Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:30]C(=O)[O-])[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:20]4[CH:27]([CH3:28])[S:26](=[O:29])[CH2:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1>C(Cl)Cl.CO>[NH2:30][C@H:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)[C:11]([N:13]1[CH2:14][CH2:15][N:16]([C:19]2[C:20]3[CH:27]([CH3:28])[S:26](=[O:29])[CH2:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:17][CH2:18]1)=[O:12]
Reactant: CC1c2c(ncnc2N2CCN(C(=O)C(Cc3ccc(Cl)cc3)NC(=O)[O-])CC2)CS1=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC1c2c(ncnc2N2CCN(C(=O)[C@H](N)Cc3ccc(Cl)cc3)CC2)CS1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
HCl (4M, 1 mL) was added to a solution of 3-(4-chlorophenyl)-1-(4-(5-methyl-6-oxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (0.050 g, 0.091 mmol) in DCM (4 mL) and MeOH (1 mL). The mixture was stirred at room temperature for 6 hours. The solvent was removed to afford (2R)-2-amino-3-(4-chlorophenyl)-1-(4-(5-methyl-6-oxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one as the di-hydrochloride salt (0.40 g). LCMS: 450.1 [M+H+] (APCI+).
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1)[C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[BH4-].[Na+].O>C(O)C.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][N:2]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:20]=1)[C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(CN(C)c2nc(-c3ccccc3)cs2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCc1ccc(CN(C)c2nc(-c3ccccc3)cs2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
To a solution of ethyl (E)-3-[4-[[methyl(4-phenyl-2-thiazolyl)amino]methyl]phenyl]propenoate (0.60 g, 1.6 mmol) and nickel chloride hexahydrate (0.41 g, 3.2 mmol) in ethanol (25 mL) was added sodium borohydride (0.30 g, 8.0 mmol), and the mixture was stirred at room temperature for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=18:1) to give the title compound (0.39 g, yield 64%). oil.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)=[CH:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:24]=1)=[O:5].[C:30](OC(=O)C)(=[O:32])[CH3:31].N1C=CC=CC=1.C(Cl)(=O)C>C(N(CC)CC)C>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:30](=[O:32])[CH3:31])=[CH:19][CH:18]=3)=[CH:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:24]=1)=[O:5]
Reactant: Nc1ccc(C2=CCCCc3cc(NC(=O)c4c(F)cccc4F)ccc32)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C2=CCCCc3cc(NC(=O)c4c(F)cccc4F)ccc32)cc1

Procedure:
Compound 9 was prepared by reacting Compound 8 with acetic anhydride in the presence of pyridine or by reacting Compound 8 with acetyl chloride in the presence of triethyl amine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)(O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(O)C1CCCC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2cc(Cl)ccc2C1C1CCCC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A suspension of rac-6-chloro-3-cyclopentyl-3-hydroxy-1,3-dihydro-indol-2-one (1.0 g, 4 mmol) (from Example 3a, supra) in a mixture of triethylsilane (2 mL, 12.5 mmol) (Aldrich) and trifluoroacetic acid (5 mL, 65 mmol) was heated in a 100° C. bath for 48 hours. After cooling to room temperature, mixture was diluted with ethyl acetate (50 mL). Solid potassium carbonate was added and mixture stirred at room temperature for 1 hour. Mixture was filtered and concentrated. Residue was redissolved in ethyl acetate and adsorbed onto silica gel (10 g). Solvent was evaporated off. Material was purified by flash chromatography (Biotage 40 M, 5% then 10% ethyl acetate in dichloromethane as solvent). Main product fractions were collected and concentrated to give rac-6-chloro-3-cyclopentyl-1,3-dihydro-indol-2-one as a dark purple solid. (Yield 0.24 g, 25.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[O:8])[O:4][N:3]=1.[F-].[Cs+].C[Si](C)(C)[C:13]([F:16])([F:15])[F:14].Cl>C1COCC1.O>[F:14][C:13]([F:16])([F:15])[CH:7]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)[OH:8]
Reactant: Cc1cc(C=O)on1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(O)C(F)(F)F)on1
Temperature: -5 °C

Procedure:
A mixture of 0.1 g (0.9 mmol) 3-Methyl-isoxazole-5-carbaldehyde and 14 mg (0.09 mmol) CsF and THF is cooled to −5° C. 540 μl (1.1 mmol) trimethyl(trifluormethyl)-silane 2 M in THF is added dropwise and after 30 min the mixture is allowed to reach RT. After cooling with ice and addition of 5 ml 1 N aq. HCl, the mixture is stirred at RT over night, diluted with water and extracted with DCM. The combined organic layers are dried and evaporated giving rise to 2,2,2-trifluoro-1-(3-methylisoxazol-5-yl)ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=O)=[N:6][CH:7]=1.[NH2:12][C:13]1[CH:18]=[C:17]([C:19]([C:21]2[C:25]3[CH:26]=[N:27][CH:28]=[CH:29][C:24]=3[N:23]([CH:30]([CH3:32])[CH3:31])[CH:22]=2)=[O:20])[CH:16]=[CH:15][N:14]=1.CCCP(=O)=O.C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:12][C:13]2[CH:18]=[C:17]([C:19]([C:21]3[C:25]4[CH:26]=[N:27][CH:28]=[CH:29][C:24]=4[N:23]([CH:30]([CH3:32])[CH3:31])[CH:22]=3)=[O:20])[CH:16]=[CH:15][N:14]=2)=[O:11])=[N:6][CH:7]=1
Reactant: CC(C)n1cc(C(=O)c2ccnc(N)c2)c2cnccc21
Reactant: O=C(O)Cc1ccc(Br)cn1
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)n1cc(C(=O)c2ccnc(NC(=O)Cc3ccc(Br)cn3)c2)c2cnccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-bromopyridin-2-yl)acetic acid (Preparation 83, 92 mg, 0.427 mmol) and (2-aminopyridin-4-yl)(1-isopropyl-1H-pyrrolo[3,2-c]pyridin-3-yl)methanone (Preparation 20, 120 mg, 0.427 mmol) in THF (3 mL) was added propylphosphonic anhydride (786 uL, 1.281 mmol) and triethylamine (151 uL, 1.99 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction was diluted with EtOAc, washed with saturated aqueous NaHCO3 solution, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified using preparative TLC eluting with 5% MeOH in DCM to afford the title compound.
Reaction SMILES: Br[CH:2]1[CH2:16][CH2:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]1=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH2:28])=[S:27])=[CH:21][CH:20]=1>C1COCC1>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[S:27][C:2]3[CH2:16][CH2:15][C:5]4[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=4[C:3]=3[N:28]=2)=[CH:21][CH:20]=1
Reactant: NC(=S)Nc1ccc(Br)cc1
Reactant: CCNC(=O)Nc1nc2c(s1)C(=O)C(Br)CC2
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2c(s1)-c1nc(Nc3ccc(Br)cc3)sc1CC2
Temperature: 65 °C

Procedure:
A suspension of N-(6-bromo-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-N′-ethylurea (50 mg, 0.16 mmol) and 4-bromo-phenyl-thiourea (36 mg, 0.16 mmol) in THF (1.0 mL) was heated to about 65° C. for about 1.5 hrs. The reaction mixture was pumped down and used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH:20]=[CH:19][C:18]=1[C:29](=[O:31])[CH3:30].[OH-].[Na+]>C(O)(C)C.O>[CH2:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[CH:30][C:29]([C:18]1[CH:19]=[CH:20][C:21]([O:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])=[CH:22][C:17]=1[OH:16])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccccc1C=O
Reactant: CC(=O)c1ccc(OCC=C(C)C)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCc1ccccc1C=CC(=O)c1ccc(OCC=C(C)C)cc1O
Temperature: 45 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of 3.11 g of 2-heptylbenzaldehyde and 3.35 g of 2'-hydroxy-4'-(3-methyl-2-butenyloxy)-acetophenone in 65 ml of isopropanol was added a solution of 2.9 g of sodium hydroxide in 6 ml of water under a nitrogen atmosphere, and the mixture was stirred at 45° C. for 8 hours. After neutralization with dilute hydrochloric acid with ice cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography with n-hexane including 1% ethyl acetate. The resulting fractions containing the end compound was recrystallized from isopropanol to give 3.23 g of 2-n-heptyl-2'-hydroxy-4'-(3-methyl-2-butenyloxy)-chalcone as yellow needles.
Reaction SMILES: [N+:1]1([O-:10])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH3:9].C([O-])([O-])=O.[K+].[K+].[Br:17]Br.CCOC(C)=O>C(Cl)(Cl)(Cl)Cl.CO.CCOC(C)=O>[Br:17][C:4]1[C:5]([CH3:7])=[CH:6][N+:1]([O-:10])=[C:2]([CH3:9])[C:3]=1[CH3:8]
Reactant: BrBr
Reactant: Cc1cc(C)c(C)[n+]([O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: Cc1c[n+]([O-])c(C)c(C)c1Br
Yield: 48.6 %

Procedure:
2,3,5-collidine-N-oxide (1.3 g, 10 mmol) and K2CO3 (2.9 g, 20 mmol) were suspended in 10 mL of CCl4. Bromine (1 mL, 20 mmol) was added dropwise, and the reaction mixture was heated to reflux for 2 h. Work-up (EtOAc) and flash chromatography (10% MeOH/EtOAc) afforded the title compound as a solid (1.05 g, 51% yield). R.t.: 5.24 min. 1H-NMR (CDCl3): δ 8.06 (s, 1H), 2.56 (s, 3H), 2.43 (s, 3H), 2.31 (s, 3H). m/z (%) 216.2 (M+1, 100%), 218.2 (M+3, 100%). Rf (20% MeOH/EtOAc): 0.45.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2([F:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]#[C:12]2)=[CH:6][CH:5]=1.[Li+].[OH-]>O1CCOCC1.O>[F:19][C:11]1([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:20])=[O:2])=[CH:9][CH:8]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]#[C:12]1
Reactant: COC(=O)c1ccc(CC2(F)C#CCCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(CC2(F)C#CCCCCC2)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of cyclooctyne 8b (1.8 g, 6.6 mmol) in dioxane (30 mL) and H2O (7.5 mL) was added finely crushed LiOH (3.1 g, 130 mmol). The suspension was heated to 50° C. and stirred for 3 h. The dioxane was removed on a rotary evaporator and the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with 1 N HCl (2×100 mL), H2O (3×100 mL), and brine (1×25 mL), and dried over MgSO4, yielding a white solid (1.7 g, 98%, Rf=0.30 in 27:3:1 hexane/EtOAc/AcOH), mp 132.0-132.5° C. (dec). IR: 3442, 2926, 2851, 2674, 2557, 2224, 1686, 1611 cm−1. 1H NMR (DMSO-d6, 400 MHz): δ 1.39 (app quintet, 1H, J=7.6 Hz), 1.64 (m, 2H), 1.76 (m, 2H), 2.10 (m, 5H), 3.07 (s, 1H), 3.11 (d, 1H, J=8.0 Hz), 7.38 (d, 2H, J=8.0 Hz), 7.87 (d, 2H, J=8.4 Hz), 12.9 (br s, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 19.8, 25.7, 29.0, 33.7, 43.7 (d, J=25.0 Hz), 47.6 (d, J=25.0 Hz), 90.7 (d, J=32.0 Hz), 95.4 (d, J=173.0 Hz), 104.5 (d, J=10.0 Hz), 129.0, 129.2, 130.4, 141.2, 167.2. 19F NMR (CD3CN, 376 MHz): δ −139.4 (m). FAB-HRMS: Calcd. for C16H18O2F+ [M+H]+: 261.1291, found: 261.1291. Anal. calcd. for C16H17O2F: C, 79.31; H, 7.49. Found: C, 79.07; H, 7.26.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[CH:4][C:3]=1[F:29].[C@H:30]12[CH2:36][C@H:33]([NH:34][CH2:35]1)[CH2:32][N:31]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[C:40]([O:39][C:37]([N:31]1[CH2:32][C@@H:33]2[CH2:36][C@H:30]1[CH2:35][N:34]2[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[CH:4][C:3]=1[F:29])=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)c(F)cc2c1=O

Procedure:
A solution of EXAMPLE 7F (500 mg), tert-butyl (1S,4S)-(−)-2,5-diazabicyclo(2.2.1)heptane-2-carboxylate (0.259 g), and diisopropylethylamine (0.622 mL) in acetonitrile (11.9 mL) was heated at 50° C. for 18 hours then cooled, diluted with dichloromethane, washed with saturated ammonium chloride and brine, and dried (MgSO4), filtered, and concentrated; and the concentrate was recrystallized from diethyl ether.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH2:25])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].Cl[C:28]1[O:29][C:30]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:31]=2[N:32]=1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][NH:25][C:28]2[O:29][C:30]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:31]=3[N:32]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN)c1
Reactant: Cc1ccc2oc(Cl)nc2c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNc2nc3cc(C)ccc3o2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-aminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and 2-chloro-5-methyl-benzooxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH3:26])[N:10]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)OCCc1cc(Cl)c(Oc2cc(C(C)C)c(=O)[nH]n2)c(Cl)c1
Agent: [K+]
Solvent: CI
Product: CC(=O)OCCc1cc(Cl)c(Oc2cc(C(C)C)c(=O)n(C)n2)c(Cl)c1
Temperature: 40 °C
Reaction time: 24 h
Yield: 71.7 %

Procedure:
A mixture of acetic acid 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-ethyl ester (34) (531 mg, 1.38 mmol), potassium carbonate (280 mg, 2.03 mmol) and methyl iodide (2 mL, 32.1 mmol) was warmed to 40° C. for 2 h. Additional methyl iodide was added (1 mL, 16.05 mmol) followed by potassium carbonate (140 mg, 1.01 mmol). The mixture was heated at 40° C. for 2 h and then was stirred at room temperature for 24 h. The reaction mixture was concentrated and the resulting residue was partitioned between ethyl acetate (50 mL) and water (25 mL). The water layer was re-extracted with ethyl acetate (25 mL). The organic layers were combined, dried with sodium sulfate, filtered, and concentrated. The resulting residue was dissolved in 25% ethyl acetate in hexanes and was purified by flash chromatography (Biotage 40S) using silica gel eluted with 25-50% ethyl acetate in hexanes. The desired fractions were collected and concentrated under vacuum. The resulting solid was dried under high vacuum to afford 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-ethyl ester (35) (395 mg, 72%) as a clear oil; LRMS for C18H20Cl2N2O4 (M+) m/z=399. Molecular Weight=399.2771; Exact Mass=398.0800
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:8][CH:7]=1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(Oc2cc(Cl)cc(Cl)c2)cc1
Product: Clc1cc(Cl)cc(Oc2ccc(CN3CCCC3)cc2)c1

Procedure:
The title compound was prepared starting from 4-(3,5-dichloro-phenoxy)-benzaldehyde and pyrrolidine by the same method (step B) described in Example 1. 1H NMR (400 MHz, CDCI3)δ7.22 (t, J=7.8 Hz, 1 H), 7.07 (d, J=7.6 Hz,1 H), 6.96 (m, 2 H), 6.81 (m,1 H), 6.76 (m, 2 H), 3.52 (s, 2 H), 2.45 (m, 4 H), 1.70 (m, 4 H).
Reaction SMILES: C([O:3][C:4](=[O:46])/[CH:5]=[CH:6]/[C:7]1[C:8]([CH3:45])([CH3:44])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[CH:21]1[C@:12]([CH3:43])([C@@:13]3([CH3:42])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)C.[OH-].[Na+].Cl>O1CCOCC1.O>[CH2:35]([O:34][C:32]([C@:16]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]1[C@@H:18]1[C@@:13]([CH3:42])([CH2:14][CH2:15]2)[C@@:12]2([CH3:43])[CH:21]([C@:22]3([CH3:25])[C@@H:9]([CH2:10][CH2:11]2)[C:8]([CH3:45])([CH3:44])[C:7](/[CH:6]=[CH:5]/[C:4]([OH:46])=[O:3])=[CH:24][CH2:23]3)[CH2:20][CH2:19]1)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(/C=C/C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(/C=C/C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C
Yield: 104.4 %

Procedure:
A mixture of (1R,3aS,5aR,5bR,7aR,11aS,13aR,13bR)-benzyl 9-((E)-3-ethoxy-3-oxoprop-1-enyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (20 mg, 0.032 mmol) and 10 N sodium hydroxide (0.032 mL, 0.319 mmol) in dioxane (0.5 mL) and water (0.5 mL) was heated at 100° C. for 3 hours. The reaction mixture was neutralized with 1N HCl to pH=6 and extracted with ethyl acetate (3×4 mL). The extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound (20 mg, 105%). This material was used in the next step without further purification. LCMS: m/e 597.68 (M−H)−, 2.50 min (method 6).
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][CH2:14][CH2:15][N:16]=[C:17]=[S:18]>CC(O)(C)C>[I:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[NH:1][C:17](=[S:18])[N:16]([CH2:15][CH2:14][O:13][CH3:12])[C:4]2=[O:6]
Reactant: COCCN=C=S
Reactant: Nc1c(I)cccc1C(=O)O
Solvent: CC(C)(C)O
Product: COCCn1c(=S)[nH]c2c(I)cccc2c1=O
Temperature: 100 °C
Yield: 89.8 %

Procedure:
A sealable flask was charged with 2-amino-3-iodobenzoic acid (5.02 g, 19.09 mmol) and 2-methoxyethyl isothiocyanate (3.35 g, 28.6 mmol) in tBuOH (30 mL) followed by TEA (3.98 mL, 28.6 mmol). The flask was sealed and heated in an oil bath at 100° C. for 4 h with a blast shield. The reaction mixture was cooled to RT and the off white solid was filtered, rinsed with 2×25 mL of ether and dried to give 8-iodo-3-(2-methoxyethyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (6.21 g, 17.15 mmol, 90% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.99 (1H, s), 8.26 (1H, dd, J=7.6, 1.2 Hz), 8.00 (1H, dd, J=7.9, 1.3 Hz), 7.17 (1H, t, J=7.7 Hz), 4.60 (2H, t, J=6.5 Hz), 3.65 (2H, t, J=6.6 Hz), 3.31 (3H, s). m/z (ESI, +ve) 362.8 (M+H)+. To a 500-mL round-bottomed flask was added sequentially 8-iodo-3-(2-methoxyethyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (6.01 g, 16.59 mmol), THF (75 mL K2CO3 (5.73 g, 41.5 mmol), and MeI (2.06 mL, 33.2 mmol). The reaction mixture was heated in an oil bath at 65° C. for 6 h. The mixture was concentrated to half of its volume, poured into ice/water (100 mL) and stirred for 10 min. The suspension was filtered and the solid was washed with cold water (20 mL) and cold ether (20 mL). The off-white solid was dried to give 8-iodo-3-(2-methoxyethyl)-2-(methylthio)quinazolin-4(3H)-one (715a; 4.91 g). The filtrate was extracted with 50 mL of EtOAc. The EtOAc layer was concentrated and the brown solid was stirred in 5 mL of ether and 5 mL of hexanes. The solid was filtered and dried to give 8-iodo-3-(2-methoxyethyl)-2-(methylthio)quinazolin-4(3H)-one (715a; 1.1 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.34 (1H, dd, J=7.6, 1.4 Hz), 8.09 (1H, dd, J=7.9, 1.3 Hz), 7.22 (1H, t, J=7.7 Hz), 4.25 (2H, t, J=6.2 Hz), 3.65 (2H, t, J=6.2 Hz), 3.30 (3H, s), 2.75 (3H, s). m/z (ESI, +ve) 376.7 (M+H)+.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[CH:37][CH:36]=1)[CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][CH:23]=1>CN>[NH2:3][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[CH:37][CH:36]=1)[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])=[CH:26][CH:27]=1
Reactant: CS(=O)(=O)Nc1ccc(CCN(CCCCCCN2C(=O)c3ccccc3C2=O)CCOc2ccc(NS(C)(=O)=O)cc2)cc1
Agent: CN
Product: CS(=O)(=O)Nc1ccc(CCN(CCCCCCN)CCOc2ccc(NS(C)(=O)=O)cc2)cc1
Reaction time: 48 h
Yield: 13.1 %

Procedure:
Crude N-[4-({2-[[6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)hexyl](2-{4-[(methylsulfonyl)amino]phenyl}ethyl)amino]ethyl}oxy)phenyl]methanesulfonamide (142 mg) was dissolved in methylamine (33% in ethanol, 10 ml, 0.216) and left at 22° C. for 48 h. Excess reagent was evaporated under reduced pressure and the oily residue azeotroped with two further portions of ethanol. The crude product was dissolved in acetonitrile/water/acetic acid (5/4/, <2 ml), half applied to a Phenomenex Jupiter C18 HPLC column and eluted using the following gradient (flow rate=10 ml/min, AU 20.0, 214 nm, AU 10, 256 nm, A=0.1% TFA/water, B=90% acetonitrile/10% water/0.1% TFA): t=0 min: B=5%; t=10 min: B=5%; t=100 min: B=35%; t=115 min: B=100%; t=130 min: B=100%. Fractions containing mainly the slower eluting component (>90%) were pooled and evaporated to give the title compound (14.9 mg). The remaining crude was applied to the C18 column but with a modified gradient: t=0 min: B=5%; t=10 min: B=5%; t=15 min: B=10%; t=95 min: B=30%; t=110 min: B=100%; t=125 min: B=100%. Fractions containing mainly the desired product were combined and evaporated as before to yield the title compound (21.3 mg˜80% purity). The material was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:11][CH:12]=[CH2:13])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20].[H-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([NH:7][C@H:8]([CH2:11][CH:12]=[CH2:13])[CH2:9][O:10][CH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccccc1CBr
Reactant: C=CC[C@H](CO)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@H](COCc1ccccc1C(=O)OC)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
A solution of compound 18g (6.2 g, 30.8 mmol) and compound 18c (8.5 g, 36.9 mmol) in THF (30 mL) was cooled in an ice bath under argon. To this mixture was added NaH (2.5 g, 61.6 mmol, 60% wt in oil) portionwise. The ice bath was removed and the reaction mixture was allowed to stir at rt for 2 h and then quenched with MeOH (10 mL). The mixture was concentrated under reduced pressure and the residue was purified by CC to give the desired compound 18h (4.2 g, 39% yield) as a yellow oil. LCMS (m/z): 350.2 (MH+).