Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:28])[CH:22]=2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:29][C@H:30]([CH3:52])[CH2:31][O:32]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(OC)C=CC=CC=1>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:28])[CH:22]=2)(=[O:19])=[O:20])[CH:14]=[C:13]([O:29][C@H:30]([CH3:52])[CH2:31][OH:32])[N:12]=1
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)c2ccc(=O)n(C)c2)nc(SCc2cccc(F)c2F)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: COc1ccccc1
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)c2ccc(=O)n(C)c2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-methyl-2-(triphenylmethoxy)ethoxy]-4-pyrimidinyl]-1,6-dihydro-1-methyl-6-oxo-3-pyridinesulfonamide (the product from step (0.16 g) in MeOH (10 mL) was added p-toluenesulfonic acid (50 mg) and anisole (0.22 g). The reaction was then stirred at room temperature for 18 h. The reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The aqueous layer was then further extracted with EtOAc (2×100 mL). Combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by reverse phase HPLC using TFA (0.2%)/MeCN to give a white solid. Yield: 9 mg.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[C:11](=[O:16])[C:12]([F:15])([F:14])[F:13].B(Br)(Br)Br.O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[C:11](=[O:16])[C:12]([F:15])([F:13])[F:14]
Reactant: COc1cc(Cl)cc(C(=O)C(F)(F)F)c1N
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Nc1c(O)cc(Cl)cc1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 102.1 %

Procedure:
To a stirred, cooled (0° C.) solution of 31.2 g (123 mmol) of 2'-amino-5'-chloro-3'-methoxy-2,2,2-trifluoroacetophenone in 150 mL of CH2Cl2 was added 550 mL (550 mmol) of 1M BBr3 in CH2Cl2 over 20 min. The dark solution was stirred 17 h at ambient temperature, re-cooled to 0° C., and fitted with a pressure-equalizing dropping addition funnel and a Claisen adapter connected by rubber tubing to a large water scrubber. The reaction was carefully quenched by dropwise addition of aqueous Na2CO3 until a pH of 7-8 was reached. The phases were separated, and the aqueous phase was extracted with 1 liter of 1:1 ether-hexanes. The combined organic phases were washed with water then brine, dried (MgSO4), and concentrated under reduced pressure to afford 30.1 g (100%) of 2'-amino-5'-chloro-3'-hydroxy-2,2,2-trifluoroacetophenone as a chalky brown solid, mp 120°-122° C. 1H NMR (300 MHz, CDCl3) δ7.33-7.36(m, 1H); 6.88(d, 1H, J=1.8 Hz); 6.75(br. s, 2H); 5.78(br. s, 1H). High resolution mass spec: calculated for C8H6NO2ClF3 (M+H)+ : 240.0039, found: 240.0029.
Reaction SMILES: [BH4-].[Na+].[N:3]([C@@H:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][C@H:7]1OS(C1C=CC(C)=CC=1)(=O)=O)=[N+]=[N-].N([C@H]1[C@H](OS(C2C=CC(C)=CC=2)(=O)=O)CCN(C(OCC2C=CC=CC=2)=O)C1)=[N+]=[N-].[P:63](Cl)(=[O:70])([O:67][CH2:68][CH3:69])[O:64][CH2:65][CH3:66]>CO.C(Cl)Cl.O>[CH2:65]([O:64][P:63]([N:3]1[CH:7]2[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH2:8]2)([O:67][CH2:68][CH3:69])=[O:70])[CH3:66]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OCc3ccccc3)CC[C@H]2N=[N+]=[N-])cc1
Reactant: CCOP(=O)(Cl)OCC
Agent: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2N=[N+]=[N-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCOP(=O)(OCC)N1C2CCN(C(=O)OCc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
NaBH4 (3.41 g, 90.3 mmol) was added portion wise to a solution of CuSO4-5H2O (10.73 g, 42.98 mmol) in methanol (200 mL) at 0° C. After 5 minutes, a solution of trans-benzyl 4-azido-3-(tosyloxy)piperidine-1-carboxylate and trans-benzyl 3-azido-4-(tosyloxy)piperidine-1-carboxylate (37 g, 85.95 mmol; mixed product from last step) in methanol (100 mL) was added at 0° C. After addition, additional NaBH4 (10.2 g, 270.6 mmol) was added in four portions over the course of 1 hour. After one hour at 0° C., the reaction mixture was filtered through a pad of celite and concentrated in vacuo. The residue obtained was dissolved in DCM (800 mL), washed with water (200 mL), saturated NH4Cl solution (200 mL), brine (200 mL), dried (sodium sulfate) and concentrated in vacuo. The residue obtained was dissolved in DCM (200 mL) and TEA (24.0 mL, 171.9 mmol) and diethyl phosphorochloridate (12.4 mL, 85.95 mmol) was added at 0° C. The reaction mixture was warmed to room temperature and stirred at room temperature for 30 minutes. Water (50 mL) was added. The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (ethyl acetate) to give benzyl 7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate (17.5 g, 55%) as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][CH:13]=O.Cl.[C:16]([O:20][NH2:21])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][N:21]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[CH:13]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)ON
Reactant: O=CNc1cnc2ccccc2c1Cl
Agent: Cl
Product: CC(C)(C)On1cnc2cnc3ccccc3c21
Yield: 70.5 %

Procedure:
4-Chloroquinolin-3-ylformamide (4.1 g, 0.020 mol) was treated with O-(tert-butyl)hydroxylamine hydrochloride (2.8 g, 22 mmol) according to the method of Part B of Example 20 to provide 3.4 g of 1-tert-butoxy-1H-imidazo[4,5-c]quinoline, which was used without chromatographic purification.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH3:12])[C:6]=1[CH3:13])(=[O:3])[CH3:2].Cl[CH2:15][CH:16]1[CH2:18][O:17]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:15][CH:16]2[O:17][CH2:18]2)=[C:7]([CH3:12])[C:6]=1[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(O)c(C)c1C
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)Oc1ccc(OCC2CO2)c(C)c1C

Procedure:
Using 4.30 g of 4-acetoxy-2,3-dimethylphenol, 4.6 ml of chloromethyloxirane, 3.30 g of anhydrous potassium carbonate and 100 ml of methyl ethyl ketone, reaction and workup carried out as in Example 1-A gave about 6.05 g of 1-(4-acetoxy-2,3-dimethylphenoxy)-2,3-epoxypropane as brown oil. Using the epoxy compound thus obtained, 4.60 g of 1-(2-methoxyphenyl)piperazine and 100 ml of dioxane, reaction and workup were carried out as in Examples 1-A and 4. After hydrolysis and workup followed by conversion to hydrochloride with 2N HCl, recrystallization from methanol gave 2.55 g of white crystals, m.p. 228-230° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8]C(C#N)=[C:4]([F:10])[CH:3]=1.Cl.[NH2:12][OH:13].CC[N:16]([CH2:19][CH3:20])CC>CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:20]([C:19](=[NH:16])[NH:12][OH:13])=[C:4]([F:10])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: NO
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CO
Product: N=C(NO)c1ccc(Cl)cc1F
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 77.7 %

Procedure:
To a solution of 4-chloro-2-fluorobenzonitrile 38 (400 g, 2.58 mol, 1.0 eq), hydroxylamine hydrochloride (448 g, 6.45 mol, 2.5 eq) in MeOH (1 L, 2.5 vol) was added Et3N (313 g, 3.1 mol, 1.2 eq), then the mixture was stirred at 60° C. for 40 min and checked by HPLC (no nitrile remaining) Reaction was then quenched by H2O (10 L), and lots of off-white solid was separated out, and then filtered, the filter cake was washed with water (10 L×2) and 378 g 4-chloro-2-fluoro-N-hydroxybenzimidamide 39 was obtained with 93% purity (Scheme 15).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1Cl.Cl.[NH2:13][C:14]1[CH:20]=[CH:19][C:17]([OH:18])=[CH:16][C:15]=1[OH:21].[OH-].[Na+].[CH2:24]1COCC1>CO.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:24]1[O:21][C:15]2[CH:16]=[C:17]([OH:18])[CH:19]=[CH:20][C:14]=2[N:13]=1
Reactant: Nc1ccc(O)cc1O
Reactant: C1CCOC1
Reactant: Clc1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Oc1ccc2nc(-c3ccc4ccccc4c3)oc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
20 g (104.9 mmol) of 2-naphthyl chloride and 2.5 g (15.5 mmol) of 4-aminoresorcinol hydrochloride were introduced into a three-necked flask provided with a thermometer and a cooling condenser, and the mixture was heated at 135° to 205° C. for 1 hour, then excessive acid chloride was removed by distillation. To the residue, 8.3 g (207.5 mmol) of NaOH, 60 ml of THF, 60 ml of water and 30 ml of methanol were added, and the mixture was stirred at room temperature for about 2 hours. The reaction solution was extracted with ethyl acetate, the extract was washed with saturated sodium chloride water solution, and ethyl acetate was distilled off. Recrystallizing the residue with water/methanol/THF and drying the crystal, there was obtained 1.92 mg (7.36 mmol) of 2-(2-naphthyl)-6-hydroxybenzoxazole. The yield was 47.5%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]([C:12](=[O:32])[NH:13][C@H:14]([B:19]1[O:27][C@H:26]2[C@:21]([CH3:31])([C@H:22]3[CH2:28][C@@H:24]([CH2:25]2)[C:23]3([CH3:30])[CH3:29])[O:20]1)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:9](C)C)([CH3:4])([CH3:3])[CH3:2].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]([C:12](=[O:32])[NH:13][C@H:14]([B:19]1[O:27][C@H:26]2[C@:21]([CH3:31])([C@H:22]3[CH2:28][C@@H:24]([CH2:25]2)[C:23]3([CH3:30])[CH3:29])[O:20]1)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH3:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1

Procedure:
The title compound is prepared as described for {(S)-2-Methyl-1-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-propyl}-carbamic acid tert-butyl ester (step 1.1, example 1) but using Boc-L-alanine (Fluka).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([C@:23]34[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:24]3[C@@H:25]3[C@@:38]([CH3:41])([CH2:39][CH2:40]4)[C@@:37]4([CH3:42])[C@@H:28]([C@:29]5([CH3:46])[C@@H:34]([CH2:35][CH2:36]4)[C:33]([CH3:44])([CH3:43])[C@@H:32]([OH:45])[CH2:31][CH2:30]5)[CH2:27][CH2:26]3)=[O:22])[CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CN=C(N)C=1C.[CH3:62][C:63]1([CH3:71])[CH2:68][C:67](=[O:69])[O:66][C:65](=[O:70])[CH2:64]1>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([C@:23]34[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:24]3[C@@H:25]3[C@@:38]([CH3:41])([CH2:39][CH2:40]4)[C@@:37]4([CH3:42])[C@@H:28]([C@:29]5([CH3:46])[C@@H:34]([CH2:35][CH2:36]4)[C:33]([CH3:44])([CH3:43])[C@@H:32]([O:45][C:67](=[O:69])[CH2:68][C:63]([CH3:71])([CH3:62])[CH2:64][C:65]([OH:70])=[O:66])[CH2:31][CH2:30]5)[CH2:27][CH2:26]3)=[O:22])[CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCC(Cc5ccccc5)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cc1ccnc(N)c1C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCC(Cc5ccccc5)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)CC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N-((1R,3S)-3-((4-benzylpiperidin-1-yl)methyl)cyclopentyl)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example 32, 0.5 g, 0.80 mmol) in pyridine (5 ml), dimethyl amino pyridine (0.2 g, 1.6 mmol) was added, followed by 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione (0.82 ml) was added. The contents were refluxed for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, water followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.80-0.95 (m, 17H); 1.14-1.67 (m, 23H); 1.82-2.02 (m, 15H); 2.23-3.50 (m, 15H); 4.21-4.45 (m, 2H); 4.57 (s, 1H); 4.72 (s, 1H); 6.28-6.30 (m, 1H); 7.11-7.13 (m, 2H); 7.14-7.22 (m, 1H); 7.24-7.29 (m, 2H); ES Mass: 841 (100%), [M+1].
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([NH2:15])=[CH:8][C:9]=2[C:10]([CH3:14])([CH3:13])[CH2:11][CH:12]=1)[CH3:2].Br[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>>[CH2:24]([O:23][C:21](=[O:22])[C:20]1[CH:26]=[CH:27][C:17]([NH:15][C:7]2[CH:6]=[CH:5][C:4]3[C:3]([CH2:1][CH3:2])=[CH:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]=3[CH:8]=2)=[CH:18][CH:19]=1)[CH3:25]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: CCC1=CCC(C)(C)c2cc(N)ccc21
Product: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)CC=C3CC)cc1

Procedure:
Following General Procedure L, 5-ethyl-8,8-dimethyl-7,8-dihydro-naphthalen-2-ylamine (Compound 72, 0.17 g, 0.85 mmol), was reacted with ethyl 4-bromobenzoate to give the title compound as a yellow solid.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:17]([OH:18])[C@H:16]([F:19])[C@@H:15]([CH2:20][OH:21])[O:14][C@H:5]1[O:6]CC1C=CC=CC=1)=[N+]=[N-].[C:22](OC(=O)C)(=[O:24])[CH3:23].[H][H]>CO.[Pd]>[C:22]([NH:1][C@H:4]1[C@@H:17]([OH:18])[C@H:16]([F:19])[C@@H:15]([CH2:20][OH:21])[O:14][CH:5]1[OH:6])(=[O:24])[CH3:23]
Reactant: [N-]=[N+]=N[C@@H]1[C@H](OCc2ccccc2)O[C@H](CO)[C@@H](F)[C@@H]1O
Reactant: [H][H]
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](F)[C@@H]1O
Temperature: 25 °C

Procedure:
Compound (23) (105 mg, 0.353 mmol) was dissolved in methanol (7 ml), acetic anhydride (333 μl, 3.53 mols) was added to the solution, a catalytic amount of 10% Pd/C was thereafter added to the mixture, and the resulting mixture was stirred at room temperature after replacing the atmosphere in the reactor with hydrogen. TLC indicated disappearance of the material 2 hours later, followed by filtration with activated carbon and concentration. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=5:1), giving Compound (24) (in an amount of 57 mg, 72% in yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:24][CH2:25][O:26][CH3:27].O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:24][CH2:25][O:26][CH3:27])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(c2cn(CCOC)c3ncccc23)CC1
Temperature: 25 °C

Procedure:
1.0 g (3.66 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylic acid ethyl ester were dissolved in 10 ml of DMF and, at room temperature, 0.19 g (4.76 mmol) of 60% sodium hydride were carefully added. This mixture was stirred for half an hour. 0.45 ml (5.12 mmol) of 1-bromo-2-methoxyethane were added dropwise and the mixture was further stirred for 24 hours at 60° C. The reaction mixture was cooled to room temperature and poured over cold water. The aqueous phase was extracted twice with dichloromethane and the organic phase was washed with water and brine, dried with magnesium sulphate, filtered and evaporated to dryness. This resulted in 0.86 g (71% of yield) of product.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([OH:24])[C@H:6]([OH:23])[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[N+]=[N-]>[Pd].CO>[NH2:1][CH2:4][C@H:5]([OH:24])[C@H:6]([OH:23])[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)CN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)CN
Yield: 95.5 %

Procedure:
The resultant compound from Example 8 (107 mg, 0.313 mmol) and 10% palladium on carbon (110 mg) in methanol (10 mL) were stirred under a hydrogen atmosphere for 18 hours. The mixture was filtered and evaporated to afford 94.6 mg (96%) of the desired compound, Mass spectrum: (M+H)+ =317.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C([O:8][C:9]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=1)(=O)C.[OH:16]S(O)(=O)=O.Cl[CH:22](Cl)[CH3:23]>>[C:22]([CH:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH2:14][C:9]1=[O:8])(=[O:16])[CH3:23]
Reactant: CC(=O)OC1=CC(=O)CCC1
Reactant: CC(Cl)Cl
Reactant: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)C1C(=O)CCCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
According to Scheme 4 Step 2: AlCl3 (26.5 mmol, 3.53 g) was added to a solution of 3-oxocyclohex-1-enyl acetate (13.2 mmol, 2.04 g) in dichloroethane (10 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured onto a solution of H2SO4 in ice. The aqueous phase was extracted with CHCl3 (50 mL). The organic phase was washed with water, dried over Na2SO4, was filtered and was concentrated to yield 2-acetylcyclohexane-1,3-dione (7.78 mmol, 1.20 g, 59%) as a yellow oil.
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].[CH3:16][O:17][CH2:18][CH2:19]Br>CN(C=O)C.CCOC(C)=O>[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:19][CH2:18][O:17][CH3:16])[C:6]1=[O:15]
Reactant: COCCBr
Reactant: NC1Cc2ccccc2NC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCN1C(=O)C(N)Cc2ccccc21
Yield: 77.7 %

Procedure:
Sodium hydride (60% in oil, 321 mg, 8.03 mmol) was added to 3-amino-3,4-dihydroquinolin-2(1H)-one hydrochloride (J. Med. Chem., 28, 1985; 1511–16; 759 mg, 3.82 mmol) in anhydrous DMF (10 mL) at 0° C. over a period of 5 min. After 1 hour 2-bromoethyl methyl ether (0.40 mL, 4.20 mmol) was added and stirring maintained for 18 hours. The reaction was diluted with EtOAc (100 mL) and washed with sat. aqueous K2CO3 (20 mL). The aqueous was extracted with DCM (3×50 mL) and the combined organics dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (DCM to DCM:MeOH (4:1)) to afford the title compound (654 mg, 78%) as a brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.Cl.[CH2:10]([O:12][NH2:13])[CH3:11]>CO>[CH2:10]([O:12][N:13]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:11]
Reactant: O=Cc1cccnc1
Reactant: CCON
Agent: Cl
Solvent: CO
Product: CCON=Cc1cccnc1
Yield: 87.9 %

Procedure:
3-Pyridinecarboxaldehyde (10.7 100 mmol) and ethoxyamine, hydrochloride (10 g, 102.5 mmol) were dissolved in CH3OH (100 ml) and heated at reflux for three hours. The solvent was removed under vacuum and 10% aqueous Na2CO3 solution was added to the residue until the solution remained basic. The aqueous solution was extracted with EtOAc (3×100 ml), dried over MgSO4, filtered, and the solvent removed under vacuum. 13.2 g of 3-pyridinecarboxaldehyde-O-ethyloxime as a clear liquid was obtained 88% yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].[Cl-:12].[Al+3].[Cl-].[Cl-].[CH3:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23]#[N:24].Cl>ClCCCl>[Cl:12][C:3]1[CH:2]=[C:10]([CH3:11])[CH:9]=[CH:8][C:4]=1[C:5]([C:21]1[N:17]([CH3:16])[C:18]([CH2:22][C:23]#[N:24])=[CH:19][CH:20]=1)=[O:6]
Reactant: Cc1ccc(C(=O)Cl)cc1Cl
Reactant: [Cl-]
Reactant: Cn1cccc1CC#N
Agent: Cl
Agent: [Al+3]
Solvent: ClCCCl
Product: Cc1ccc(C(=O)c2ccc(CC#N)n2C)c(Cl)c1
Temperature: 25 °C

Procedure:
21.4 grams (0.114 mole) of 3-chloro-4-methylbenzoylchloride is added to a suspension of 15.2 g. (0.114 mole) aluminum chloride in 50 ml. 1,2-dichloroethane. The resulting solution is added dropwise to a chilled solution of 13.7 g. (0.114 mole) of 1-methylpyrrole-2-acetonitrile in 50 ml. 1,2-dichloroethane. After the addition is complete, the mixture is stirred for ten minutes at room temperature, and then heated to reflux for three minutes. It is poured into ice acidified with dilute HCl. The organic phase is separated and washed consecutively with N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid and saturated sodium chloride solution. It is then dried over anhydrous magnesium sulfate, and the solvent evaporated off. A white solid, 5-(3'-chloro-p-toluoyl)-1-methylpyrrole-2-acetonitrile, precipitates from the resulting oily residue upon trituration with methanol which is purified by recrystallization from methanol, m.p. 116-118° C. Analysis: Calcd. for C15H13ClN2O: N, 10.26%. Found: N, 10.38%.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1Cl>CN1C(=O)CCC1>[Br:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[O:18][C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([NH:8][C@@H:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]3[OH:1])[S:10][C:11]=2[CH:17]=1
Reactant: Oc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Reactant: Clc1ccncc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Oc3ccncc3Br)cc2s1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To the reaction mixture of 2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (12.5 mg, 0.047 mmol) in 0.4 ml of NMP was added Cesium Carbonate (39 mg, 0.118 mmol) and stirred at RT for 1-3 minutes. To this mixture was added 3-bromo-4-chloropyridine (18.2 mg, 0.094 mmol). The reaction mixture was stirred at 90° C. for 4 hours or until done by LC. The crude reaction mixture was filtered, purified on prep HPLC and lyophilized to (1R,2R)-2-(6-(3-bromopyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol as TFA salt (9.2 mg). ES/MS m/z 420.1/422.0 (MH+).