Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:39])[N:24]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:25][CH2:26][CH2:27][CH2:28][N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)[CH:20]=[C:19]([Cl:40])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:40][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH:33]=[N:32][CH:31]=[N:30]1)=[O:39]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCCn2cncn2)C2CCCC2)c1)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CCCCn1cncn1)C1CCCC1
Yield: 45.5 %

Procedure:
A solution of {2-[3-chloro-5-(cyclopentyl-(4-[1,2,4]triazol-1-yl-butyl)-carbamoyl)-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.069 g) and trifluoroacetic acid (0.5 ml) in dichloromethane (0.5 ml) was stirred at room temperature for 1 h then concentrated under vacuum. The residue was purified by flash chromatography eluting with dichloromethane:methanol:ammonia (92:8:1 v/v/v), to give the title compound as a white foam (0.026 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=[O:25])[CH2:21][C:22](=O)[CH3:23])=[CH:16][CH:15]=3.Cl.[NH2:32]O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[O:25][N:32]=[C:22]([CH3:23])[CH:21]=1)=[CH:16][CH:15]=3
Reactant: NO
Reactant: CC(=O)CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Agent: Cl
Product: Cc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)on1

Procedure:
The process is carried out as indicated in Example 44 above, using 1-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]butane-1,3-dione from preparation 1.14 and hydroxylamine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH:13][NH2:14])=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:15].[Si:16]([O:23][CH2:24][C:25]1([CH3:34])[S:31][CH2:30][CH2:29][N:28]=[C:27](SC)[CH2:26]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:28]4[CH2:29][CH2:30][S:31][C:25]([CH2:24][O:23][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])([CH3:34])[CH2:26][C:27]4=[N:14][N:13]=3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:15]
Reactant: NNC(=O)C1(c2ccc(Br)c(F)c2)CC1
Reactant: CSC1=NCCSC(C)(CO[Si](C)(C)C(C)(C)C)C1
Solvent: CCCCO
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)c(F)c4)CC3)n2CCS1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of the compound (4.1 g, 15 mmol) obtained in Example 25-2) and 7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-methyl-5-(methylthio)-2,3,6,7-tetrahydro-1,4-thiazepine (4.79 g, 15 mmol) in n-butanol (30 mL) was stirred at 140° C. for 3.5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Isco Combiflash, 40 g, ethyl acetate:dichloromethane=0:100 to 100:0, gradient) to obtain the title compound (3.47 g, 44%) as a brown solid.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH3:5]>Cl>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH:4]([CH3:5])[C:3]([OH:16])=[O:2])=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: COC(=O)C(C)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A mixture of 2-(4-nitrophenoxy)propionic acid methyl ester 35 (50 g) and concentrated HCl (500 ml) was refluxed for 8 hours. The reaction mass was cooled to room temp. Crude 47 was filtered, dried and recrystallised from a mixture of ethyl acetate:hexane (1:5) to give pure 47 (40 g, 85.3%) as a white powder. M.p: 139-141° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH2:29][C:30]#[N:31])[CH:22]=[CH:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C=O)C>[C:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH2:29][C:30]2[NH:36][N:35]=[N:34][N:31]=2)[CH:22]=[CH:21]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCOc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-c2ccc(-c3ccc4cc(OCc5nnn[nH]5)ccc4c3)n2-c2ccccc2)cc1
Yield: 78.6 %

Procedure:
In a similar manner as described in step 2 of Example 3, the title compound was prepared from {[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile (0.180 g, 0.373 mmol), prepared in the previous step, ammonium chloride (0.060 g, 1.12 mmol) and sodium azide (0.073 g, 1.12 mmol) in DMF (10 mL). The precipitated solids were isolated by vacuum filtration to give 5-({[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole as an off-white solid (0.130 g, 98%), mp 269–270° C. (dec). Elemental Analysis for C28H21N5O Calc'd: C, 75.83; H, 4.77; N, 15.79. Found: C, 75.83; H, 4.69; N, 15.50.
Reaction SMILES: C(C([O:7][CH2:8][CH2:9][CH:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:11])=O)(C)(C)C.C[O-].[Na+].CO>CO>[O:12]([CH:10]([CH3:11])[CH2:9][CH2:8][OH:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(CCOC(=O)C(C)(C)C)Oc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(CCO)Oc1ccccc1
Temperature: 55 °C
Reaction time: 9 h
Yield: 109.5 %

Procedure:
To a solution of 4.32 g (17.3 mmol) of pivaloyl ester 26 (prepared in 30-(2)) in 90 ml of dry methanol is added 17.3 ml (17.3 mmol) of 1M sodium methoxide-methanol solution and the mixture is stirred at 55° C. for 9 hours. After cooling, 35 g of ion exchange resin IRC-50 is added and the mixture is stirred for 20 minutes. The ion exchange resin is filtrated off and the filtrate is evaporated under reduced pressure to give 3.15 g of the crude desired alcohol 27 as an oil, which is employed in the next step without further reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:29])=[O:28])[C:19]([C:33]([F:36])([F:35])[F:34])=[CH:18][N:17]=1.[CH:37](=O)[CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:37]([N:12]1[CH2:13][CH2:14][CH:9]([C:7]2[CH:6]=[CH:5][C:4]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([NH2:29])=[O:28])[C:19]([C:33]([F:34])([F:35])[F:36])=[CH:18][N:17]=3)=[C:3]([O:2][CH3:1])[CH:8]=2)[CH2:10][CH2:11]1)[CH3:38]
Reactant: CC=O
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2cccc(C(N)=O)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(N)=O)c4)n3)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 16.6 %

Procedure:
To a solution of 3-(2-(2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)benzamide (5) (0.021 g, 0.04 mmol) in methanol (2.00 mL) was added acetaldehyde (0.010 mL, 0.18 mmol) followed by sodium triacetoxyborohydride (0.044 g, 0.21 mmol) under a N2 atmosphere. The mixture was then stirred at room temperature for 5 hours. The resulting mixture was concentrated under reduced pressure and purified using silica gel column chromatography (0-30% MeOH/EtOAc+1% 2 M ethanolic NH3). The product was further purified using mass directed auto-preparative HPLC to give the title compound (7) (3.5 mg, 16%); 1H NMR (400 MHz, d6-Acetone) δ 8.62 (s, 1H), 8.24 (m, 2H), 7.91 (s, 1H), 7.78 (ddd, J=7.5, 1.4, 1.4 Hz, 1H), 7.41 (m, 3H), 7.01 (d, J=1.7 Hz, 1H), 6.89 (dd, J=8.3, 1.7 Hz, 1H), 6.60 (m, 1H), 3.97 (s, 3H), 3.21 (m, 4H), 3.12 (m, 2H), 2.55 (m, 3H), 2.16 (m, 2H), 1.85 (m, 4H), 1.11 (t, J=7.2 Hz, 3H). LCMS Method C: rt 4.98 min; m/z 528.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:11]([O:10][C:8]([NH:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCC(O)CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCC(O)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
A mixture of 1-amino-2-butanol (5.5 g, 61.8 mmol), benzyl chloroformate (11.5 g, 67.6 mmol) and sodium carbonate (7.16 g, 67.7 mmol) in water (50 mL) was stirred at 0° C. for 3 h. Water (50 mL) was added to the reaction mixture and the product was extracted with methylene chloride (3×20 mL). The methylene chloride extract was dried over Na2SO4 and concentrated. The residue was passed through a short column (SiO2, hexanes: ethyl acetate/10:1; then ethyl acetate) to afford 1-benzyloxycarbonylamino-2-butanol (13.9 g, 100%) as a liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[NH2:13][OH:14].Cl.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[N:13][OH:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C=NO)cc1OC
Reaction time: 1 h
Yield: 7154.4 %

Procedure:
After dissolving 3,4-dimethoxybenzaldehyde (1.00 g, 0.081 mmol) in 60 mL of ethyl alcohol/water (1/1, v/v) solution, H2NOH HCl (0.54 g, 7.823 mmol) was added. While stirring the reaction mixture, Na2CO3 (0.83 g, 7.823 mmol) was added slowly at below 0° C. The reaction was continued for 1 hr in an oil bath preheated to 60-65° C. After the reaction was completed, 1.05 g (96.4%) of the target product was obtained by extracting with ethyl acetate, drying over anhydrous MgSO4 and removing the solvent under reduced pressure.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:38][OH:39])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([CH2:32][N:33]([CH3:35])[CH3:34])=[CH:30][CH:31]=[C:26]4[C:25]([C:36]#[N:37])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:42])C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:38][OH:39])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([CH2:32][N:33]([CH3:35])[CH3:34])=[CH:30][CH:31]=[C:26]4[C:25]([C:36]([NH2:37])=[O:42])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)Cc1ccc2c(C#N)cn(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)c2n1
Reactant: CCO
Solvent: O
Product: CN(C)Cc1ccc2c(C(N)=O)cn(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)c2n1
Temperature: 45 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
In a 25 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (8 mg, 15.3 μmol, Eq: 1.00) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (655 μg, 1.53 μmol, Eq: 0.1) were combined with Ethanol (1 mL) and Water (1 mL) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 1 h. The crude reaction mixture was concentrated in vacuo. The LCMS of crude shows the desired product. The reaction mixture was diluted with acetonitrile and water and filtered and passed through HPLC purification followed by lyophalization to give 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (2.5 mg, 30%, [M+H]+ 543)
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][C:10]#[N:11])[CH:6]=[N:5][C:4]=1[N+:12]([O-:14])=[O:13].S(=O)(=O)(O)[OH:16]>>[Br:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][C:10]([NH2:11])=[O:16])[CH:6]=[N:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: N#CCCn1cnc([N+](=O)[O-])c1CBr
Reactant: O=S(=O)(O)O
Product: NC(=O)CCn1cnc([N+](=O)[O-])c1CBr

Procedure:
3-[5-(Bromomethyl)-4-nitro-1H-imidazol-1-yl]propanenitrile (115) (680 mg, 2.62 mmol) was treated with 90% sulphuric acid (5 mL) at 65-70° C. for 1 hour, before being poured onto ice. After a standard ethyl acetate/NaHCO3 workup, the crude product obtained was precipitated from THF by the addition of i-Pr2O to give 3-[5-(bromomethyl)-4-nitro-1H-imidazol-1-yl]propanamide (116) (420 mg, 58%) as an off-white solid, m.p. 139-141° C. 1H NMR (d6-DMSO) δ 7.90 (s, 1H), 7.44 (br, 1H), 7.00 (br, 1H), 5.06 (s, 2H), 4.32 (t, J=6.8 Hz, 2H), 2.70 (t, J=6.8 Hz, 2H). LR-MS (APCI +ve): m/e 277.5/279.5 (1:1, M+1).
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[C:5]([N+:14]([O-])=O)=[CH:4][CH:3]=1.O.NN>C(O)C.[Ni]>[NH2:14][C:5]1[C:6]2[CH2:7][CH2:8][N:9]([CH3:13])[CH2:10][CH2:11][C:12]=2[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CN1CCc2c(Cl)ccc([N+](=O)[O-])c2CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CN1CCc2c(N)ccc(Cl)c2CC1

Procedure:
A solution of 10 g (0.04 mol) of the nitro compound and 6.0 ml of hydrazine hydrate in 400 ml of ethanol was warmed to 45° while activated Raney nickel was added in small portions until the evolution of gas ceased. The mixture was cooled, filtered through a filter aid and concentrated to give 9-amino-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH:19]=[N:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[C:13]=3[CH:14]=[N:15][CH:16]=2)=[O:10])=[CH:5][N:6]=1>C(OC(=O)C)(=O)C.[OH-].[Na+]>[C:9]([N:8]([CH3:7])[C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH:19]=[N:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[C:13]=3[CH:14]=[N:15][CH:16]=2)=[O:10])=[CH:5][N:6]=1)(=[O:10])[CH3:11]
Reactant: O=C(NCc1cnc(Br)s1)c1cncc2c1cnn2-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(C)c1ncc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)s1
Reaction time: 0.17 h

Procedure:
A solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (2-bromo-thiazol-5-ylmethyl)-amide (80 mg, 0.2 mmol) in acetic anhydride (2 mL) was heated at 60° C. for 18 hours. The solution was diluted with 10 mL of a 1 N solution of aqueous NaOH and stirred for 10 minutes. The solution was then extracted with dichloromethane (20 mL). The organic layers were dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane. The purification was repeated eluting with a gradient of 0-7% methanol in dichloromethane. The material from the purification was diluted with dichloromethane (1 mL) followed by hexanes (5 mL). The solid was collected by filteration to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([N:12]1[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[CH2:14][CH2:13]1)[CH2:6][CH2:5]2.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([N:12]1[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[CH2:16][CH2:17]1)[CH2:6][CH2:5]2)(=[O:28])[CH3:27]
Reactant: COc1ccccc1N1CCN(C2CCc3cc(O)ccc3C2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccccc1N1CCN(C2CCc3cc(OC(C)=O)ccc3C2)CC1
Reaction time: 3 h

Procedure:
170 mg of 1,2,3,4-tetrahydro-6-hydroxy-2-[4-(2-methoxyphenyl)-1-piperazinyl]-naphthalene are added to 2 ml of pyridine, 70 μl of acetic anhydride are added dropwise and the solution left to stand at room temperature for 3 hours. The reaction solution is finally evaporated to dryness, the residue taken up in ethyl acetate, washed with IN sodium carbonate solution, dried and evaporated to dryness. The raw title product so obtained is converted to the hydrochloride salt form and recrystallized from methanol/ether. M.P. 249°-253° [Hydrochloride salt form].
Reaction SMILES: [Cl:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:13][CH2:14][C@@H:15]1[CH2:20][O:19][CH2:18][CH2:17][N:16]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[O:30][CH3:31]>CO.ClCCl.[Cl-].[NH4+].[Zn]>[NH2:10][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([O:13][CH2:14][C@@H:15]2[CH2:20][O:19][CH2:18][CH2:17][N:16]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:2]=1[Cl:1])[C:6]#[N:7]
Reactant: COc1ccc(CN2CCOC[C@H]2COc2cc(C#N)cc([N+](=O)[O-])c2Cl)c(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN2CCOC[C@H]2COc2cc(C#N)cc(N)c2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
Zinc (107 mg, 1.630 mmol) was added to a mixture of (S)-4-chloro-3-((4-(2,4-dimethoxybenzyl)morpholin-3-yl)methoxy)-5-nitrobenzonitrile (isomer B, 73 mg, 0.163 mmol) and ammonium chloride (174 mg, 3.26 mmol) in methanol (5 mL) and the reaction mixture was stirred at room temperature for 2 hours. More zinc (107 mg, 1.630 mmol) was added and stirring continued until reactions complete. The reaction mixture was diluted with dichloromethane and ammonium chloride precipitated. Solids were filtered and the filtrate was concentrated. The residue was partitioned between dichloromethane and saturated sodium bicarbonate. The layers were separated and aqueous layer was extracted with dichloromethane two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 5-35% ethyl acetate/hexanes) to give (S)-3-amino-4-chloro-5-((4-(2,4-dimethoxybenzyl)morpholin-3-yl)methoxy)benzonitrile (53 mg) as a oil.
Reaction SMILES: [C@@H:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[OH:10].S(=O)(=O)(O)O.O.[OH-].[Na+].C(#[N:22])C>>[NH2:22][C@@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[OH:10]
Reactant: O[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 0 °C

Procedure:
Cis-1,2-indandiol (1.5 g) was dissolved in acetonitrile (25 mL) cooled to 0° C, and concentrated sulfuric acid (1.1 mL) was added. The mixture was gradually warmed to 20° C. and aged to 3 hours. Water (2 mL) was added and the mixture heated to reflux. Concentrated aqueous sodium hydroxide was added to adjust the pH to 12. The resulting solid was removed by filtration to provide an aqueous acetonitrile solution of cis-1-amino-2-indanol.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].[OH-].[Na+].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1>C(O)C>[CH3:6][N:5]([CH2:4][CH2:3][S:17][C:14]1[CH:15]=[CH:16][C:11]([Br:10])=[CH:12][CH:13]=1)[CH3:7]
Reactant: CN(C)CCCl
Reactant: Sc1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCSc1ccc(Br)cc1
Reaction time: 0.03 h
Yield: 86 %

Procedure:
A solution of 23.5 g of chloroethyldimethylamine HCl in 75 ml of ethanol was added to 160 ml of sodium hydroxide solution formed by dissolving 20 g of sodium hydroxide pastilles in 500 ml of ethanol. A solution of 30 g of 4-bromothiophenol in 100 ml of ethanol was added to 160 ml of the said sodium hydroxide solution and the first solution was added thereto over 2 minutes at 20° C. The mixture was refluxed for 3 hours and was evaporated to dryness. Water was added to the residue and the mixture was extracted with methylene chloride. The organic phase was washed with aqueous 1N sodium hydroxide solution, then with water, dried and evaporated to dryness. The residue was distilled to obtain 35.5 g of 4-(N,N-dimethylaminoethylthio)-bromobenzene boiling at 110° C. at 0.1 mm Hg.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[N:13]=[C:12]([O:18][CH3:19])[C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)=[C:10]2[Cl:27].[CH3:28][N:29]1[C:33]([C:34]([C:36]2[CH:37]=[N:38][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:41]=2)=[O:35])=[CH:32][N:31]=[CH:30]1>C1COCC1>[Cl:27][C:10]1[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]([C:34]([C:33]3[N:29]([CH3:28])[CH:30]=[N:31][CH:32]=3)([C:36]3[CH:37]=[N:38][C:39]([C:42]([F:44])([F:43])[F:45])=[CH:40][CH:41]=3)[OH:35])[CH:8]=2)[N:13]=[C:12]([O:18][CH3:19])[C:11]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1
Reactant: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Reactant: COc1nc2c(C)cc(Br)cc2c(Cl)c1-c1cccc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2c(C)cc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1-c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.02 h

Procedure:
n-BuLi (1.6 M in hexane, 2.19 mL, 3.50 mmol) was added over approximately 1 min to a solution of 6-bromo-4-chloro-3-(3-fluorophenyl)-2-methoxy-8-methylquinoline (1.40 g, 3.68 mmol, Intermediate 52) in THF (5 mL) under argon at −78° C. After 1 min, a solution of (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (939 mg, 3.68 mmol, Intermediate 15, step c) in 5 mL THF under argon was added via cannula. The resulting mixture was stirred at −78° C. for 10 min, then transferred to an ice water bath and stirred 30 min. The reaction was quenched by addition of saturated aqueous NH4Cl, diluted with water and extracted with EtOAc (3×). The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 45-60% CH3CN in [2% conc. aqueous NH4OH in DCM, aqueous phase removed]) to afford the title compound as a white foam.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:17]=[C:16]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[N:15]=2)=[CH:8][C:7]=1[CH3:36].O.[OH-].[Li+].O>O1CCOCC1>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([C:16]2[CH:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[N:19]=[C:14]([CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:37])=[O:2])=[C:7]([CH3:36])[CH:8]=3)[N:15]=2)=[CH:33][CH:32]=1
Reactant: COC(=O)COc1ccc(OCc2nc(-c3ccc(OC)cc3)cc(-c3ccc(OC)cc3)n2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(-c3ccc(OC)cc3)nc(COc3ccc(OCC(=O)O)c(C)c3)n2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
{4-[4,6-Bis-(4-methoxy-phenyl)-pyrimidin-2-ylmethoxy]-2-methyl-phenoxy}-acetic acid methyl ester 25 (0.14 g, 0.28 mmol) from Step D above is dissolved in dioxane (2 mL). Solid lithium hydroxide monohydrate (80 mg, 2.0 mmol) is added, followed by water (0.2 mL). After stirring at room temperature for 5 hours, the mixture is concentrated to dryness. Purification by reversed-phase HPLC afforded {4-[4,6-Bis-(4-methoxy-phenyl)-pyrimidin-2-ylmethoxy]-2-methyl-phenoxy}-acetic acid B1 as a solid. MS calculated for C28H27N2O6 (M+H+) 487.18. found 487.2.
Reaction SMILES: [C:1](=[C:4]1[NH:8][C:7](=O)[NH:6][C:5]1=[O:10])([CH3:3])[CH3:2].CC(C)=O.N1CC(=O)NC1=[S:17]>N1CCCCC1>[C:1](=[C:4]1[NH:8][C:7](=[S:17])[NH:6][C:5]1=[O:10])([CH3:3])[CH3:2]
Reactant: O=C1CNC(=S)N1
Reactant: CC(C)=C1NC(=O)NC1=O
Solvent: CC(C)=O
Solvent: C1CCNCC1
Product: CC(C)=C1NC(=S)NC1=O

Procedure:
Doyle et al, J. Chem. Soc. 1955, 2265-73 (Chemical Abstracts 1956, 50, 8602g at 8603b) teach the preparation of 5-iso-propylidenehydantoin via the reaction of acetone with 2-thiohydantoin in piperdine to yield 5-iso-propylidene-2-thiohydantoin which is then desulfurized with chloroacetic acid to yield 5-iso-propylidenehydantoin.