Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[OH:2][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Br[CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:10][CH2:11][CH3:12].[I-].[K+]>CN(C)C=O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH:9]([O:2][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCC(Br)c1ccc(Cl)cc1Cl
Reactant: On1cncn1
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: CCCC(On1cncn1)c1ccc(Cl)cc1Cl

Procedure:
1.2 g (10 mmol) of the potassium salt of 1-hydroxy-1,2,4-triazole were dissolved in 100 ml of dimethylformamide and the solution was added at room temperature to a solution of 4.0 g (10 mmol) of 1-bromo-1-(2,4-dichlorophenyl)-butane in 50 ml of dimethylformamide. 0.1 g of potassium iodide was added to the mixture, which was refluxed for 10 minutes. Thereafter, the solvent was removed under reduced pressure, the residue was taken up in ether and the solution was washed three times with water. After the organic phase had been dried with Na2SO4, the solvent was removed under reduced pressure.
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[SH:33])([CH3:26])[CH3:25].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][C:3](=[O:23])[C:2]=1[S:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)c1ccccc1S
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)c1ccccc1SC1=C(O)CC(CCc2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.50 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 1.60 mmol of 2-isopropylbenzenethiol, and 1.60 mmol of piperidine in 30 mL of dichloromethane. The product was triturated with hexane:ether (1:1) to afford a solid. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 66°-67° C.). 1H NMR (DMSO-d6) δ1.16 (t, 6H), 2.21-2.35 (m, 3H), 2.60 (m, 1H), 3.21 (m, 1H), 3.42 (q, 2H), 5.88 (d, 1H), 6.56 (t, 1H), 6.94 (t, 1H), 7.13 (m, 4H), 7.25 (m, 2H), 7.45 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[C:7]=1[N+:13]([O-:15])=[O:14].[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>>[NH2:12][C:8]1[C:7]([N+:13]([O-:15])=[O:14])=[C:6]([O:5][C:4]2[CH:3]=[C:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([O:22][C:21]([F:20])([F:32])[F:33])[CH:24]=3)[CH:18]=[C:17]([Cl:19])[CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: Nc1cc(Cl)cc(Oc2ccnc(N)c2[N+](=O)[O-])c1
Product: Nc1nccc(Oc2cc(Cl)cc(NC(=O)c3cccc(OC(F)(F)F)c3)c2)c1[N+](=O)[O-]
Yield: 74 %

Procedure:
Method H was used with 4-(3-Amino-5-chlorophenoxy)-3-nitropyridin-2-amine and 3-(trifluoromethoxy)benzoyl chloride to afford the title compound as a yellow solid (0.155 g, 74%). 1H NMR δ (DMSO): 6.21 (d, 1H, Hpy,5, J=5.5 Hz), 7.13 (t, 1H, Harom, J=2 Hz), 7.25 (s, 2H, NH2), 7.58 (t, 1H, Harom, J=2 Hz), 7.63 (dt, 1H, Harom, J=1+8 Hz), 7.70 (t, 1H, Harom,5, J=8 Hz), 7.86 (d, 1H, Harom, J=2 Hz), 7.89 (s, 1H, Harom,2′), 8.02 (dt, 1H, Harom, J=1+8 Hz), 8.09 (d, 1H, Hpy,6, J=5.5 Hz), 10.6 (s, 1H, NHamide). 19F NMR 6 (DMSO): −56.77 (s, 3F, CF3). MS m/z 469/71(M++1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=[C:18]([C:20]#[N:21])[N:19]=2)=[O:14])=[C:8]([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)[CH:7]=1)[CH2:4][NH2:5].CS[C:38](SC)=[N:39][S:40]([CH3:43])(=[O:42])=[O:41]>ClCCCl>[C:30]1([C:8]2[CH:7]=[C:6]([CH:3]3[CH2:2][NH:1][C:38](=[N:39][S:40]([CH3:43])(=[O:42])=[O:41])[NH:5][CH2:4]3)[CH:11]=[CH:10][C:9]=2[NH:12][C:13]([C:15]2[N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[CH:17]=[C:18]([C:20]#[N:21])[N:19]=2)=[O:14])[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(CN)CN)cc1C1=CCCCC1
Reactant: CSC(=NS(C)(=O)=O)SC
Solvent: ClCCCl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CNC(=NS(C)(=O)=O)NC2)cc1C1=CCCCC1
Yield: 38.7 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-(2-amino-1-aminomethyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide (as prepared in Example 12, step (d), 250 mg, 0.506 mmol) and N-(bis-methylsulfanyl-methylene)-methanesulfonamide (Australian Journal of Chemistry, 46(6), 873, (1993), 100 mg, 0.506 mmol) in 1,2-dichloroethane (20 mL) was heated at reflux for 4 h. The reaction mixture was concentrated, and the residue was purified on silica (20-100% EtOAc-hexane) to obtain the title compound (117 mg, 39%): Mass spectrum, (ESI, m/z): Calcd. for C28H39N7O4SSi, 598.2 (M+H). found 598.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.[C:27](OC(=O)C)(=[O:29])[CH3:28].CO>N1C=CC=CC=1>[C:27]([O:15][C:10]1[CH:11]=[C:12]2[C:7]3=[C:8]([C:16](=[O:26])[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][N:6]3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]2=3)[CH:9]=1)(=[O:29])[CH3:28]
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)Oc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 2 was suspended in pyridine (5 ml), and to the suspension was added acetic anhydride (0.14 ml), and the mixture was stirred at room temperature for 2 hours. A small amount of methanol was added dropwise to the reaction mixture, and the solvent was evaporated under reduced pressure. The residual crude crystals were washed with methanol and ether in succession to produce the title compound (100 mg; 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([NH:21][C:31]([NH:30][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:32])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CC(N)CC4)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: COc1ccc(Cn2ncc3c4c(cnc32)CC(NC(=O)Nc2ccccc2)CC4)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of 3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-ylamine (0.095 g, 0.308 mmol) in dichloromethane (5 mL) was added phenyl isocyanate (37 μL, 0.34 mmol). The reaction mixture was shaken at room temperature for 1 hour. The solvent was removed under reduced pressure and the crude product purified using flash column chromatography (SiO2, gradient from 50% EtOAc in hexane to 66% EtOAc in hexane) to give the desired product, 1-(3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-yl)-3-phenylurea as a white solid (0.112 g, 84%). Alternative the crude product can be used in the next step without any further purification. M.p. 192-194° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.31 (s, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 7.36 (m, 2H), 7.20 (m, 4H), 6.86 (m, 3H), 6.32 (d, J=7.6 Hz, 1H), 5.54 (s, 2H), 4.05 (m, 1H), 3.70 (s, 3H), 3.17 (m, 1H), 3.08 (m, 3H), 2.81 (m, 1H), 2.11 (m, 1H), 1.89 (m, 1H); LCMS [M+H]: 428.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH3:12][N:13]1[CH2:17][CH2:16][CH:15](O)[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH:15]1[CH2:16][CH2:17][N:13]([CH3:12])[CH2:14]1
Reactant: CN1CCC(O)C1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc([N+](=O)[O-])cc2Cl)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-chloro-4-nitrophenol (2.0 g) in tetrahydrofuran (60 mL) is added 1-methyl-3-pyrrolidinol (2.3 g), triphenyl phosphine (6.0 g), and diethylazo-dicarboxylate (3.6 mL) and the mixture is stirred at room temperature under an atmosphere of argon for 1.5 hours. The solution is then concentrated under reduced pressure, diluted with ethyl acetate, washed successively with 10% aqueous sodium hydroxide, water, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is chromatographed over silica gel (ethyl acetate then 10% methanol in dichloromethane is used as the eluant). Pooled product fractions are then recrystallized from hexanes to provide the desired product as a yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12][N:13]=2)[CH:6]=[CH:7][CH:8]=1.Cl.N1C=CC=CC=1.[OH-].[Na+]>O>[C:14]1([N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(-c2nccn2-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: Oc1cccc(-c2nccn2-c2ccccc2)c1
Temperature: 200 °C

Procedure:
To a 500 mL round bottom flask was added 2-(3-methoxyphenyl)-1-phenyl-1H-imidazole (6.52 g, 26.0 mmol) and pyridine hydrochloride (24.08 g, 208 mmol). The reaction mixture was heated to 200° C. for 3 h under nitrogen. The reaction mixture was cooled to room temperature and the solid was added to water. The aqueous mixture was adjusted to pH 7 with sodium hydroxide solution. A gray solid was filtered off, washed with water, and dried (5.38 g, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[O:9])[CH:7]=1.Br[CH:23]([CH3:29])[C:24]([O:26]CC)=[O:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH:23]([CH3:29])[C:24]([OH:26])=[O:25])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[O:9])[CH:7]=1
Reactant: O=C(c1cnn(-c2ccccc2)c1)c1cc(Br)ccc1O
Reactant: CCOC(=O)C(C)Br
Product: CC(Oc1ccc(Br)cc1C(=O)c1cnn(-c2ccccc2)c1)C(=O)O

Procedure:
Prepared from (5-bromo-2-hydroxyphenyl)-(1-phenyl-1H-pyrazol-4-yl)ketone and ethyl 2-bromopropionate according to GP2 and GP3: LC/MS (an 10p8) Rt 2.51 min, m/z 415 [M+H]+; 1H NMR (CDCl3): δ 1.65 (d, J=6.8 Hz, 3H), 4.93 (q, J=6.8 Hz, 1H), 6.96 (d, J=8.9 Hz, 1H), 7.35-7.43 (m, 1H), 7.46-7.53 (m, 2H), 7.62 (dd, J=8.9, 2.5 Hz, 1H), 7.70-7.76 (m, 3H), 8.17 (s, 1H), 8.52 (s, 1H); 13C NMR (CDCl3): δ18.8, 75.2, 114.8, 116.7, 120.1, 124.4, 128.3, 130.0, 133.3, 136.2, 139.2, 143.3, 155.0, 173.1, 187.8.
Reaction SMILES: C([N:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[C:7]2[CH:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[S:20][C:6]=2[C:5]1=[O:27])C=C.C(O)CC>[Rh](Cl)(Cl)Cl>[Cl:17][C:12]1[CH:11]=[C:10]([CH:8]2[CH2:9][NH:4][C:5](=[O:27])[C:6]3[S:20][C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[CH:18][C:7]2=3)[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: C=CCN1CC(c2ccc(Cl)c(Cl)c2)c2cc(N3CCOCC3)sc2C1=O
Agent: Cl[Rh](Cl)Cl
Solvent: CCCO
Product: O=C1NCC(c2ccc(Cl)c(Cl)c2)c2cc(N3CCOCC3)sc21
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A solution of 6-allyl-4-(3,4-dichlorophenyl)-2-(morpholin-4-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (0.26 g, 0.60 mmol) in 1-propanol (10.0 mL, 134 mmol) was degassed for 10 minutes. Rhodium(III)chloride, (87.0 mg g, 0.41 mmol) was added and the reaction mixture was heated to 120° C. After 18 hours, rhodium(III)chloride (59.6 mg g) was added and the mixture was stirred for additional 18 hours. The reaction was cooled to ambient temperature and quenched by the addition of a solution of saturated aqueous solution of sodium bicarbonate (10.0 mL) and extracted with EtOAc (20.0 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (12 g cartridge, gradient hexanes to 100% EtOAc) to afford the pure product (114 mg g, 49%) as a white solid. The purified racemic mixture was separated into enantiomers on a Chiralpak IA 4.6×250 column using 70/15/15/01% Hexane/IPA/EtOH/DEA, 1.0 mL/minute for 40 minutes. Peak one (13.8 mg, 43.7%) was collected with retention time of 14.9 min. and peak two (14.8 mg, 46.9%) was collected with retention time of 21.5 min., both as a white solid. Absolute configuration of the obtained enantiomers is unknown. LCMS (AA): ES+ 383, 385, 387. 1H NMR (DMSO-d6, 400 MHz): δ 7.59 (d, J=8.4 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 7.35 (br s, 1H), 5.88 (s, 1H), 4.19 (t, J=5.6 Hz, 1H), 3.69-3.63 (m, 5H), 3.37 (ddd, J=12.4, 6.0, 3.2 Hz, 1H), 3.13-3.11 (m, 4H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]2[N:20]([CH3:21])[C:19](=[O:22])[CH2:18][N:17]=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:15]=2[CH:30]=1)=[O:9])(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:16]1[C:15]2[CH:30]=[C:11]([NH:10][C:8]([NH:7][CH2:6][CH2:5][OH:4])=[O:9])[CH:12]=[CH:13][C:14]=2[N:20]([CH3:21])[C:19](=[O:22])[CH2:18][N:17]=1
Reactant: CC(=O)OCCNC(=O)Nc1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2C
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)NCCO)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
300 mg (0.73 mM) of 2-[3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]ureido]ethyl acetate dissolved in 20 ml of absolute methanol are treated with 500 mg of sodium methylate and stirred at room temperature for 1 hour. The mixture is then buffered with a small amount of acetic acid and concentrated. The residue is treated with methylene chloride/10% sodium bicarbonate solution, the aqueous solution is extracted several times with methylene chloride and the organic solution is dried over sodium sulphate, filtered and concentrated. After crystallisation from acetone, there is obtained 1-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea which according to the IR spectrum is identical with a sample of this substance prepared in another manner (see Example 7).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].[CH3:13][NH:14][CH3:15]>C(O)C>[CH3:13][N:14]([CH3:15])[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6]
Reactant: CNC
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Solvent: CCO
Product: CN(C)c1cc(C#N)ccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
The mixture of 16.7 g (100 mmol) of 3-fluoro-4-nitrobenzonitrile and 100 mL of the solution of dimethylamine in ethanol (5 M) was refluxed overnight. The resulting dark red solution was then poured in to 100 mL of ice-water. The precipitate was collected by filtration and washed by H2O (50 mL×2) and ethanol (50 mL×2) to give 16.9 g of a organe needle crystal as the desired product. MS ESI (m/z) 192 (M+1)+.
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[N:5]1>[Pd].C(O)C>[NH2:9][C:6]1[CH:7]=[CH:8][N:4]([CH2:3][C:2]([CH3:12])([OH:13])[CH3:1])[N:5]=1
Reactant: CC(C)(O)Cn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(O)Cn1ccc(N)n1
Reaction time: 1 h
Yield: 93.1 %

Procedure:
In a Parr shaker bottle was placed 2-methyl-1-(3-nitro-pyrazol-1-yl)-propan-2-ol (100 mg, 0.54 mmol), 10% palladium on activated carbon (10 mg) and ethanol (5 mL). The bottle was then placed on the Parr shaker under hydrogen (50 psi) for 1 h. The reaction was then filtered through a pad of diatomaceous earth, washed with ethanol, and concentrated in vacuo to afford 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (78 mg, 94%), which was taken on to the next step without characterization.
Reaction SMILES: C1COCC1.C([Si](C)(C)[O:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([CH2:34][C:35]5[CH:36]=[C:37]6[C:42](=[CH:43][C:44]=5[F:45])[N:41]=[CH:40][CH:39]=[CH:38]6)=[CH:32][N:33]=4)[N:30]=3)[CH:22]=[N:21]2)[CH2:16][CH2:15]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOC(C)=O>[F:45][C:44]1[CH:43]=[C:42]2[C:37]([CH:38]=[CH:39][CH:40]=[N:41]2)=[CH:36][C:35]=1[CH2:34][C:31]1[N:29]2[N:30]=[C:25]([C:23]3[CH:22]=[N:21][N:20]([CH:17]4[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][OH:11])[CH2:15][CH2:16]4)[CH:24]=3)[CH:26]=[CH:27][C:28]2=[N:33][CH:32]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCN1CCC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A flask was charged with THF (5 mL), 6-[6-(1-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-piperidin-4-yl}-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-7-fluoro-quinoline (Stage 147.1, 96 mg, 0.164 mmol) and tetrabutylammonium fluoride (819 μL of a 1 M solution, 0.819 mmol). The mixture was stirred at rt for 2 h. The RM was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by MPLC, then taken up in NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated to afford the title compound (tR 2.99 min (conditions 3), MH+=472.1, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.50 (s, 1H); 8.34 (m, 1H); 8.08 (m, 2H); 8.06 (m, 1H); 7.76 (d, 1H); 7.60 (s, 1H); 7.53 (d, 1H); 7.47 (m, 1H); 4.55 (s, 2H); 4.41 (t, 1H); 3.50 (m, 2H); 2.97 (m, 2H); 2.42 (t, 2H); 2.13 (m, 2H); 1.97 (m, 4H)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[CH2:13]([NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH2:13]([N:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C1CCc2cccc(Cl)c2C1
Reactant: CCCCNCCCC
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)C1CCc2cccc(Cl)c2C1
Yield: 28.7 %

Procedure:
8-Chloro-2-tetralone (3 gm, 16.6 mMol) in toluene (25 mL) was reacted with dibutylamine (5.6 mL, 33.2 mMol) and sodium borohydride (2.0 gm) as described in Example 2 to give the title compound as a colorless oil (1.4 gm, 29%). The tosylate salt was formed and recrystallization (ethyl acetate) gave a colorless, crystalline solid (m.p.=73°-74° C.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7](=O)[CH3:8].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH:7]([NH:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)[CH3:8]
Reactant: CC(=O)C1COCCO1
Reactant: COc1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(CNC(C)C2COCCO2)cc1
Reaction time: 3 h
Yield: 70.8 %

Procedure:
To a solution of 1-(1,4-dioxan-2-yl)ethanone (12 g, 92.2 mmol) in 1,2-dichloroethane (100 mL) was added (4-methoxyphenyl)methanamine (25 g, 184.4 mmol) at room temperature. The mixture was allowed to stir for 3 hours, and then sodium triacetoxyborohydride (39 g, 184.4 mmol) was added. The resulting mixture was allowed to stir for 48 hours at room temperature. The reaction mixture was quenched by adding water, extracted with dichloromethane (100 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel (elute: dichloromethane/methanol 100:1→50:1→20:1) to give 1-(1,4-dioxan-2-yl)-N-(4-methoxybenzyl)ethanamine (16.4 g, 71%) as a yellow solid. LCMS (M+H+) m/z: calcd. 251.15. found 251.9. To a solution of 1-(1,4-dioxan-2-yl)-N-(4-methoxybenzyl)ethanamine (5 g, 19.9 mmol) in anhydrous methanol (100 mL) was added palladium 10% on carbon (240 mg, 2 mmol), then purged with hydrogen (30 psi), the mixture was allowed to stir overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated to afford the title compound (2.5 g, 96%) as a brown solid.
Reaction SMILES: [S-2].[Na+].[Na+].C[O:5][C:6]1[CH:23]=[C:22]2[C:9]([C@@:10]3([CH3:27])[C@H:19]([CH2:20][O:21]2)[C@:18]2([CH3:24])[C@H:13]([C:14]([CH3:26])([CH3:25])[CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11]3)=[C:8]([CH3:28])[CH:7]=1>CN1C(=O)CCC1>[CH3:27][C@@:10]12[CH2:11][CH2:12][C@@H:13]3[C@:18]([CH3:24])([CH2:17][CH2:16][CH2:15][C:14]3([CH3:25])[CH3:26])[C@H:19]1[CH2:20][O:21][C:22]1[C:9]2=[C:8]([CH3:28])[CH:7]=[C:6]([OH:5])[CH:23]=1
Reactant: COc1cc(C)c2c(c1)OC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Agent: [Na+]
Agent: [S-2]
Solvent: CN1CCCC1=O
Product: Cc1cc(O)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CO2
Temperature: 25 °C
Yield: 29 %

Procedure:
Sodium sulfide (0.14 g, 1.17 mmol) was added to a solution of (1R,10R,11S,16S)-5-methoxy-1,3,11,15,15-pentamethyl-8-oxatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 5) (0.08 g, 0.2 mmol) in anhydrous NMP (1.6 mL) in a microwave vessel. The reaction vessel was sealed and placed in a CEM-Discovery reactor and irradiated at 180° C. for 20 min. The reaction mixture was allowed to cool to room temperature and then quenched with 2 M HCl and ethyl acetate. The organic layer was separated, washed with water and concentrated to dryness. The crude product was purified by flash chromatography (Hexanes/EtOAc, 9:1) to yield (1R,10R,11S,16S)-1,3,11,15,15-pentamethyl-8-oxatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-5-ol (Compound No. 6) (0.022 g, 29% yield) as a white solid. 1H NMR (CDCl3): δ 6.08 (m, 2H), 4.43 (s, 1H), 4.30 (m, 1H), 4.08 (m, 1H), 2.80 (m, 1H), 2.40 (s, 3H), 1.40-1.78 (m, 8H), 1.36 (s, 3H), 0.98-1.28 (m, 3H), 0.92 (s, 3H), 0.88 (s, 3H), 0.84 (s, 3H). MS m/z 329 (C22H32O2+H+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>CN(C=O)C>[O:6]=[C:2]1[NH:3][CH2:4][CH2:5][N:1]1[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: O=C1NCCN1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCNC1=O
Reaction time: 1 h
Yield: 26.1 %

Procedure:
To a solution of imidazolidin-2-one (0.2 g; 2.3 mmol) in anhydrous DMF (5 ml) 60% NaH in mineral oil (0.18 g; 4.6 mmol) was added at room temperature, under N2. After stirring for 1 h, tert-butyl 2-bromoacetate (0.35 ml; 2.3 mmol) was added. The resulting mixture was stirred for additional 2 h and solvents were removed in vacuo. The residue was diluted to 15 ml with EtOAc, washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, EtOAc) to give the title compound (0.12 g; 26%) as a colourless solid. 1H-NMR (CDCl3) 4.61 (broad s, 1H); 3.83 (s, 2H); 3.58-3.41 (m, 4H); 1.44 (s, 9H).