Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=[CH:7][C:8]2[S:12][C:11]([C:13](Cl)=[O:14])=[CH:10][CH:9]=2)[C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.CC1(C)OC(CO)C[O:22]1>N1C=CC=CC=1>[S:1]1[CH:5]=[C:4]([CH:6]=[CH:7][C:8]2[S:12][C:11]([C:13]([OH:22])=[O:14])=[CH:10][CH:9]=2)[C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2
Reactant: O=C(Cl)c1ccc(C=Cc2csc3ccccc23)s1
Reactant: CC1(C)OCC(CO)O1
Solvent: c1ccncc1
Product: O=C(O)c1ccc(C=Cc2csc3ccccc23)s1

Procedure:
The acid chloride of 5-[2-(benzo[b]thiophen-3-yl)ethenyl]thiophene-2-carboxylic acid was prepared as described in Example 9. To a solution of 5-[2-(benzo[b]thiophen-3-yl)ethenyl]thiophene-2-carboxylic acid chloride (5.0 g) and pyridine (50 ml) was added 2,2-dimethyl-1,3-dioxolane-4-methanol (2.17 g). After refluxing overnight, the mixture was evaporated. The residue was dissolved in ethyl acetate, filtered, and concentrated. The residue was purified by high performance liquid chromatography (silica gel, loaded and eluted in 2:1 ethyl acetate:hexane). The appropriate fractions were combined and evaporated. Trituration of the residue with hexane yielded 2.60 g (39%) of product, mp 77°-79° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:13]1[N:18]=[C:17]([NH2:19])[C:16]([F:20])=[CH:15][N:14]=1>O1CCOCC1>[F:20][C:16]1[C:17]([NH2:19])=[N:18][C:13]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)=[N:14][CH:15]=1
Reactant: OCc1ccc(F)cc1
Reactant: Nc1nc(Cl)ncc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1nc(OCc2ccc(F)cc2)ncc1F
Temperature: 25 °C
Yield: 52 %

Procedure:
To a solution of 4-fluorobenzyl alcohol (2.56 g, 20.3 mmol) in 1,4-dioxane (20 mL) was added 60% NaH (0.813 g, 20.3 mmol) in several portions over a period of 10 min. To the magnetically stirred solution was added 2-Chloro-5-fluoropyrimidin-4-amine* (2.00 g, 13.6 mmol) and the mixture was stirred at room temperature until gas evolution subsided. The reaction mixture was then heated in a CEM Discover microwave reactor at 120° C. for 90 min. The cooled reaction mixture was partitioned between ethyl acetate and water, the organic phase was concentrated, and the product was purified by column chromatography (hexane/ethyl acetate gradient) to yield 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-amine (1.66 g, 52% yield) as a white solid: mp 129-131° C.; 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J=2.6 Hz, 1H), 7.42 (m, 2H), 7.03 (m, 2H), 5.27 (s, 2H), 5.05 (br s, 2H); MS (ESI) m/z 238 (M+H)+. *4-Amino-2-chloro-5-fluoropyrimidine can be purchased commercially or can be prepared through known literature methods.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9](I)[O:10][C:3]=12.[Li][CH2:13]CCC.CI.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH3:13])[O:10][C:3]=12
Reactant: [Li]CCCC
Reactant: Clc1ccnc2cc(I)oc12
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2nccc(Cl)c2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven-dried round bottom flask, 7-chloro-2-iodofuro[3,2-b]pyridine (0.200 g, 0.72 mmol) was dissolved in 3 mL THF and cooled to −78° C. nBuLi (0.43 ml, 1.1 mmol) was slowly added and the reaction was stirred for one hour. Meanwhile, a vial was filled with MeI and warmed to RT. Magnesium sulfate was added and the mixture was stirred for 5 minutes and filtered into another vial. Immediately from this vial, MeI (0.11 ml, 1.8 mmol) was added to the reaction which was stirred at −78° C. for 3 hours. The reaction was quenched with saturated ammonium chloride solution and warmed to RT. DCM was added, the layers were separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (gradient elution 0-50% EtOAc:Hex) to afford 7-chloro-2-methylfuro[3,2-b]pyridine as a light brown oil. MS: M+H+=168.3.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Br:25][CH2:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([CH:1]3[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4]3)[S:9][C:10]=2[CH:16]=1
Reactant: Cc1ccc2nc(Cc3ccccc3)sc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: BrCc1ccc2nc(C3CCCCC3)sc2c1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
Combine 2-benzyl-6-methyl-benzothiazole (0.6 g, 2.42 mmol), NBS (0.5 g, 2.54 mmol), AIBN (40 mg, 0.24 mmol), carbon tetrachloride (10 mL) and reflux for 3 h. Cool the reaction mixture to ambient temperature, dilute with chloroform and wash with water. Dry the organic extracts over anhydrous Na2SO4, concentrate in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the title compound as a white solid (0.4 g, 53%). MS (ES+) m/z: 311 (M+H)+.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([CH2:19][O:20][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:13]=2)[C:9]2[C:4](=[N:5][C:6]([Cl:38])=[CH:7][CH:8]=2)[CH:3]=1.[O:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[N:45]1[C:49](B2OC(C)(C)C(C)(C)O2)=[CH:48][CH:47]=[N:46]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:21]([O:20][CH2:19][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([Cl:18])[CH:15]=1)[CH2:11][N:10]1[C:9]2[C:4](=[N:5][C:6]([Cl:38])=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:49]1[N:45]([CH:40]2[CH2:41][CH2:42][CH2:43][CH2:44][O:39]2)[N:46]=[CH:47][CH:48]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: CC(C)(C)[Si](OCc1cc(Cl)cc(Cn2c(Br)cc3nc(Cl)ccc32)c1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)[Si](OCc1cc(Cl)cc(Cn2c(-c3ccnn3C3CCCCO3)cc3nc(Cl)ccc32)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.65 g, 0.56 mmol, Strem) was added to a degassed mixture of 2-bromo-1-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-chlorobenzyl]-5-chloro-1H-pyrrolo[3,2-b]pyridine (3.5 g, 5.6 mmol, from Step 1), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.5 g, 9.0 mmol, Aldrich) and Na2CO3 (3.0 g, 28 mmol) in 1,2-dimethoxyethane (60 mL) and Water (10 mL). The mixture was heated at reflux for 2 hours. Additional 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.50 g, 1.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.32 g, 0.28 mmol) were added, and the reaction mixture was heated at reflux until LCMS indicated that the reaction was complete. After cooling to room temperature, the reaction was diluted with water, and the aqueous mixture was extracted with three portions of EtOAc. The combined organic extracts were washed with water, followed by brine, dried over Na2SO4, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes afforded product as a light yellow oil. Yield: (2.73 g, 70%).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH3:10])(C)(C)C>CO.ClCCl>[ClH:1].[ClH:1].[CH2:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([N:20]2[CH2:19][CH2:18][CH:17]([C:14]3[CH:13]=[CH:12][C:11]([C@@H:9]([NH2:8])[CH3:10])=[CH:16][CH:15]=3)[CH2:22][CH2:21]2)=[CH:28][CH:27]=1)[CH3:31]
Reactant: CCOc1ccc(N2CCC(c3ccc([C@H](C)NC(=O)OC(C)(C)C)cc3)CC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOc1ccc(N2CCC(c3ccc([C@H](C)N)cc3)CC2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
11.3 mL (14.1 mmol) 1.25 N HCl in methanol are added to 900 mg (2.12 mmol) (S)-(1-{4-[1-(4-ethoxy-phenyl)-piperidin-4-yl]-phenyl}-ethyl)-carbamic acid tert-butyl ester (XII.1) in 25 mL dichloromethane. The mixture is stirred for 14 h at rt and for 1 h at 50° C. After that time, the solvent is removed in vacuo to yield the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.Br[CH2:13][CH2:14][O:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:13][CH2:14][O:15][CH3:16])[C:6]=2[CH:11]=1
Reactant: COCCBr
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COCCn1c(=O)oc2ccc(Br)cc21
Temperature: 60 °C

Procedure:
A mixture of 5-bromobenzo[d]oxazol-2(3H)-one (2.06 g), 1-bromo-2-methoxyethane (1.085 mL) and potassium carbonate (3.99 g) in acetonitrile (15 mL) was heated at 60° C. for 16 h. Water was added and the mixture was extracted with ethyl acetate (3 times). The organic layers were dried over magnesium sulfate, evaporated and purified by flash silica chromatography eluting with 5:1 isohexane/acetone to give the subtitled compound (1.359 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=[O:13])[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.O[Li].O.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Br)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
Dimethyl 5-bromobenzene-1,3-dicarboxylate (5 g, 18.3 mmol, 1.0 eq) was dissolved in THF (50 mL) and LiOH.H2O (1.1 g, 27.5 mmol, 1.5 eq) and H2O (10 mL) were added. The mixture was stirred at room temperature overnight. The THF was removed in vacuo and the aqueous phase acidified with diluted HCl. The aqueous phase was extracted with EtOAc, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (CH2Cl2:MeOH, 50:1) to give the title compound as a white solid (3 g, 63%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([OH:19])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Na+]>O>[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:10]=1[CH2:15][CH2:16][C:17]2=[O:19])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccccc1C(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C1CCc2c1cccc2C(=O)c1ccccc1
Temperature: 160 °C

Procedure:
Five g. of o-benzoyl-β-phenylpropionic acid, 13 g. of anhydrous aluminum chloride and 1.3 g. of sodium chloride are admixed together and heated at 160° C for 1 hour. After cooling, water is added to the mixture, followed by extraction with chloroform. The extract is washed with a 5% aqueous solution of sodium bicarbonate and water in that order and, then, dried. The solvent is distilled off under reduced pressure and the residue is dissolved in ethanol. The solution is decolorized with activated carbon and recrystallized from ethanol. The procedure yields 4-benzoylindan-1-one as crystals melting at 86°-88° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]CC)=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:21][CH2:20][CH2:19][S:18](=[O:23])(=[O:22])[CH2:17]1.CO.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:21][CH2:20][CH2:19][S:18](=[O:22])(=[O:23])[CH2:17]1
Reactant: CCOC(=O)c1cc(Br)cc2c(C3CCCS(=O)(=O)C3)c[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(Br)cc2c(C3CCCS(=O)(=O)C3)c[nH]c12
Temperature: 85 °C
Yield: 92 %

Procedure:
Ethyl 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-indole-7-carboxylate (0.380 g, 0.949 mmol), was stirred in a methanol (5 mL)/water (3 mL) solution. 6M NaOH (1.5 mL, 0.900 mol, 10 eq) was added and the reaction was heated to 85° C. for 1.5 hours. The methanol was concentrated and the aqueous solution was acidified with 6M HCl. The resulting white solid was filtered and dried under vacuum to give 0.325 g (92%) of the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1([CH3:30])[C@H:10]([CH:11]=O)[C@H:9]1[C:13]([O:15][CH2:16][C:17]1[C:22]([F:23])=[C:21]([F:24])[C:20]([CH2:25][O:26][CH3:27])=[C:19]([F:28])[C:18]=1[F:29])=[O:14].C(OP([CH:39]([Cl:42])[C:40]#[N:41])(=O)OCC)C>O1CCCC1>[Cl:42]/[C:39](/[C:40]#[N:41])=[CH:11]\[C@H:10]1[C@@H:9]([C:13]([O:15][CH2:16][C:17]2[C:22]([F:23])=[C:21]([F:24])[C:20]([CH2:25][O:26][CH3:27])=[C:19]([F:28])[C:18]=2[F:29])=[O:14])[C:8]1([CH3:7])[CH3:30]
Reactant: CCOP(=O)(OCC)C(Cl)C#N
Reactant: COCc1c(F)c(F)c(COC(=O)[C@@H]2[C@@H](C=O)C2(C)C)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCc1c(F)c(F)c(COC(=O)[C@@H]2[C@H](/C=C(\Cl)C#N)C2(C)C)c(F)c1F
Yield: 3.7 %

Procedure:
A solution of 0.27 g of potassium tert-butoxide in 2 ml of tetrahydrofuran was added dropwise to a mixture of 0.70 g of 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl (1R,3R)-2,2-dimethyl-3-formylcyclopropanecarboxylate, 0.42 g of diethyl(chlorocyanomethyl)phosphonate and 5 ml of anhydrous tetrahydrofuran with ice-cooling under a nitrogen atmosphere. After stirring with ice-cooling for 15 minutes, the reaction mixture was poured into a saturated saline solution and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was subject to silica gel column chromatography to obtain 0.03 g of 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl (1R,3R)-3-((Z)-2-chloro-2-cyanovinyl)-2,2-dimethylcyclopropanecarboxylate represented by the formula (3):
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17](O)=[N:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:21][C:22]1[CH:23]=[C:24]([CH:28]2[N:33]([CH3:34])[CH2:32][CH2:31][N:30]([CH3:35])[C:29]2=[O:36])[CH:25]=[CH:26][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([NH:21][C:22]4[CH:23]=[C:24]([CH:28]5[N:33]([CH3:34])[CH2:32][CH2:31][N:30]([CH3:35])[C:29]5=[O:36])[CH:25]=[CH:26][CH:27]=4)=[N:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cnc(O)nn23)cc1
Reactant: CN1CCN(C)C(c2cccc(N)c2)C1=O
Product: CN1CCN(C)C(c2cccc(Nc3ncc4ccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)c2)C1=O

Procedure:
3-{3-[7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-1,4-dimethyl-piperazin-2-one was prepared from 7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 3-(3-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1052a. Product isolated as a yellow foam (75 mg, 50%). LCMS (m/e) 491 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.76 (s, 1H), 8.38 (d, 2H, J=8.4 Hz), 8.05 (d, 2H, J=8.4 Hz), 7.68 (s, 1H), 7.51 (d, 1H, J=8.2 Hz) 7.37-7.29 (m, 1H), 7.11 (d, 1H, J=7.6 Hz), 7.08 (d, 1H, J=4.8 Hz), 6.91 (s, 1H), 6.86 (d, 1H, J=4.8 Hz), 3.75-3.65 (m, 1H), 3.66 (s, 1H), 3.25-3.18 (m, 1H), 3.10 (s, 3H), 3.08-3.00 (m, 1H), 2.99 (s, 3H), 2.77-2.67 (m, 1H), 2.18 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]([CH3:12])[OH:11])=[C:4]([F:13])[CH:3]=1.OS(O)(=O)=O>CC(C)=O.O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10](=[O:11])[CH3:12])=[C:4]([F:13])[CH:3]=1
Reactant: COc1cc(C(C)O)c(F)cc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C(C)=O)c(F)cc1Cl
Reaction time: 2 h
Yield: 90.3 %

Procedure:
A stirred solution of 10.4 g of 4-chloro-2-fluoro-5-methoxybenzaldehyde in 150 mL of anhydrous THF was cooled in a dry ice-acetone bath and treated with 35 mL of a 3M solution of methyl magnesium chloride in THF over a period of one minute. The ice bath was removed and the mixture allowed to warm to room temperature. After warming, the solution was slowly poured into ice water. The water slurry was extracted three times with diethyl ether, the ether extracts dried and concd to afford a crude oil. Crystallization from hexanes yielded 10.8 g (95.6%) of 4-chloro-2-fluoro-5-methoxy-α-methyl-benzenemethanol: mp 68.5°-69.5° C. This benzenemethanol intermediate was dissolved in 100 mL of acetone, cooled in an ice water bath and treated dropwise with 50 mL of freshly prepared Jones'reagent (prepared from 6.7 g of CrO3, 6 mL of H2SO4 and 50 mL of water), keeping the temperature below 10° C. After stirring for 2 hrs., the solution was diluted with water and extracted three times with methylene chloride. The organic extracts were dried and concd to give a crude product. Recrystallization from methanol yielded 9.66 g (90.3%) of 1-(4-chloro-2-fluoro-5-methoxyphenyl) ethanone as a white solid: mp 96.5-98.5 ° C.; 1HNMR (CDCl3) δ 2.50 (d, 3H, 5.4 Hz), 3.80 (s, 3H), 7.10 (d, 1H, 10.1 Hz), 7.30 (d, 1H, 6.3 Hz).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[C:5](=[C:6]([NH:15][CH:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]4)[N:7]=[CH:8][N:9]=3)[C:4]1=2.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH3:37][S:38]([O:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[C:5](=[C:6]([NH:15][CH:16]4[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:20][CH2:21]4)[N:7]=[CH:8][N:9]=3)[C:4]1=2)(=[O:40])=[O:39]
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3sc4c(c23)[C@@H](CO)CC4)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3sc4c(c23)[C@@H](COS(C)(=O)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a solution of tert-butyl N-(4-[[(3S)-3-(hydroxymethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino]cyclohexyl)carbamate (400 mg, 0.96 mmol, 1.00 equiv) and triethylamine (0.27 mL, 2.00 equiv) in dichloromethane (20 mL) was added dropwise MsCl (164 mg, 1.43 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 2×40 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). Purification afforded 379 mg (80%) of tert-butyl N-(4-[[(3S)-3-[(methanesulfonyloxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino]cyclohexyl)carbamate as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][O:9][C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:16]=4[N:15]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:14]=3[N:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:33](=O)[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH2:33]([N:5]1[CH2:4][CH2:3][C:2]([CH2:8][O:9][C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:16]=4[N:15]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:30])[CH3:32])[C:14]=3[N:13]=[CH:12][CH:11]=2)([CH3:1])[CH2:7][CH2:6]1)[CH3:34]
Reactant: CC1(COc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)CCNCC1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CCC(C)(COc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-((4-methylpiperidin-4-yl)methoxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (75 mg, 0.17 mmol) in methylene chloride (1.1 mL) was added acetaldehyde (14 uL, 0.25 mmol) and sodium triacetoxyborohydride (53 mg, 0.25 mmol), and the mixture was stirred at ambient temperature for 10 minutes. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and methylene chloride (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 0-20% methanol in methylene chloride) to afford the title compound as a yellow solid, which was used in the next step without any further purification (58 mg, 73%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][C:8]([OH:17])=[CH:9][CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1.[N:19]1([CH2:25][CH2:26][Cl:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[ClH:28].[N:29]1([CH2:35][CH2:36][Cl:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.O>[OH-].[K+].C1(C)C(C)=CC=CC=1>[OH2:1].[ClH:27].[ClH:37].[N:19]1([CH2:25][CH2:26][O:1][C:2]2[CH:15]=[CH:14][C:13]3[C:12](=[O:16])[C:11]4[C:6](=[CH:7][C:8]([O:17][CH2:36][CH2:35][N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:9][CH:10]=4)[C:5](=[O:18])[C:4]=3[CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[N:19]1([CH2:25][CH2:26][O:1][C:2]2[CH:15]=[CH:14][C:13]3[C:12](=[O:16])[C:11]4[C:6](=[CH:7][C:8]([O:17][CH2:36][CH2:35][N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:9][CH:10]=4)[C:5](=[O:18])[C:4]=3[CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[ClH:28].[ClH:27]
Reactant: ClCCN1CCCCC1
Reactant: O=C1c2ccc(O)cc2C(=O)c2cc(O)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1c2ccc(OCCN3CCCCC3)cc2C(=O)c2cc(OCCN3CCCCC3)ccc21

Procedure:
With efficient stirring, 100 g (0.42 mole) of 2,7-dihydroxyanthraquinone is dissolved in 500-700 ml of about 10% potassium hydroxide solution. This solution is filtered and evaporated to dryness in a rotary evaporator. The reddish brown solid is dried in a vacuum oven at 100°C, ground to a fine powder, then redried at 100°C. To a stirred suspension of 30 g of the powdered diphenoxide, containing about 24 g (0.075 mole) of the dipotassium salt of 2,7-dihydroxyanthraquinone, in 200 ml of xylene is heated to reflux and a small amount of water collected. A solution of 2-piperidinoethyl chloride in 100 ml of xylene, prepared from 53.3 g (0.29 mole) of 2-piperidinoethyl chloride hydrochloride, is added and the resulting mixture heated to reflux for about 24 hours. The mixture is poured into about 500 ml of water, and the solid which separates at the xylene/water interface is removed by filtration, washed with hot water and dried. This major portion of the free base is recrystallized from a mixture of hot methanol and chloroform, then dissolved in chloroform and acidified to Congo Red with ethereal HCl and diluted with ether. The precipitate is suspended in boiling methanol (12-20 ml per gram) and a small volume of water is added to effect solution. This solution is filtered, reduced about 1/4 in volume, diluted with additional methanol and chilled. The recrystallized dihydrochloride is filtered and dried in a vacuum oven at 100°C to give 2,7-bis(2-piperidinoethoxy)anthraquinone dihydrochloride hemihydrate, M.P. 275°-277°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH:2]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[OH-].[Na+]>O>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:10][CH2:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCCCCCBr
Reactant: OCCCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCc1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-pyridinepropanol (10 g), 1,6-dibromohexane (40 ml) 50% (w/v) sodium hydroxide (40 ml) and TAB (1.0 g) was stirred at room temperature for 3 h, water (150 ml) was added and the mixture was extracted with ether (2×200 ml). The organic extracts were washed with water and brine, dried and concentrated to an oil which was purified by FCC eluting with hexane→hexane-ether (1:1), to give the title compound as a yellow oil (11.0 g), t.l.c. (hexane-ether 1:1) Rf 0.16.