Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[F:3][C:4]1[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N+:20]([O-:22])=O)=[CH:14][CH:13]=2)=[N:6][CH:7]=[CH:8][CH:9]=1.C[O-].[Li+].C(Cl)[Cl:27]>[Ti](Cl)(Cl)(Cl)Cl.O>[F:3][C:4]1[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([Cl:27])=[N:20][OH:22])=[CH:14][CH:13]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: ClCCl
Reactant: O=[N+]([O-])CCc1ccc(COc2ncccc2F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: ON=C(Cl)Cc1ccc(COc2ncccc2F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
To a methanol (10 mL) solution of 3-fluoro-2-(4-(2-nitro-ethyl)-benzyloxy)-pyridine (674 mg, 2.44 mmol) described in Manufacturing Example 149-1-3 was added lithium methoxide (185 mg, 4.87 mmol), which was stirred for 5 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure. To a suspension of this residue in tetrahydrofuran (10 mL) and methylene chloride (10 mL) was added titanium (IV) tetrachloride (590 μL, 5.37 mmol) under nitrogen atmosphere at −78° C., which was stirred for 1 hour at 0° C. Water was added to the reaction mixture at 0° C., which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered with neutral silica gel. The filtrate was concentrated under a reduced pressure to obtain the title compound (629 mg, 88%). This compound was used in the following reaction without any further purification.
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([OH:21])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[CH2:28]([N:30]([CH2:31][CH3:32])[C:19](=[O:21])[CH2:18][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:4]=1[N+:1]([O-:3])=[O:2])[CH3:29]
Reactant: O=C(O)Cc1cccc(Oc2ccccc2F)c1[N+](=O)[O-]
Reactant: CCNCC
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCN(CC)C(=O)Cc1cccc(Oc2ccccc2F)c1[N+](=O)[O-]

Procedure:
2-[2-Nitro-3-(2-fluorophenoxy)phenyl]acetic acid (4 g.), phosphorus pentachloride (3.1 g.) and diethylamine (3 g.) were treated in a similar manner to that of the Preparation 33 to give the oily captioned compound (5.2 g.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[C:10]([F:16])[CH:9]=1)[C:5](Cl)=[O:6].[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[NH:18][NH2:19].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[C:10]([F:16])[CH:9]=1)[C:5]([NH:19][NH:18][C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:6]
Reactant: O=C(Cl)C(CCCl)c1cc(F)c(F)c(F)c1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NNC(=O)C(CCCl)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
oxalyl chloride (0.63 mL) and DMF (1 drop) were added to a solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid (1.17 g) in methylene chloride (30 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure to obtain 4-chloro-2-(3,4,5-trifluorophenyl)butyryl chloride. A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyryl chloride in THF (5 mL) was added to a solution of tert-butyl carbazate (600 mg) and triethylamine (3.1 mL) in THF (20 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was added to a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.35 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH2:1]([N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of ethyl [4-({butyl[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)-2-methylphenoxy]acetate (105 mg, 0.21 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL), was added 2M NaOH (2 mL) aq. After stirring for 1 h at room temperature the solvent was removed in vacuo and the residue acidified with 2M HCl, before extraction into ethyl acetate (2×20 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo to afford the title compound as a pale yellow foam (90 mg).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[C:14]1([S:20]([O:22][Na])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CS(C)=O>[C:14]1([S:20]([C:2]2[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=2)[C:7]([NH2:9])=[O:8])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(O[Na])c1ccccc1
Reactant: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 85.3 %

Procedure:
5-Fluoro-2-nitro-benzamide (2.5 g, 13.59 mmol) in DMSO (40 mL) was treated with solid 97% PhSO2Na (2.48 g, 14.95 mmol) and heated at 50° C. (oil bath temperature) for 60 hours. The reaction was added dropwise into 40 mL of iced water. Filtration of the solid afforded 3.55 g (85% yield) of title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]1[CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:13]1=[C:12]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[OH-].[K+].O>C(O)COCCOCCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:13]1=[C:12]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCCn2c1c(-c1ccccc1)c1cc(OCc3ccccc3)ccc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: c1ccc(COc2ccc3c(c2)c(-c2ccccc2)c2n3CCCCC2)cc1

Procedure:
An amount of 2.3 g (6 m mole) of 2-benzyloxy-7,8,9,10-tetrahydro-10-oxo-11-phenyl-6H-azepino[1,2-a]indole 4.5 ml of 80% hydrazine hydrate and 1.5 g of potassium hydroxide were heated in 6 ml of triethylene-glycol for two hours to 180° C. and for four hours to 220° C. After cooling, the reaction mixture was mixed with water and extracted with chloroform. After evaporation of the chloroform extracts, the residue was purified by column chromatography on silicagel (solvent: toluene). When the eluates were evaporated, colorless crystals were obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH:37]([N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)([CH3:39])[CH3:38].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:25]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][NH:22][C:5]2[N:4]=[C:3]([CH2:2][NH:1][CH:43]3[CH2:44][CH2:45][N:40]([CH:37]([CH3:39])[CH3:38])[CH2:41][CH2:42]3)[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)N1CCC(=O)CC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC4CCN(C(C)C)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.1 %

Procedure:
(2R,3R,4S,5R)-2-{2-(Aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (310 mg, 0.63 mmol) was dissolved (using gentle heating) in dry tetrahydrofuran (20 ml). The resulting solution was cooled to room temperature and, with stirring, treated with a solution of 1-isopropyl-4-piperidinone (90 mg, 0.63 mmol) and acetic acid (45 mg) in dry tetrahydrofuran (5 ml). The mixture was stirred for 1 hr, sodium triacetoxyborohydride (200 mg, 0.94 mmol) added and stirring continued for a further 18 hr. The solvent was then removed under reduced pressure and the residue partitioned between a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate. The organic phase was separated and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:ammonia (90:10:0.5) changing to dichloromethane:methanol:ammonia (85:15:0.75) to afford the title compound as a foam (140 mg). MS: 616 (MH+).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([C:20](N)=[O:21])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:23].[K+].Cl.O>C(O)CO>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([C:20]([OH:21])=[O:23])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)C1CN(c2ccccc2)CCN1Cc1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: O=C(O)C1CN(c2ccccc2)CCN1Cc1ccccc1
Temperature: 150 °C

Procedure:
Suspend 4-phenyl-1-(phenylmethyl)-2-piperazinecarboxamide (14.5 g, 49 mmol) in ethylene glycol (400 mL) and add potassium hydroxide (27.5 g, 490 mmol). Heat this mixture to 150° C. for 18 h. After this time, remove the solvent in vacuo. Add 6M hydrochloric acid (81.5 mL, 0.49 mol) and water (300 mL) and filter the resultant solid to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:4]=1[CH2:5][C:6]1[NH:7][C:8]2[C:13]([N:14]=1)=[C:12]([NH2:15])[N:11]=[C:10]([NH2:16])[N:9]=2.N1C=C2C(N=CN2)=NC=1.Cl[CH2:33][CH2:34][CH2:35][C:36]#[CH:37].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:4]=1[CH2:5][C:6]1[N:7]([CH2:37][CH2:36][CH2:35][C:34]#[CH:33])[C:8]2[C:13]([N:14]=1)=[C:12]([NH2:15])[N:11]=[C:10]([NH2:16])[N:9]=2
Reactant: C#CCCCCl
Reactant: COc1ccc(OC)c(Cc2nc3c(N)nc(N)nc3[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ncc2[nH]cnc2n1
Solvent: CN(C)C=O
Product: C#CCCCn1c(Cc2cc(OC)ccc2OC)nc2c(N)nc(N)nc21
Temperature: 50 °C
Yield: 25.1 %

Procedure:
A mixture of the purine 8-(2,5-Dimethoxy-benzyl)-9H-purine-2,6-diamine (19.0 g, 63 mmol), 5-chloro-pent-1-yne (12.3 ml, 116 mmol), and Cs2CO3 (37.8 g, 116 mmol) in DMF (180 g) was heated to 50° C. for 16 h. Filtration and washing (2×200 ml H2O) afforded some desired product (5.8 g, 25%). The mother liquor was concentrated, diluted with EtOAc, and heated to reflux for 1 h to yield additional product (6.0 g, 26%). After cooling to room temperature, addition of 1 volume hexane to the EtOAc mother liquor gave additional product (2.6 g, 11%). Final work-up (CH2Cl2:MeOH 4:1—water) yielded additional product (5.3 g, containing 1 equivalent penty-4-yn-1-ol, 18%). Rf=0.65 in 1:10 MeOH:EtOAc. 1H NMR (DMSO-d6) δ 6.92 (d, J=8.9 Hz, 1H), 6.98 (dd, J=8.9 & 3.0 Hz, 1H), 6.59 (s, J=2.9 Hz, 1H), 6.58-6.53 (br. s, 2H), 5.72-5.68 (br. s, 2H), 4.02 (s, 2H), 3.92 (t, J=7.4 Hz, 2H), 3.73 (s, 3H), 3.62 (s, 3H), 2.84 (t, J=2.5 Hz, 1H), 2.13 (td, J=7.0 & 1.7 Hz, 2H), 1.74 (quint., J=7.3 Hz, 2H); MS 367 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[Br:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34](O)=[O:35])[CH:29]=1>>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:34]([C:30]2[CH:29]=[C:28]([Br:27])[CH:33]=[CH:32][N:31]=2)=[O:35])[CH2:7]1
Reactant: O=C(O)c1cc(Br)ccn1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cc(Br)ccn2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-bromo-pyridine-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.O.[NH2:13][NH2:14]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:13][NH2:14]
Reactant: NN
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: O
Solvent: CCO
Product: NNc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 92.2 %

Procedure:
690 μL 3,4-difluoronitrobenzene was added to 15 mL anhydrous ethanol, and then the blend was heated to reflux. Hydrazine hydrate (611.5 μL) was slowly dropped into the blend and the resultant mixture was refluxed for another 2 hours to complete reaction, after which the reaction mixture was cooled down to room temperature. The yellow solid precipitated upon cooling was filtered. The filter cake was washed with petroleum ether, and then was dried to get 884.5 mg of a yellow solid, with a yield of 92.2%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CC(C)([O-])C.[K+].[Br:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[CH:17][C:18]=1[CH2:19]Br.C1OCCOCCOCCOCCOCCOC1>CCOCC.O>[Br:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[CH:17][C:18]=1[CH2:19][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)C=Cc1ccc(CBr)c(Br)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C=Cc1ccc(Cn2ccnc2)c(Br)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of imidazole (0.25 g, 3.67 mmol), potassium tert-butoxide (0.42 g, 3.75 mmol), ethyl 3-(3-bromo-4-bromomethylphenyl)prop-2-enoate (1.29 g, 3.7 mmol) and 18-crown-6 (0.1 g) in dry ether was stirred at room temperature for 72 h. Water (5 ml) was then added, and the aqueous layer was extracted with ether (3×50 ml). The ether solutions were combined, dried (MgSO4) and then concentrated to afford a pale yellow oil. The oil was `flash` chromatographed using chloroform/methanol 9:1 as eluant. The product fractions were combined, dried (MgSO4) and concentrated to afford ethyl 3-[3-bromo-4-(imidazol-1-ylmethyl)phenyl]prop-2-enoate as a white solid. NMR data was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)CC)C.C(O)C>>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)csc2n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1nc(N2CCOCC2)c2c(-c3ccccc3)csc2n1
Temperature: 50 °C

Procedure:
2,4-Dichloro-5-phenyl-thieno[2,3-d]pyrimidine (2 g, 7.112 mmol), morpholine (0.9294 g, 10.67 mmol) and triethylamine (1.454 g, 2.00 mL, 14.22 mmol) were combined in ethanol (23.7 g, 30 mL, 493 mmol) and heated to 50° C. for 1 hour. The reaction mixture was allowed to cool to room temperature. The solvent volume was reduced by half and the resulting precipitate filtered off and washed with water and dried in vacuo overnight at 40° C. to afford 4-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)morpholine as a white solid.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[Cl:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.P(=O)(O)(O)O.O>ClC1C=CC=CC=1Cl.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[Cl:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[C:11]2[C:12]=1[CH2:1][CH2:2][C:3]2([CH3:5])[CH3:4]
Reactant: Oc1cccc(Cl)c1
Reactant: C=CC(=C)C
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: O
Solvent: Clc1ccccc1Cl
Product: CC1(C)CCc2c(Cl)cc(O)cc21
Reaction time: 8 h
Yield: 16.4 %

Procedure:
449 g of isoprene, stabilized with 1.35 g of phenothiazine, were added dropwise over the course of 5.5 hours to a solution of 771 g of m-chlorophenol, 77 g of 85% strength phosphoric acid and 6 ml of water in 1.44 liters of o-dichlorobenzene at 150° C. To complete the reaction, stirring was continued overnight at 150° C. After cooling, the acid phase was separated off and extracted by shaking with toluene. The combined organic phases were washed until neutral. Fractional distillation gives 194 g of 7-chloro-3,3-dimethyl-5-hydroxy-indane; boiling point 105°-110° C/0.5 mm Hg; melting point 86.5° - 87.5° C. ##STR38##
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([CH3:11])=[CH:5][N:4]=1.[Cl:12][C:13]1[N:21]=[C:20]([NH2:22])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][NH:17]2.C([O-])([O-])=O.[K+].[K+]>>[Cl:12][C:13]1[N:21]=[C:20]([NH2:22])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([CH3:11])=[CH:5][N:4]=1
Reactant: Cc1cnc(CBr)c(C)c1C
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cnc(Cn2cnc3c(Cl)nc(N)nc32)c(C)c1C

Procedure:
The compound was obtained by reacting 2-bromomethyl-3,4,5-trimethyl-pyridine with 6-chloro-9H-purin-2-ylamine in the presence of K2CO3 at 5° C. for 0.5 h as described in the general procedure 1.1. HPLC Rt: 3.903 min. 1H-NMR (CDCl3): δ 8.18 (s, 1H), 7.84 (s, 1H), 5.38 (s, 2H), 5.08 (s, 2H), 2.29 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1)=[O:2].[BH4-].[Na+].C(O)C>O>[OH:2][CH2:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1
Reactant: COC(=O)c1ccc(C=O)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(CO)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.6 %

Procedure:
A mixture of methyl 4-formyl-2-methylbenzoate (200 mg, 1.1 mmol), sodium borohydride (210 mg, 5.5 mmol) and ethanol (10 mL) was stirred at room temperature for 4 hours. To the resultant mixture, water (0.4 mL) was added. The organic phase was separated, concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give methyl 4-(hydroxymethyl)-2-methylbenzoate (126 mg, 64%). 1H NMR (300 MHz, d6-DMSO): δ 7.78 (d, J=7.8 Hz, 1H), 7.15 (dd, J=7.8 Hz, J=1.8 Hz, 1H), 7.06 (d, J=1.8 Hz, 1H), 5.39 (t, J=5.7 Hz, 1H), 4.79 (d, J=5.7 Hz, 2H), 3.88 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [C:1](C1C2C(=CC=CC=2)C=CC=1C)#[CH:2].BrC1C2C(=CC=CC=2)C=CC=1C.Br[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[C:1]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37]([O:39][CH2:40][CH3:41])=[O:38])#[CH:2]
Reactant: CCOC(=O)c1ccc2ccccc2c1Br
Reactant: C#Cc1c(C)ccc2ccccc12
Agent: Cc1ccc2ccccc2c1Br
Product: C#Cc1c(C(=O)OCC)ccc2ccccc12

Procedure:
Ethyl 1-ethynyl-2-naphthoate was prepared in a similar manner to 1-ethynyl-2-methylnaphthalene, except that 1-bromo-2-methylnaphthalene was replaced by ethyl 1-bromo-2-naphthoate.
Reaction SMILES: CO.[C:3]([O:7][C:8](=[O:48])[N:9]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][N:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([O:39]CC3C=CC=CC=3)=[CH:31][C:30]2=[O:47])[CH2:23][CH2:22]1)[CH2:10][C:11]1[CH:20]=[CH:19][C:14]2[O:15][CH2:16][CH2:17][O:18][C:13]=2[CH:12]=1)([CH3:6])([CH3:5])[CH3:4]>[Pd].O1CCCC1>[C:3]([O:7][C:8](=[O:48])[N:9]([CH2:10][C:11]1[CH:20]=[CH:19][C:14]2[O:15][CH2:16][CH2:17][O:18][C:13]=2[CH:12]=1)[CH:21]1[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][N:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([OH:39])=[CH:31][C:30]2=[O:47])[CH2:25][CH2:26]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(OCc3ccccc3)c3ccccc32)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(O)c3ccccc32)CC1
Reaction time: 3.5 h

Procedure:
To a mixed solution of 130 mL methanol and 10 mL tetrahydrofuran containing 1.76 g of tert-butyl(1-(2-(4-benzyloxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate, 0.86 g of 5% palladium on carbon was added, and stirred under hydrogen atmosphere for 3.5 hours. The insoluble material was filtered off, and the solvent was removed under reduced pressure to afford 1.48 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-hydroxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([NH2:16])=[N:12][NH:13][C:14]=2[NH2:15])=[CH:6][CH:5]=1.CN(C)[CH:21]=[CH:22][C:23](=O)[CH3:24].C(O)(=O)C>C(O)C>[CH3:24][C:23]1[CH:22]=[CH:21][N:13]2[N:12]=[C:11]([NH2:16])[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:17])[F:18])=[CH:5][CH:6]=3)=[C:14]2[N:15]=1
Reactant: Nc1n[nH]c(N)c1-c1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)C=CN(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccn2nc(N)c(-c3ccc(OC(F)(F)F)cc3)c2n1
Temperature: -10 °C

Procedure:
The product from Example 1B (200 mg, 0.775 mmol) was charged to a microwave vial with a stir bar. A solution of 4-(dimethylamino)but-3-en-2-one (175 mg, 1.55 mmol) in ethanol (2 mL) was added, and the mixture was stirred at room temperature as acetic acid (25 ΞL, 0.437 mmol) was added. The solution was irradiated in the microwave at 150° C. for 35 minutes, then cooled to room temperature and finally to −10° C. The precipitate was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluted with hexanes-EtOAc, 70:30-40:60) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.47 (s, 3H), 5.71 (s, 2H), 6.69 (d, J=7.1 Hz, 1H), 7.39 (d, J=8.1 Hz, 2H), 7.87-7.98 (m, 2H), 8.62 (d, J=7.1 Hz, 1H).