under reduced pressure. The residue was purified through silica gel column chromatography to yield 2.47 g of the titled compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:8])=O.[Cl:9][C:10]1[CH:11]=[C:12]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][C:33]=3[O:35][CH2:36][CH2:37][NH:38][CH3:39])[N:28]=[CH:27][N:26]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[Cl:9][C:10]1[CH:11]=[C:12]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][C:33]=3[O:35][CH2:36][CH2:37][N:38]([CH3:39])[C:6]([CH:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[O:8])[N:28]=[CH:27][N:26]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: O=C(O)C1CCCO1
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)C1CCCO1
Yield: 89 %

Procedure:
The procedure described in Example 1 was repeated using tetrahydrofuran-2-carboxylic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give the title compound in 89% yield; NMR spectrum (DMSO-d6) 1.64-1.94 (m, 4H), 3.09 (s, 3H), 3.57-3.70 (m, 2H), 3.82-3.97 (m, 2H), 4.42 (t, 2H), 4.60-4.66 (m, 1H), 5.31 (s, 2H), 7.16 (d, 1H), 7.23 (d, 1H), 7.33 (d, 1H), 7.35-7.39 (m, 1H), 7.52-7.57 (m, 1H), 7.59 (d, 1H), 7.70-7.75 (m, 1H), 7.85-7.91 (m, 1H), 7.92 (d, 1H), 8.42 (s, 1H), 8.61 (d, 1H), 9.70 (s, 1H); Mass spectrum MH+ 534.