Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]4[C:25]5[C@H:32]([CH3:33])[CH2:31][CH2:30][C:26]=5[N:27]=[CH:28][N:29]=4)=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:13][NH2:14])=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]4[C:25]5[C@H:32]([CH3:33])[CH2:31][CH2:30][C:26]=5[N:27]=[CH:28][N:29]=4)=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:13][NH:14][CH:2]([CH3:4])[CH3:1])=[CH:8][CH:7]=1
Reactant: C[C@@H]1CCc2ncnc(-c3ccc4c(C(CN)c5ccc(Cl)cc5)c[nH]c4c3)c21
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)NC[C@H](c1ccc(Cl)cc1)c1c[nH]c2cc(-c3ncnc4c3[C@H](C)CC4)ccc12
Reaction time: 0.17 h
Yield: 16.7 %

Procedure:
Acetone (0.0195 mL, 0.266 mmol) was added to a solution of 2-(4-chlorophenyl)-2-(6-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indol-3-yl)ethanamine (107 mg, 0.266 mmol) and N,N-diisopropylethylamine (0.139 mL, 0.797 mmol) in methylene chloride (2.0 mL). The reaction mixture was stirred for 10 minutes, and then sodium triacetoxyborohydride (0.0188 g, 0.0885 mmol) was added. After stirring for 2.5 hours, saturated NaHCO3 was added, and the mixture was stirred vigorously 10 minutes. The mixture was extracted with DCM (3×10 mL). The combined organic were dried (Na2SO4), filtered and concentrated. The crude product was purified by SFC chiral chromotagraphy (Chiral OJH (21.2×250 mm) 25% methanol+0.1% TEA) to give N-((R)-2-(4-chlorophenyl)-2-(6-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indol-3-yl)ethyl)propan-2-amine (19.8 mg, 16.8%) as the first peak. LCMS: M+1 445.3. 1H NMR (CDCl3, 400 MHz) δ 11.16 (s, 1H), 8.93 (s, 1H), 7.93 (s, 1H), 7.49-7.46 (m, 3H), 7.38 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 4.36 (t, 1H), 3.89 (m, 1H), 3.23 (m, 1H), 3.14-2.99 (m, 2H), 2.94-2.86 (m, 1H), 2.77 (m, 1H), 2.34 (m, 1H), 1.68 (m, 1H), 0.96 (d, 6H), 0.92 (d, 3H).
Reaction SMILES: Cl[CH2:2][CH:3]1[O:7][N:6]=[C:5]([CH2:8][OH:9])[CH2:4]1.[H-].[Na+].[CH3:12]I>C1COCC1>[CH3:12][O:9][CH2:8][C:5]1[CH:4]2[CH:3]([CH2:2]2)[O:7][N:6]=1
Reactant: OCC1=NOC(CCl)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1=NOC2CC12
Reaction time: 0.25 h

Procedure:
To a solution of (5-(chloromethyl)-4,5-dihydroisoxazol-3-yl)methanol (6c rac, 2.2 g, 14.71 mmol) in THF (40 mL) was added sodium hydride (60% dispersion in mineral oil, 0.372 ml, 17.65 mmol). The resulting mixture was stirred for 15 min followed by dropwise addition of methyl iodide (1.005 ml, 16.18 mmol). After 15 min, the reaction mixture was carefully quenched with aqueous saturated ammoniumchloride solution and diluted with water. The phases were separated and the aqueous phase was extracted with Et2O. The combined organic layers were dried over Na2SO4 and the filtrate was concentrated under reduced pressure to afford the title compound as a pale yellow oil. The oil was dissolved in THF (20 mL) and the solution was cooled 0° C. A solution of potassium tert-butoxide (1M in THF, 17.65 ml, 17.65 mmol) was added dropwise and the reaction mixture was stirred for 30 min at 0° C. The mixture was quenched with aqueous saturated ammoniumchloride solution, the phases were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and the filtrate was concentrated under reduced pressure to afford the title compound as an orange oil as MS m/z=128.1[M+H]+. Calculated for C6H9NO2: 127.06.
Reaction SMILES: [CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7](=S)[C:6]=2[N:5]=1)([CH3:3])[CH3:2].[CH3:19][O:20][C@@H:21]([CH3:29])[CH2:22][C@H:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1.CO[C@H](C)C[C@H]1CNCCN1>>[CH3:19][O:20][C@H:21]([CH3:29])[CH2:22][C@@H:23]1[NH:24][CH2:25][CH2:26][N:27]([C:7]2[C:6]3[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[S:13][C:12]=3[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=2)[CH2:28]1
Reactant: CO[C@@H](C)C[C@H]1CNCCN1
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1NC2=S
Agent: CO[C@H](C)C[C@H]1CNCCN1
Product: CO[C@H](C)C[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)nc32)CCN1

Procedure:
In a manner similar to that described in Example 359, combine 2-isopropyl-4,9-dihydro-3-thia-1,4,9-triazabenzo[f]azulene-10-thione (0.865 g, 3.14 mmol) and the isomer mixture of 2(S)-(2(S)-methoxypropyl)piperazine and 2(S)-(2(R)-methoxypropyl)piperazine (0.497 g, 3.14 mmol) to obtain the title compound as a mixture of isomers: mass spectrum (APCI): m/z 400.2 (M+1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[C:9]([C:14]([O:16]C2C(F)=C(F)C(F)=C(F)C=2F)=O)=[N:10][CH:11]=[CH:12][CH:13]=1.[F:28][C:29]([F:42])([F:41])[O:30][C:31]1[CH:32]=[C:33]([CH2:37][C:38](Cl)=[O:39])[CH:34]=[CH:35][CH:36]=1>C(#N)C.O>[OH:16][C:14]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[O:7][C:38](=[O:39])[C:37]=1[C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([O:30][C:29]([F:28])([F:41])[F:42])[CH:32]=1
Reactant: O=C(Cl)Cc1cccc(OC(F)(F)F)c1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=c1oc2cccnc2c(O)c1-c1cccc(OC(F)(F)F)c1
Temperature: 22.5 °C
Reaction time: 12 h
Yield: 44.3 %

Procedure:
3.5 g of K2CO3 were added to a solution of 0.64 g of pentafluorophenyl 3-hydroxy-pyridine-2-carboxylate (from step 1) and 0.5 g of (3-trifluoromethoxyphenyl)acetyl chloride in 150 ml of acetonitrile, and the mixture was stirred at 20-25° C. under an atmosphere of nitrogen for about 12 hours. After filtration, the solvent was removed from the filtrate and the residue obtained was taken up in water and, after acidification to pH<4, extracted with CH2Cl2. The organic phase was dried, then freed from the solvent. The residue gave, after preparative HPLC [column: Luna (2), from Phenomenex, 300*50 mm 10 μm; mobile phase: water (+0.0375% trifluoroacetic acid) and acetonitrile in mixing ratios of 80:20 and 50:50; flow rate 80 ml/min; detection at 220 and 254 nm), 20-25° C.], 300 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[NH:31]1[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]1>>[Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:31]5[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:29])([F:28])[F:30])[CH:3]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Br)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)C1CNC1
Product: O=C1N=C(N2CC(C(=O)O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Br)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(4-Bromo-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylic acid was prepared from 5-[1-(4-Bromo-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and azetidine-3-carboxylic acid following General Procedure C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[C:11](Cl)(=[O:15])[C:12]([CH3:14])=[CH2:13].[K+].[Br-]>ClCCl>[C:11]([C:2]([C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])([CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10])[N:1]([C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])[C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])(=[O:15])[C:12]([CH3:14])=[CH2:13]
Reactant: NCCNCCNCCN
Reactant: C=C(C)C(=O)Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: C=C(C)C(=O)N(C(=O)C(=C)C)C(CNCCNCCN)(C(=O)C(=C)C)C(=O)C(=C)C
Temperature: 25 °C

Procedure:
Triethylene tetramine (2.93 g, 0.02 moles) in dichloromethane (100 ml) was added drop wise over 6 hrs to a solution of methacryloyl chloride (8.32 g, 0.08 moles) in dichloromethane (40 ml), stirring vigorously at room temperature. The reaction was continued stirring at room temperature overnight and the suspension formed was filtered. The filtrate was extracted with NaOH (aq). The water was rotary evaporated and the residue was washed with acetone and filtered. The acetone filtrate was concentrated down and put through a silica gravity chromatography column with acetone as the elutant to obtain a white solid. The solid is recrystallized from diethyl ether to give white crystals, m.p. 168-170° C. 1H n.m.r. (D2O) δ, 5.71(19.7 Hz), 5.51 (7.8 Hz), 5.31(9.7 Hz), 5.06 (17.7 Hz), (8 H, d×4) C—CH2; 3.61 (6 H, m) N—CH2—CH2; 3.48(6 H, m) N—CH2—CH2; 1.96(4.1 Hz); 1.93(5.8 Hz); 1.91(6.0 Hz); 1.88(4.5 Hz), (12 H, d×4) CH3; 13C n.m.r. (D2O), δ 178.76, 178.70, 174.71, 174.61 (C=O); 142.19, 142.0, 141.71, 141.56 (C=CH2), 124.52, 124.19, 120.06, 119.60 (C=CH2); 22.30, 22.20, 20.48; (CH3), 50.33, 49.22, 46.45, 44.00, 40.22, 39.49 (N—CH2—CH2). MS: mz: 419.3 (MH+, 100%), 391.3(4), 266.2(10), 223.1(42); HRMS: found: 419.26695 C22H34N4O4 requires 418.5299. Elemental analysis: found: C, 62.97; H, 8.09; N, 13.31; C22H34N4O4 requires C, 63.13; H, 8.19; N, 13.39. I.R. (KBr) (CM−1) 3353, 1665, 1650, 1530, 1279.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[S:8][C:9](Cl)=[C:10]([Cl:13])[C:11]=1[Cl:12].C([O:17][C:18](=O)[C:19]([F:22])([F:21])[F:20])C>C1COCC1>[F:20][C:19]([F:22])([F:21])[C:18]([C:9]1[S:8][C:7]([Cl:6])=[C:11]([Cl:12])[C:10]=1[Cl:13])=[O:17]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Clc1sc(Cl)c(Cl)c1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1sc(Cl)c(Cl)c1Cl)C(F)(F)F
Reaction time: 2 h
Yield: 81.5 %

Procedure:
Add a solution of n-BuLi (21.6 mL, 2.5 M in hexane, 54.0 mmol) to a solution of 2,3,4,5-tetrachloro-thiophene (10 g, 45.0 mmol) in dry THF (160 mL) at −78° C. and stir the mixture for 2 hours. Add a solution of trifluoro-acetic acid ethyl ester (9.59 g, 67.6 mmol) in THF (15 mL) and stir at −78° C. for additional 2.5 hours. Quench the reaction with saturated NH4Cl solution (100 mL). Extract the aqueous mixture with EtOAc (100 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4, and evaporate under vacuum. Purify the residue by a flash column on silica gel eluting with PE:EtOAc (10:1 to 5:1) to afford 2,2,2-trifluoro-1-(3,4,5-trichloro-thiophen-2-yl)-ethanone as a brown oil (10.4 g, 81.9%). 13F NMR (400 MHz, CDCl3) δ −73.38 (s, 3F).
Reaction SMILES: [H-].[Na+].OC1C=CC=C2C=1N=CC=C2.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:24])[CH3:23].[CH2:25]([OH:28])[CH2:26][OH:27]>>[OH:27][CH2:26][CH2:25][O:28][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:24])[CH3:23]
Reactant: CC(=O)Nc1ccccc1Br
Reactant: OCCO
Agent: Oc1cccc2cccnc12
Agent: [H-]
Agent: [Na+]
Product: CC(=O)Nc1ccccc1OCCO
Yield: 74 %

Procedure:
440 mg of sodium hydride solution (concentration 40%) was added portionwise to 30 ml of ethylene glycol. After abating of the froth occurred, 50 mg of cuprous chloride, 75 mg of 8-hydroxyquinoline and 1.07 g of 2-bromo-1-acetylamino-benzene were added to the solution and the mixture was heated at 70° to 80° C. for 50 minutes. The reaction mixture was treated in a usual manner, and then crystallization was effected from a solvent mixture of n-hexane and ethyl acetate to give 720 mg of the desired compound. Yield: 74%, melting point: 89°-91° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([C:7]1[CH:8]=[CH:9][C:10]2[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[CH2:14][N:13]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:11]=2[CH:27]=1)(=O)[CH3:5].C([BH3-])#N.[Na+]>CO.Cl>[CH3:1][N:2]([CH3:3])[CH:4]([C:7]1[CH:8]=[CH:9][C:10]2[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[CH2:14][NH:13][CH:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:11]=2[CH:27]=1)[CH3:5]
Reactant: CNC
Reactant: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)=O)ccc21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN1C(=O)CNC(c2ccccc2F)c2cc(C(C)N(C)C)ccc21

Procedure:
To a solution, stirred at room temperature, of 9.1 ml of dimethylamine in 140 ml of methanol and 0.1 ml of 5 N methanolic hydrochloric acid are added 7.0 g (21.7 mmol) of 7-acetyl-1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one, followed by 0.24 g of sodium cyanoborohydride. The mixture is stirred at room temperature for 14 days, with 924 mg of sodium cyanoborohydride being added after 2 days and after 7 days. The solvent is removed in vacuo and the residue is adjusted to pH 10 with 10 N sodium hydroxide and then taken up in chloroform. The organic phase is washed with water, dried and evaporated. The residue is chromatographed on 200 g of silica gel using chloroform as the elution agent and there is obtained 7-[1-(dimethylamino)ethyl]-1-ethyl-5-(o-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one as an oil.
Reaction SMILES: FC1C=CC=C(F)C=1C(Cl)=O.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1.C1(C)C=CC=CC=1>C(O)C>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[CH:41][CH:42]=1)=[S:24])=[O:21]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1c(F)cccc1F
Agent: O=C(N=C=S)c1c(F)cccc1F
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4c(F)cccc4F)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
2,6-Difluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,6-difluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,6-Difluoro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (62 mg, yield 74%).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]([OH:14])[CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:14][C@H:12]1[CH2:11][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)[CH2:9][NH:8][CH2:13]1
Reactant: [H][H]
Reactant: OC1C=C(c2ccc(C(F)(F)F)cc2)CN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: O[C@@H]1CNC[C@H](c2ccc(C(F)(F)F)cc2)C1

Procedure:
A solution of 1-benzyl-5-hydroxy-1,2,5,6-tetrahydro-3-(p-trifluoromethylphenyl)pyridine (5.9 g) in methanol (200 ml) was hydrogenated over 10% palladium on carbon (500 mg) in a Parr apparatus at 30 psi (about 2.11×104 kg/sq.m.) and room temperature. After the theoretical uptake of hydrogen had occurred (about 3 hours), the catalyst was removed by filtration and the solvent evaporated under reduced pressure. Recrystallisation of the residue from toluene gave the title compound as the free base (4 g). The free base was dissolved in a small volume of IPA and treated with an excess of etherial hydrogen chloride. On cooling crystals of the title compound hydrochloride separated, m.p. 189°-92°.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:18]1[C:19]2[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=2[N:21]=[CH:22][N:23]=1>CN(C=O)C.O>[Cl:28][C:26]1[CH:25]=[CH:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]([O:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)[C:19]=2[N:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3ccc(Cl)nc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.201 g, 1.000 mmol) in DMF (5.00 ml) was added NaH (0.052 g, 55% dispersion in mineral oil, 1.20 mmol) at 0° C. After stiffing for 30 min at room temperature, the reaction mixture was cooled to 0° C. and 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.2 g, 1.000 mmol) was added to the mixture. After stiffing for 3 hours at room temperature, the reaction mixture was diluted with water, and extracted with EtOAc. The organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=5:1) to give tert-butyl 4-(6-chloropyrido[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate (0.236 g, 65%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.49 (9H, s), 1.91-1.99 (2H, m), 2.10-2.13 (2H, m), 3.21-3.27 (2H, m), 3.83-3.97 (2H, m), 5.55-5.62 (1H, m), 7.74 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=8.8 Hz), 8.41 (1H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C:5]1[C:15]([CH2:16][CH2:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:14]([OH:26])[C:8]2[N:9]=[C:10]([CH3:13])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4].[BH4-].[Na+].[Cl-].[NH4+]>C(O)C.O>[CH3:27][N:2]([CH3:1])[C:3]([C:5]1[C:15]([CH2:16][CH2:17][CH:18]([OH:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:14]([OH:26])[C:8]2[N:9]=[C:10]([CH3:13])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4]
Reactant: Cc1nc2c(O)c(CCC(=O)c3ccccc3)c(C(=O)N(C)C)cc2n1C
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1nc2c(O)c(CCC(O)c3ccccc3)c(C(=O)N(C)C)cc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a suspension of 1.0 g (2.7 mmol) 7-hydroxy-2,3-dimethyl-6-(3-oxo-3-phenyl-propyl)-3H-benzo-imidazole-5-carboxylic acid dimethylamide in ethanol (10 ml) were cautiously added 124 mg (3.3 mmol) sodium borohydride (exothermic reaction 1) and the reaction was stirred for 2 h at room temperature. The reaction mixture was poured into saturated ammonium chloride solution (20 ml) and diluted with water (80 ml). The precipitate was filtered off and dried in vacuo to afford 880 mg (89%) of the title compound as a beige solid. m. p. 257°-260° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:21]3[C:20](=O)[CH2:19][CH2:18][CH2:17][C:16]=3[NH:15][C:14]3[CH2:13][CH2:12][CH2:11][C:10](=[O:23])[C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].C(O)C>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]3[C:10](=[O:23])[CH2:11][CH2:12][CH2:13][C:14]=3[NH:15][C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2=3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCC2=C1C(c1cccc(F)c1)C1=C(CCCC1=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1CCCC2=C1C(c1cccc(F)c1)C1=C(CCCC1)N2
Temperature: 70 °C
Yield: 44 %

Procedure:
A mixture of 9-(3-fluorophenyl)-3,4, 6,7,9,10-hexahydro-1,8(2H,5H)-acridinedione (5.0 g), sodium borohydride (6.1 g), ethanol (140 mL) and pyridine (50 mL) was heated at 70° C. overnight and cooled to room temperature. The solvent was removed and the resulting yellow solid was collected and washed well with water. Chromatography (ethyl acetate/hexane; 80/20) provided the title compound (2.1 g) as a yellow solid. Recrystallization from ethanol/hexane returned analytically pure light yellow solid, mp 249°-251° C.; NMR: 1.45-1.55 (m,3, CH2), 1.66-1.90 (m,5, CH2); 2.10-2.15 (m,4, CH2), 2.39-2.45 (m,2, CH2 (s,1, CH), 6.87-6.92 (m,2, Ar), 7.00 (d,1, J=7.8, Ar), 7.20-7.27 (m,1, Ar), 8.41 (s,1, NH); (CI, CH4) MS: m/z=298(M+1). Analysis for C19H20FNO: Calculated: C, 76.74; H, 6.78; N, 4.71; Found: C, 76.32; H, 6.71; N, 4.62.
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[OH:26])=[CH:14][CH:13]=[CH:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.COC[O:30][CH2:31][CH2:32]Br.C(Cl)(Cl)Cl>CN(C=O)C>[O:3]([C:10]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[O:26][CH2:32][CH2:31][OH:30])=[CH:14][CH:13]=[CH:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COCOCCBr
Reactant: Oc1cnccc1CCCOc1cccnc1Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: OCCOc1cnccc1CCCOc1cccnc1Oc1ccccc1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 0.08 g, 2.0 mmol) is suspended in DMF (5 ml), and thereto is added 2-phenoxy-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine (0.20 g, 0.62 mmol) obtained in Example 30 at room temperature, and the mixture is stirred for 30 minutes. To the mixture is added 2-methoxymethoxyethyl bromide (0.32 g, 2.0 mmol) under ice-cooling, and the mixture is stirred at 50° C. for 30 minutes. To the reaction solution is added chloroform (100 ml), and the mixture is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue are added ethanol (20 ml) and a 35% aqueous hydrochloric acid solution (2 ml), and the mixture is stirred at 60° C. for 30 minutes. The pH value of the reaction solution is adjusted to pH 10 with a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform (50 ml×2), washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol) to give 2-phenoxy-3-[3-(3-(2-hydroxyethoxy)pyridin-4-yl)propoxy)pyridine, which is further treated with fumaric acid to give the title compound (0.17 g), m.p. 129-132° C. (recrystallized from ethanol/isopropyl ether).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1)=[O:3].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=O>C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:1][C:2]([C:4]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=2)=[O:3])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: C=CCOc1ccc(C(C)=O)cc1
Reactant: COc1ccc(C=O)cc1OC
Solvent: CCO
Product: C=CCOc1ccc(C(=O)C=Cc2ccc(OC)c(OC)c2)cc1
Reaction time: 18 h
Yield: 92.5 %

Procedure:
1.76 g (10 mmol) of 4-allyloxyacetophenone and 1.66 g (10 mmol) of 3,4-dimethoxy-benzaldehyde were under a dry inert atmosphere (argon) dissolved in 10 ml dry ethanol and the solution was stirred for 18 h. The solution was filtered to give 3.0 g (99%) of 3,4-dimethoxy-4′-prop-2-enyloxychalcone which was recrystallized from ethanol, m.p. 74.5-75° C.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:3]1[C:27]#[N:28].[OH:29][NH2:30].Cl.N1C=CC=CC=1>C(O)C>[OH:29][N:30]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:3]1[C:27]#[N:28]
Reactant: NO
Reactant: N#CC1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: N#CC1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=NO
Temperature: 70 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
1-Oxo-3-phenyl-6-(3-phenylpropoxy)-1H-indene-2-carbonitrile (200 mg, 0.547 mmol) was dissolved in ethanol. Hydroxy amine.hydrochloric acid (114 mg, 1.64 mmol) and pyridine (173 mg, 2.18 mmol) were added thereto and the mixture was stirred for 4 hours at 70° C. The organic layer extracted with ethyl acetate was washed with distilled water, dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography (ethyl acetate:hexane=1:2) to obtain trails 1-hydroxy imino-3-phenyl-6-(3-phenylpropyloxy)-1H-indene-2-carbonitrile (95 mg, yield 45%) as a red solid,