Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([Cl:26])[CH:17]=4)[O:13][N:12]=3)[CH:9]=2)[NH:4][CH:3]=1.Br[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31].Cl.[OH-].[Na+:37]>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([Cl:26])[CH:17]=4)[O:13][N:12]=3)[CH:9]=2)[N:4]([CH2:28][CH2:29][C:30]([O-:32])=[O:31])[CH:3]=1.[Na+:37]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]cc(Cl)c4c3)no2)cc1Cl
Reactant: CCOC(=O)CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)c(Cl)cn4CCC(=O)[O-])no2)cc1Cl
Temperature: 120 °C

Procedure:
D7 (200 mg) and Cs2O3 (336 mg) were placed in a microwave vial, treated with DMF (2.8 ml) and ethyl 3-bromopropionate (99 ul) and sonicated for 10 minutes. The mixture was then heated to 120° C. in a microwave reactor for 25 mins. The reaction mixture was then evaporated, re-dissolved in MeOH (10 ml) and treated with 2 M aq. NaOH (10 ml). This mixture was sonicated briefly and then heated to 50° C. overnight. The reaction mixture was then evaporated, diluted with H2O (70 ml) and extracted with EtOAc, adding NaCl and acetone to improve the extraction. The organic extracts were evaporated to give the crude product which was acidified with HCl to give the free-acid. This was insufficiently soluble for purification by chromatography and so was triturated with MeOH, treated with 2M aq. NaOH (1.5 eq.), evaporated, dissolved in EtOAc, filtered and evaporated to give the title compound (56 mg) as a brown solid. δH (methanol-d4, 400 MHz): 1.42 (6H, d), 2.66 (2H, t), 4.47 (2H, t), 4.82 (1H, m), 7.29 (1H, d), 7.44 (1H, s), 7.65 (1H, d), 7.98 (1H, d), 8.12 (1H, d), 8.20 (1H, s), 8.30 (1H, s). MS (ES): C22H1935Cl2N3O4 requires 459; found 460 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.[C:17]([O:25]C)(=[O:24])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]>C(O)(C)(C)C>[C:20]([C:19](=[CH:12][C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([O:8][CH3:7])[CH:10]=1)[CH2:18][C:17]([OH:25])=[O:24])([O:22][CH3:23])=[O:21]
Reactant: COc1cccc(C=O)c1
Reactant: COC(=O)CCC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C(=Cc1cccc(OC)c1)CC(=O)O

Procedure:
To a refluxing suspension of 15.71 g (140 mmol, 1.4 eq) of potassium t-butoxide in 50 ml of t-butylalcohol is dropped in a mixture of 12.17 (100 mmol) of 3-methoxybenzaldehyde and 15.70 ml (120 mmol, 1.2 eq) of dimethyl succinate dissolved in 20 ml of t-butylalcohol. The mixture is refluxed for 3 hours, concentrated in vacuo, acidified to pH ~1 using 1N HCl, and extracted with ethylacetate. The organics are dried (MgSO4) and concentrated in vacuo to give 3-carbomethoxy-4-(3-methoxyphenyl)-3-butenoic acid in the form of a yellow oil which is used directly in the next step.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])(OCC)OCC.C(O[C@@H:15]1[C@H:21]2[C@H:22]3[C@H:31]([CH2:32][CH2:33][C@:18]2([CH2:19][CH3:20])[C:17](=[O:35])[CH2:16]1)[C@@H:30]1[C:25](=[CH:26]C(=O)[CH2:28][CH2:29]1)[CH2:24][CH2:23]3)(=O)C.C1(N)CCCCC1.O>C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([O:8][C:1]1[CH2:28][CH2:29][C@H:30]2[C:25](=[CH:24][CH2:23][C@@H:22]3[C@@H:31]2[CH2:32][CH2:33][C@@:18]2([CH2:19][CH3:20])[C@H:21]3[CH:15]=[CH:16][C:17]2=[O:35])[CH:26]=1)[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: NC1CCCCC1
Solvent: CCO
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)C=C[C@@H]34)[C@H]2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
Triethyl orthoformate (3 ml, 18 mmol) and p-Toluenesulfonic acid (30 mg, 0.16 mmol) were added to a suspension of 15α-acetoxy-18-methyl-estr-4-en-3,17-dione (3 g, 8.72 mmol) in ethanol (20 ml). The mixture was stirred at room temperature for 1 h. Cyclohexylamine (1 ml, 8.75 mmol) was added and the mixture was heated at 30° C. for 2 h, cooled to 10° C. and water (20 ml) was then added. The precipitate was filtered, washed with water and dried under vacuum, to afford 3-ethoxy-18-methyl-estra-3,5,15-trien-17-one (2.0 g yield: 80%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)[CH3:2].[CH2:9]1[CH2:16][O:15][S:12](=[O:14])(=[O:13])[CH2:11][CH2:10]1>>[CH2:1]([N+:3]1([CH2:16][CH2:9][CH2:10][CH2:11][S:12]([O-:15])(=[O:14])=[O:13])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCOCC1
Reactant: O=S1(=O)CCCCO1
Product: CC[N+]1(CCCCS(=O)(=O)[O-])CCOCC1

Procedure:
1.15 grams of N-ethylmorpholine was alkylated with 1,4-butanesultone in similar fashion to the previous example to give 1.09 grams of a white solid. The structure was confirmed by positive mode electrospray mass spectroscopy (M+H)=252.6 and (M+Na) 274.2 m/z and 1H NMR.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14]CC2C=CC=CC=2)=[C:10](I)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31]1([C:37]#[C:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]2[C:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:38]([Si:39]([CH3:42])([CH3:40])[CH3:41])[O:23][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(I)c(OCc2ccccc2)ccn1Cc1ccccc1
Reactant: C[Si](C)(C)C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)c1oc2c(c1-c1ccccc1)c(=O)ccn2Cc1ccccc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A resealable tube was charged with 1-benzyl-4-benzyloxy-3-iodo-2-pyridone 3 (5.000 g, 11.98 mmol), acetonitrile (100 mL), and triethylamine (6.06 g, 8.35 mL, 59.9 mmol). Dichlorobis(triphenylphosphine)palladium (II) (0.841 g, 1.20 mmol) and 1-phenyl-2-(trimethylsilyl)acetylene were added and argon was bubbled through the solution. The tube was sealed and the mixture stirred at 100° C. for 4 h. The reaction mixture was concentrated to afford 7-benzyl-3-phenyl-2-(trimethylsilyl)furo[2,3-b]pyridin-4(7H)-one 4d as a brown oil. MS (MH+) 374.2; Calculated 373 for C23H23NO2Si.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:11])[N:5]=[CH:4][N:3]=1.N[CH2:13][C:14]1C=C(C=CC=1)CN(CC1NC2C=CC=CC=2N=1)C1C2N=CC=CC=2CCC1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:13]([O:9][C:8]([C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[N:5][C:6]=1[CH3:11])=[O:10])[CH3:14]
Reactant: NCc1cccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)c1
Reactant: Cc1ncnc(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1c(C)ncnc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure F: A solution of 4,6-dimethyl-pyrimidine-5-carboxylic acid from above (prepared as described in patent application PCT/US00/11632) (42 mg, 0.28 mmol), (3-aminomethyl-benzyl)-(1 H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (100 mg, 0.25 mmol), HOBT (38 mg, 0.28 mmol) and 4-methylmorpholine (40 μL, 0.38 mmol) in DMF (0.8 mL) was flushed with N2. EDCI (54 mg, 0.28 mmol) was added and the mixture was stirred at room temperature overnight. Purification of the colorless syrup (150 mg) by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:2:1) followed by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 100:2:1) afforded AMD11084 (80 mg, 60%) as a white foam. 1H NMR (CDCl3) δ 1.64-1.77 (m, 1H), 1.91-2.08 (m, 2H), 2.18-2.34 (m, 1H), 2.37 (s, 6H), 2.69-2.91 (m, 2H), 3.73 (s, 2H), 3.80 (d, 1H, J=16.5 Hz), 400 (d, 1H, J=16.5 Hz), 4.07-4.13 (m, 1H), 4.69 (d, 2H, J=5.7 Hz), 6.53 (t, 1H, J=5.7 Hz), 6.96-7.10 (m, 3H), 7.16-7.22 (m, 2H), 7.29-7.31 (m, 2H), 7.40-7.45 (m, 3H), 8.64 (d, 1H, J=3.6 Hz), 8.81 (s, 1H); 13C NMR (CDCl3) δ 21.71, 22.28, 24.38, 29.55, 44.29, 49.22, 55.11, 61.90, 111.12, 118.82, 121.68, 122.78, 127.32, 128.67, 129.09, 129.24, 130.48, 135.22, 137.66, 137.83, 140.30, 147.22, 156.42, 157.60, 157.91, 163.43, 166.96. ES-MS m/z 532.4 (M+H). Anal. Calcd. for C32 H33N7O•0.4CH2Cl2: C, 68.80; H, 6.02; N, 17.33. Found: C, 68.56; H, 6.09; N, 17.34.
Reaction SMILES: [Cl:1][C:2]1[C:7]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:17].[C:18](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.Cl>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]1
Reactant: CC1(C)OB(c2cccc(O)c2Cl)OC1(C)C
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1cccc(B2OC(C)(C)C(C)(C)O2)c1Cl
Reaction time: 0.17 h
Yield: 85.3 %

Procedure:
To a stirred solution of 2-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (830 g, 3.26 mol) in dry DMF (4.15 L) was added potassium carbonate (1126.4 g, 8.15 mol) under an inert atmosphere. Me2SO4 (402 mL, 4.24 mol) was added slowly to control the resulting exotherm (addition over 30 minutes gave a temperature rise from 28° C. to 55° C.) and after complete addition the reaction was stirred for 10 minutes. The reaction mixture was added to stirring HCl (5.98 L, 2 N, aq.) very slowly to control effervescence and the resulting precipitate stirred for 2 hours. The solids were filtered and washed with water (1 L) and dried in a vacuum oven over drying agent for 4 days to give 2-(2-chloro-3-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane 7a as a white powder (746.7 g, 2.78 mol, 85%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)[CH:8]([CH3:10])[CH3:9]>C1COCC1>[CH2:7]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][OH:16])=[CH:18][CH:19]=1)[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of lithium aluminum hydride (30 mL, 1M in THF, 30 mmol) was added dropwise to a solution of 4-isobutylbenzoic acid (5.34 g, 30 mmol) in THF (50 mL) at 0° C. The ice bath was removed and the reaction was stirred at room temperature for 1 h. The reaction was carefully poured onto a mixture of ice and aqueous HCl (10 mL, 6N). The product was extracted into EtOAc and the organic solution was dried (MgSO4), filtered, and concentrated to obtain (4-isobutyl-phenyl)-methanol which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ7.26 (d, 2H), 7.13 (d, 2H), 4.65 (s, 2H), 2.46 (d, 2H), 1.85 (m, 1H), 0.89 (d, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=O)(C)(C)C.[CH:36]1([CH2:39][NH2:40])[CH2:38][CH2:37]1.[BH4-].[Na+]>C(Cl)Cl.CO>[CH:36]1([CH2:39][NH:40][CH2:34][C@@H:10]2[CH2:9][NH:8][CH2:12][C@H:11]2[CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH2:38][CH2:37]1
Reactant: NCC1CC1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CNCC2CC2)C(C)C)ccc1OC

Procedure:
from (3S*,4R*)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.75 g, 1.52 mmol), cyclopropanemethylamine (0.652 mL, 7.61 mmol) and NaBH4 (0.115 g, 3.04 mmol) and purification by flash chromatography on silica gel (CH2Cl2/MeOH 96:4, then CH2Cl2/MeOH (10% NH3 conc.) gradient from 9:1 to 8:2) to give the title compound as colorless oil. MS: 548.4 [M+H]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 4.66 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:23])[C:20]=1[O:21][CH3:22])[C:15](O)=[O:16].P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]([N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:10]=[CH:9][N:8]=[CH:7][C:3]2=3)=[O:16])[CH:18]=[C:19]([Cl:23])[C:20]=1[O:21][CH3:22]
Reactant: COc1c(Cl)cc(C(=O)O)cc1Cl
Reactant: c1cc2c(cn1)NCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1c(Cl)cc(C(=O)N2CCOc3ccncc32)cc1Cl
Reaction time: 12 h
Yield: 54.4 %

Procedure:
To a mixture of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (80 mg, 0.58 mmol) and 3,5-dichloro-4-methoxy-benzoic acid (141 mg, 0.64 mmol), phosphorus oxychloride (4 ml) was added and then stirred at 100□ for 12 hours. The reaction mixture was cooled to 0□ and adjusted to pH of 8-9 by using saturated solution of sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of n-hexane:ethyl acetate=4:1. The fractions containing the product were collected and evaporated to obtain white solid (107 mg, 54%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[C:12]([CH3:23])=[N:11][C:10]=2[OH:24])[CH:5]=[N:6][CH:7]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].O>CCO.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(COC)OC>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[C:12]([CH3:23])=[N:11][C:10]([OH:24])=[C:9]2[CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH:3]=1
Reactant: COc1cc2c(C)nc(O)c(Cc3cncc(Br)c3)c2cc1OC
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2cncc(Cc3c(O)nc(C)c4cc(OC)c(OC)cc34)c2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-((5-bromopyridin-3-yl)methyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 34166 (53 mg, 136 μmol) in absolute EtOH (0.9 mL) in a 20 mL microwave vial equipped with a magnetic stirrer were added 4-methoxyphenylboronic acid (41 mg, 270 μmol), Pd(PPh3)2Cl2 (10 mg, 14 μmol), a 2 N aq. Na2CO3 solution (0.30 mL, 0.60 mmol), H2O (2.7 mL) and dimethoxyethane (3.5 mL) and the resulting mixture was stirred at 140° C. for 25 min. After cooling to RT, the mixture was diluted with EtOAc (30 mL) and this solution was filtered through a celite plug, then washed with brine (10 mL). The organic phase was isolated and the celite plug was then further washed with CH2Cl2 (50 mL) and the organic layer was washed with brine (20 mL). The organic layers were then combined, dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) provided 32 mg of 6,7-dimethoxy-4-((5-(4-methoxyphenyl)pyridin-3-yl)methyl)-1-methylisoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.5 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to give 6,7-dimethoxy-4-((5-(4-methoxyphenyl)pyridin-3-yl)methyl)-1-methylisoquinolin-3-ol dihydrochloride 16 as a pale brown solid (37 mg, 56% yield).
Reaction SMILES: [BH3-]C#N.[Na+].[C:5]([O:8][CH2:9][CH:10]([O:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2)[CH2:11][O:12][C:13](=[O:15])[CH3:14])(=[O:7])[CH3:6]>C(O)(=O)C>[C:13]([O:12][CH2:11][CH:10]([O:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][CH2:20][NH:21]2)[CH2:9][O:8][C:5](=[O:7])[CH3:6])(=[O:15])[CH3:14]
Reactant: CC(=O)OCC(COC(C)=O)Oc1cccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCC(COC(C)=O)Oc1cccc2c1CCN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
NaBH3CN (0.94 g, 15 mmol) was added portionwise to a solution of 24 (1.46 g, 5 mmol) in acetic acid (40 mL) and the mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue was diluted with water, neutralised with NaHCO3 and extracted with EtOAc. The combined organic phases were washed with brine, dried and evaporated to give crude 4-(1,3-diacetoxypropan-2-yloxy)indoline (1.47 g, 100%) as a viscous oil: 1H NMR (90 MHz) δ 6.95 (t, J=7.2 Hz 1H), 6.24-6.68 (m, 2H), 4.62 (quintet, J=5.4 Hz, 1H), 4.20-4.46 (m, 4H), 3.64 (s, 1H), 4.52 (t, J=7.2 Hz, 2H), 2.94 (t, J=7.2 Hz, 2H), 2.06 (s, 6H). Without further purification, this material was dissolved in dry MeCN (40 mL) and treated with 4-azidobutyric acid (0.78 g, 6 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.34 g, 7 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was taken up in EtOAc (50 mL) washed with dilute aq. HCl, saturated aq. NaHCO3 and brine, dried and evaporated. Flash chromatography [EtOAc-hexanes (2:3)] gave 25 (1.33 g, 64%) as white crystals, mp 61-63° C. (Et2O-hexanes); 1H NMR (500 MHz) δ 7.87 (d, J=8.2 Hz, 1H), 7.16 (t, J=8.2 Hz, 1H), 6.68 (d, J=8.2 Hz, 1H), 4.70 (quintet, J=5.3 Hz, 1H), 4.34 (dd, J=11.9, 5.7 Hz, 2H), 4.29 (dd, J=11.9, 4.8 Hz, 2H), 4.07 (t, J=8.5 Hz, 2H), 3.45 (t, J=6.4 Hz, 2H), 3.12 (t, J=8.4 Hz, 2H), 2.51 (t, J=6.9 Hz, 2H), 2.06 (s, 6H), 2.03 (quintet, J=6.6 Hz, 2H). Anal. Calcd for C19H24N4O6: C, 56.43; H, 5.98; N, 13.85. Found: C, 56.23; H, 5.98; N, 13.61.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[C@:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.[BH4-].[Na+].[Cl-].[Na+].[CH2:27]([Si](C)(C)C)[CH:28]=[CH2:29]>O1CCCC1.C(O)C.ClCCl.[I-].[Zn+2].[I-].O.CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@@H:7]([CH2:29][CH:28]=[CH2:27])[C@:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: C=CC[Si](C)(C)C
Reactant: COc1ccc([C@@]2(C)CSc3cc(OC)ccc3C2=O)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [I-]
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CC[C@@H]1c2ccc(OC)cc2SC[C@]1(C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.3 %

Procedure:
The (3R)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-one prepared in Example 1 (11.4 g, 36.26 mmol) was dissolved in tetrahydrofuran (40 ml) and ethanol (20 ml). To this solution, sodium borohydride (2.74 g, 72.51 mmol) was added at −78° C., and the resulting mixture was stirred for 15 hours at room temperature. After the reaction was completed, dichloromethane, methanol and saturated aqueous sodium chloride were added to the reaction mixture, which was then extracted under heating conditions. The organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent, allyltrimethylsilane (10.74 ml, 67.6 mmol) and zinc iodide (12.9 g, 40.57 mmol) were added to a solution of the residue in dichloromethane (300 ml) followed by stirring for 15 hours at room temperature. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride and dried over anhydrous magnesium sulfate, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/90) to give (3S,4S)-7-methoxy-3-(4-methoxyphenyl)-3-methyl-4-(2-propenyl)thiochroman (7.2 g, Yield 58%) as an oil.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[OH:18])[CH2:6][CH2:5]1)(=O)C.[ClH:20]>>[ClH:20].[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([CH:7]2[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]2)=[O:19])=[C:12]([OH:18])[CH:13]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2O)CC1
Agent: Cl
Product: O=C(c1ccc(F)cc1O)C1CCNCC1
Yield: 87 %

Procedure:
A mixture of 40 parts of 1-acetyl-4-(4-fluoro-2-hydroxybenzoyl)piperidine and 150 parts of a hydrochloric acid solution 6N is stirred and refluxed for 3 hours. The reaction mixture is cooled. The precipitated product is filtered off, washed with 2-propanone and dried, yielding 29 parts (87%) of (4-fluoro-2-hydroxyphenyl)(4-piperidinyl)methanone hydrochloride; mp. +300° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=O>Cl>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][N:10]=[C:14]([CH3:16])[C:13]([OH:18])=[O:17])=[CH:7][CH:8]=1
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)C(=O)O
Agent: Cl
Product: CC(=NNc1ccc(C(F)(F)F)cc1)C(=O)O
Yield: 89.1 %

Procedure:
4-Trifluoromethylphenyl hydrazine (8.40 g, 47.7 mmol) was suspended in 1 N hydrochloric acid (130 ml) and fully stirred with a mechanical stirrer to obtain a suspension. A aqueous solution (50 ml) of pyruvic acid (4.20 g, 47.7 mmol) was added to the suspension and vigorously stirred to a mixture. 6 hours later, the mixture was extracted with ethyl acetate and washed with a saturated brine. The washed mixture was dried on sodium sulfate and then filtered. The residue obtained by concentrating the resulting filtrate was washed with a mixed solvent of hexane and chloroform (1:1) to obtain 2-(4-trifluoromethylphenyl hydrazono) propionic acid (10.47 g, 42.52 mmol, 89%). mp 190–191° C.; 1H NMR (400 MHz, CDCl3) δ 2.19 (3H, s), 7.23 (2H, d), 7.60 (2H, d), 7.87 (1H, brs).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:10]1[CH:15]=[C:14]([Cl:16])[N:13]=[C:12]([NH2:17])[N:11]=1.Cl>O1CCOCC1>[Cl:16][C:14]1[N:13]=[C:12]([NH2:17])[N:11]=[C:10]([N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:15]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CNc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CN(c1ccccc1)c1cc(Cl)nc(N)n1

Procedure:
A 20-mL screw-cap vial was charged with N-methylaniline (0.653 g, 6.1 mmol), 4,6-dichloro-2-pyrimidinamine (1 g, 6.1 mmol), 1,4-dioxane (5 mL), and HCl (0.152 mL, 0.61 mmol, 4M in 1,4-dioxane). The vial was capped and stirred at reflux overnight. At this time, LCMS analysis indicated good conversion to the desired product, so the reaction mixture was poured into 1:1 NaHCO3 (sat) and water (20 mL) and extracted with EtOAc (3×50 mL). The combined organics were dried (Na2SO4) and concentrated. The solid residue was triturated with CH2Cl2, to yield the title compound (644 mg) as an off-white solid. LC-MS (ES) m/z=235 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[C:19]1([CH2:25][C:26]([NH2:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:25]([C:26]1[O:27][CH:15]=[C:14]([C:8]2[CH:9]=[C:10]([Br:13])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]([OH:3])=[O:18])[N:28]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Reactant: NC(=O)Cc1ccccc1
Product: O=C(O)COc1ccc(Br)cc1-c1coc(Cc2ccccc2)n1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and 2-phenylacetamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.47 min, m/z 388 [M+H]+; 1H NMR (CDCl3): δ 4.22 (s, 2H), 4.84 (s, 2H), 7.04 (d, 1H), 7.25 (m, 5H), 7.43 (d, 1H), 8.06 (s, 1H), 8.69 (s, 1H), 13 (br s, 1H).