Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[C:10]3[CH:16]=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)=[C:10]3[CH:16]=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(-c3cccc(F)c3)cnc3[nH]ccc23)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(-c2cnc3[nH]ccc3c2N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
tert-Butyl 4-(5-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.162 g, 0.409 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added dropwise to a stirring solution of 1M HCl in ether. The solid product was filtered, washed with ether, and dried to give 5-(3-fluorophenyl)-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.116 g, 95.8% yield) as the dihydrochloride salt.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][NH:6][C:7](=[O:36])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][CH2:21][C@H:22]([OH:35])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:24]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)C.[OH-].[Na+]>>[OH:35][C@H:22]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([NH:30][S:31]([CH3:34])(=[O:32])=[O:33])[CH:24]=1)[CH2:21][NH:20][CH:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][C:4]([OH:37])=[O:3])=[O:36])=[CH:13][CH:12]=2)[CH2:15][CH2:16]1
Reactant: CCOC(=O)CNC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(C(=O)NCC(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from ethyl [(4-{(4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)amino]acetate (which was obtained in Example 196) by sodium hydroxide hydrolysis as a white solid; mp>85° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.75–1.90 (m, 2 H), 2.55–2.90 (m, 5 H), 2.80 (s, 3 H), 3.49 (d, J=4.5 Hz, 2 H), 3.70–3.80 (m, 2 H), 4.43 (dd, J=7.9, 4.4 Hz, 1 H), 6.70 (d, J=7.4 Hz, 1 H), 6.81 (dd, J=7.4, 2.0 Hz, 1 H), 6.92 (d, J=8.9 Hz, 2 H), 7.12 (d, J=2.0 Hz, 1 H), 7.54 (t, J=4.5 Hz, 1 H), 7.64 (d, J=8.9 Hz, 2 H); MS (ES) m/z: 507.2 (MH+); HRMS Calcd. for C23H31N4O7S (MH+): 507.1908. Found: 507.1912.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([C:14]([O:16]CC)=[O:15])[N:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8][CH2:7]2.C1COCC1.O.[OH-].[Li+]>CO>[C:22]([O:21][C:19]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([CH2:3][O:2][CH3:1])[CH:5]=2)[CH:10]1[C:14]([OH:16])=[O:15])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)C1c2ccc(COC)cc2CCN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Temperature: 60 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of 1-ethyl 2-tert-butyl 6-(methoxymethyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (160 mg, 0.0.46 mmol) in a mixture of MeOH (5 mL), THF (5.00 mL) and water (5.00 mL) was added lithium hydroxide (65.8 mg, 2.75 mmol), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in water, and the solution was washed with ethyl acetate. The pH of the aqueous layer was adjusted to 3 with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2-(tert-butoxycarbonyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (148 mg, 0.461 mmol, 101%) as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[OH:19])[NH:15][C:12]2=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4]>[CH2:26]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:19])[NH:15][C:12]2=[CH:13][N:14]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: OC(c1ccccc1)c1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Product: O=C(c1ccccc1)c1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1

Procedure:
[5-(Dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl](phenyl)methanol (Example 54) was oxidized using manganese dioxide to provide [5-(dibenzylamino)-1 h-pyrrolo[2,3-c]pyridin-2-yl](phenyl)methanone following the procedure described for Example 139 using methylene chloride as a solvent. Trituration of the crude material with Et2O provided [5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl](phenyl)methanone (220 mg, 44%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ4.77 (4H, s), 6.69 (1H, s), 6.82 (1H, s), 7.19-7.27 (10H, m), 7.53-7.65 (3H, m), 7.92-7.95 (2H, m), 8.57 (1H, s); ESI MS m/z 418 [C28H23N3O+H]+; HPLC (Method A) >99% (AUC), tR=20.9 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C@H:13]1[C@:17]([CH3:22])([CH2:18][C:19]([OH:21])=[O:20])[C@@H:16]([OH:23])[CH2:15][CH2:14]1)[CH2:7][CH2:6]2.[CH3:24]OC(OC)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C@H:13]1[C@:17]([CH3:22])([CH2:18][C:19]([O:21][CH3:24])=[O:20])[C@@H:16]([OH:23])[CH2:15][CH2:14]1)[CH2:7][CH2:6]2
Reactant: COC(C)(C)OC
Reactant: COc1ccc2c(c1)CCC([C@@H]1CC[C@H](O)[C@@]1(C)CC(=O)O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)C[C@]1(C)[C@@H](O)CC[C@H]1C1CCc2cc(OC)ccc2C1

Procedure:
A solution of 2.19 g of (1S,2S,5S)-5-(1,2,3,4-tetrahydro-6-methoxy-2-naphthyl)-2-hydroxy-1-methylcyclo-pentaneacetic acid and 5 ml of 2,2-dimethoxypropane in 40 ml of methanol containing 0.05 g of p-toluenesulfonic acid monohydrate is refluxed for 18 hours. The resultant solution is partitioned between aqueous 5% sodium bicarbonate and ether. The ether phase is separated, dried over magnesium sulfate, and stripped of solvent by vacuum distillation. The residue is crystallized from a mixture of acetone and hexane to give methyl (1S,2S,5S)-5-(1,2,3,4-tetrahydro-6-methoxy-2-naphthyl)-2-hydroxy-1-methylcyclopentaneacetate melting at approximately 86°-87°.
Reaction SMILES: [Br:1][C:2]1[C:3](I)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([NH:15][O:16][CH3:17])=[O:14].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]([NH:15][O:16][CH3:17])=[O:14])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1cc(I)c(Br)cn1
Reactant: CONC(=O)c1ccccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1Br

Procedure:
A mixture of 5-bromo-2-chloro-4-iodo-pyridine (5 g, 15.72 mmole, 1 eq), 2-amino-N-methoxy-benzamide (2.61 g, 15.72 mmole, 1 eq) and K3PO4 (8.34 g, 39.3 mmole, 2.5 eq), and 1,4-dioxane (30 mL) was degassed with N2 for 1 h. To this was added DPEPhos (0.67 g, 1.25 mmole, 0.08 eq) and Pd(OAc)2 (0.07 g, 0.31 mmole, 0.02 eq) and this mixture was degassed again with N2 for 30 min. The resulting mixture was refluxed for overnight. After completion of reaction, solvent was removed under reduced pressure and residue was diluted with water (100 mL) and extracted with 5% MeOH-DCM (3×100 mL). Combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude compound. It was purified by column chromatography over silica gel (60-120 mesh) using 20% Ethyl acetate-hexane as the eluant to yield the title compound as off white solid (3.5 g, 62%). 1H-NMR (400 MHz, DMSO-d6): δ 3.56 (s, 3H), 6.88-6.98 (m, 1H), 7.08 (s, 1H), 7.17-7.25 (m, 1H), 7.26-7.35 (m, 1H), 7.82-7.90 (m, 1H), 8.23 (s, 1H), 12.86 (brs, 1H). LC-MS [M+H]+=356.30.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[CH3:8]>C(OCC)(=O)C.CO>[CH3:8][N:7]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)[CH2:6][CH2:5][O:4][C:3]1[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=1[CH3:1]
Reactant: Cc1ccccc1OCCN(C)CCc1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccccc1OCCN(C)CCc1ccc(N)cc1

Procedure:
The title compound is prepared as described in Example 7, except that N-[2-(2-methylphenoxy)ethyl]-N-methyl-2-(4-nitrophenyl)ethylamine (Example 3) is used as starting material to obtain a yield of 82% of the base (oil), Rf=0.35 (ethyl acetate/methanol=9:1).
Reaction SMILES: [OH-].[K+].[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6][NH:5]1.Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>O.CS(C)=O>[O:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[O:17][CH2:16][CH2:15][N:5]1[N:6]=[CH:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]1=[O:3]
Reactant: O=c1[nH]ncc2ccccc12
Reactant: BrCCOC1CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=c1c2ccccc2cnn1CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 41.5 g of potassium hydroxide in 53 ml of water is added at room temperature to a solution of 61 g of 1-oxophthalazine in 430 ml of dimethyl sulfoxide. After 30 minutes, 130 g of tetrahydro-2-pyranyl 2-bromoethyl ether are added to the suspension obtained. The mixture is left stirring for 30 hours at room temperature and then concentrated, the residue is taken up in 400 ml of water and the product is extracted with dichloromethane. The organic phase is concentrated.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]([OH:15])=O)[NH:10]2)=[CH:6][CH:5]=1)[CH3:3].[CH3:16][CH:17]([NH:19][C:20]1[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1)[CH3:18].C(N=C=NCCCN(C)C)C>>[CH3:18][CH:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([C:13]([C:9]2[NH:10][C:11]3[CH:12]=[C:4]([N:2]([CH3:1])[CH3:3])[CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:15])[CH2:30][CH2:31]1)[CH3:16]
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Reactant: CN(C)c1ccc2cc(C(=O)O)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2cc3ccc(N(C)C)cc3[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with 6-(N,N-dimethylamino)indole-2-carboxylic acid (PREPARATION 89, 0.40 g), 1-[3-(1-methylethylamino)-2-pyridinyl]piperazine (0.43 g) and 1-(ethyl)-3-(dimethylaminopropyl) carbodiimide (0.45 g), the title compound is obtained, mp 153°-154°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2([C:44]3[CH:49]=[CH:48][C:47]([OH:50])=[C:46]([N+:51]([O-])=O)[CH:45]=3)[C:23]3[CH:22]=[C:21]([C:24]45[CH2:33][CH:28]6[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]6)[CH2:25]4)[CH2:31]5)[CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][C:14]([C:34]24[CH2:43][CH:38]5[CH2:39][CH:40]([CH2:42][CH:36]([CH2:37]5)[CH2:35]2)[CH2:41]4)=[CH:15][CH:16]=3)[CH:7]=[CH:8][C:9]=1[OH:10])([O-])=O>[Pd].CN(C)C=O>[NH2:1][C:4]1[CH:5]=[C:6]([C:11]2([C:44]3[CH:49]=[CH:48][C:47]([OH:50])=[C:46]([NH2:51])[CH:45]=3)[C:23]3[CH:22]=[C:21]([C:24]45[CH2:31][CH:30]6[CH2:32][CH:26]([CH2:27][CH:28]([CH2:29]6)[CH2:33]4)[CH2:25]5)[CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][C:14]([C:34]24[CH2:43][CH:38]5[CH2:39][CH:40]([CH2:42][CH:36]([CH2:37]5)[CH2:35]2)[CH2:41]4)=[CH:15][CH:16]=3)[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: O=[N+]([O-])c1cc(C2(c3ccc(O)c([N+](=O)[O-])c3)c3cc(C45CC6CC(CC(C6)C4)C5)ccc3-c3ccc(C45CC6CC(CC(C6)C4)C5)cc32)ccc1O
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1cc(C2(c3ccc(O)c(N)c3)c3cc(C45CC6CC(CC(C6)C4)C5)ccc3-c3ccc(C45CC6CC(CC(C6)C4)C5)cc32)ccc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
Next, in a 300 mL recovery flask, 71.0 g of the obtained 9,9-bis(3-nitro-4-hydroxyphenyl)-2,7-di(1-adamantyl)-fluorene (0.10 mol), 0.318 g of 10% palladium-activated carbon (0.30 mmol), 273 mL of N,N-dimethylformamide and a stirrer were charged and agitated at 25° C. for 24 hours under a hydrogen atmosphere. A reaction solution was filtered and then added to 1 L of ion-exchange water. Solid precipitate was collected by filtration, then agitated in 1 L of ion-exchange water for one hour and dried under reduced pressure, thus obtaining 61.0 g of 9,9-bis(3-amino-4-hydroxy-phenyl)-2,7-di(1-adamantyl)-fluorene (0.094 mol; the yield was 94.0%).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.CN(C)C=O.C(Cl)(=O)C([Cl:21])=O>ClCCl>[CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]([Cl:21])=[O:12])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCN(C2CC2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CCN(C2CC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 1-cyclopropyl piperidine-4-carboxylic acid (10.0 grams, 48.6 mmol, obtained in above step) in dichloromethane (198 mL) cooled at 0° C. was added dry dimethyl formamide (2 mL) followed by drop wise addition of oxalyl chloride (12.5 mL, 145.8 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 1 hour. The volatiles were removed under reduced pressure and the crude 1-cyclopropyl piperidine-4-carbonyl chloride (11.0 grams). This crude product was used in the next reaction without purification.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12](Cl)(=[O:14])=[O:13])=[CH:4][CH:3]=[N:2]1.[OH-].[NH4+:17]>O1CCCC1>[O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12]([NH2:17])(=[O:14])=[O:13])=[CH:4][CH:3]=[N:2]1
Reactant: O=S(=O)(Cl)c1ccccc1-c1ccno1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1-c1ccno1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 37 g of 2-(isoxazol-5-yl)benzenesulfonyl chloride, prepared in Example 4, in 200 ml of tetrahydrofuran, was cooled in an ice-water bath while about 40 ml of concentrated aqueous ammonium hydroxide was added slowly at 10° to 30° C. The resulting suspension was stirred at room temperature for 4 hours, then the solvent was evaporated under reduced pressure. The residue was stirred in 150 ml of water for 0.5 hour, then filtered. The crude, wet solid was dissolved in tetrahydrofuran and dried over sodium sulfate. The solid was recrystallized from 2-propanol to give 20 g of the title compound; m.p. 132°-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl[C:29]1C=C2C(C3N=C(N[C@H]4CCNC4)C(F)=CN=3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.C(S(Cl)(=O)=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH2:26][CH3:29])(=[O:24])=[O:25])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCNC4)n3)c3cc(Cl)cnc32)cc1
Agent: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 49 %

Procedure:
According to the procedure for compound 398 using 50 mg (0.10 mmol) of 7c and ethanesulfonyl chloride (54 μl, 0.57 mmol) afforded 21.7 mg (49% yield) of 399, as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[N:8]/[OH:9].[Cl:10]N1C(=O)CCC1=O.O>CN(C)C=O>[OH:9][N:8]=[C:7]([Cl:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O/N=C/c1ccccn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(Cl)c1ccccn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a colorless, homogeneous solution of (E)-picolinaldehyde oxime (6.75 g, 55.3 mmol) in N,N-dimethylformamide (55 mL) at room temperature was added N-chlorosuccinimide (7.38 g, 55.3 mmol) portion-wise. After the addition of ˜⅕ of the NCS, the reaction mixture was immersed in an oil bath at 60° C., and the remaining NCS was added portion-wise over 1.5 h. After the addition was complete, the homogeneous reaction mixture was stirred for 60 min. at 60° C. and was then cooled to room temperature. Water (400 mL) was added, and the aqueous mixture was extracted with ether (3×200 mL). The organic layer was collected, washed with water (2×200 mL), washed with a saturated aqueous solution of brine (100 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded N-hydroxypicolinimidoyl chloride (6.45 g, 41.2 mmol, 75% yield) as a tan solid. The compound had an HPLC retention time=0.515 min.—Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=156.8. 1H NMR (400 MHz, CDCl3) δ ppm 7.37-7.43 (m, 1H), 7.80 (td, J=7.78, 1.76 Hz, 1H), 7.91-7.97 (m, 1H), 8.72 (d, J=4.02 Hz, 1H), and 9.85 (br. s., 1H).
Reaction SMILES: C([Mg]Cl)(C)C.[Si:6]([O:13][CH2:14][C:15]([O:17]CC)=O)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].Cl.[CH3:21][NH:22][O:23][CH3:24]>C1COCC1>[Si:6]([O:13][CH2:14][C:15]([N:22]([O:23][CH3:24])[CH3:21])=[O:17])([C:9]([CH3:10])([CH3:11])[CH3:12])([CH3:7])[CH3:8]
Reactant: CNOC
Reactant: CCOC(=O)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 79.7 %

Procedure:
2M Isopropylmagnesium chloride in THF (91.6 mL, 183 mmol) was added dropwise to ethyl 2-(tert-butyldimethylsilyloxy)acetate (10.0 g, 45.8 mmol) and N,O -dimethylhydroxylamine hydrochloride (9.38 g, 96.2 mmol) in THF (500 mL) cooled in ice. The mixture was stirred for 4.5 hours allowing to slowly warm to ambient temperature. The reaction mixture was quenched with aqueous NH4Cl and concentrated to 1/3 volume. The residue was diluted with water and extracted with EtOAc. The EtOAc was washed with brine, dried over MgSO4, filtered, and evaporated to yield 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (8.51 g, 36.5 mmol, 79.6% yield) as an oil.
Reaction SMILES: [O:1]1CCO[CH:2]1CC[C@H]1CC[C@H]([C@H]2CC[C@H](CO)CC2)CC1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1.C(Cl)Cl>[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([O:1][CH3:2])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: OC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 2.96 g of crude [trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]cyclohexyl]methanol in 20 ml of dry pyridine is treated at 0° C. with 2.1 g of p-toluenesulfonyl chloride. The mixture is stirred at room temperature for 15 hours, then diluted with 200 ml methylene chloride and washed several times with water. The organic phase is fried over magnesium sulfate, filtered and evaporated. Chromatographic purification of the resulting crude product on silica gel with ethyl acetate/petroleum ether (vol. 1:9) gives [trans-4-]trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]cyclohexyl]methyl p-toluenesulfonate.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[S:18][C:17]([CH2:19][CH2:20][CH3:21])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1)(=O)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.BrCC[N:36]1[CH:40]=[CH:39][CH:38]=[CH:37]1>ClCCl>[CH2:19]([C:17]1[S:18][C:9]2[C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH2:2][N:36]4[CH:40]=[CH:39][CH:38]=[CH:37]4)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:15])[C:10]=2[N:16]=1)[CH2:20][CH3:21]
Reactant: BrCCn1cccc1
Reactant: CCCc1nc2c(N)nc3cc(OC(C)=O)ccc3c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCc1nc2c(N)nc3cc(OCCn4cccc4)ccc3c2s1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
A mixture of 4-amino-2-propylthiazolo[4,5-c]quinolin-7-ol acetate (318 mg, 1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and DMF (20 mL) was stirred at 75° C. for 10 minutes. 1-(2-Bromoethyl)pyrrole (200 mg, 1.1 mmol) was added dropwise over a period of 10 minutes. After 3 hours an additional equivalent of cesium carbonate was added in a single portion followed by the dropwise addition of an equivalent of 1-(2-bromoethyl)pyrrole. The reaction mixture was stirred overnight and then an additional equivalent of both cesium carbonate and 1-(2-bromoethyl)pyrrole were added. After 1 hour the heat source was removed; the reaction mixture was diluted with water (250 mL), stirred for 1 hour, and then filtered. The isolated solid was rinsed with water and then dried to provide a brown powder. This material was dissolved in dichloromethane and then purified by HPFC eluting with a gradient of 0-15% CMA in chloroform over 1500 mL. The resulting solid was recrystallized from acetonitrile to provide 143 mg of 2-propyl-7-[2-(pyrrol-1-yl)ethoxy]thiazolo[4,5-c]quinolin-4-amine as an off-white solid, mp 158.0-160.0° C. MS (ESI) m/z 353 (M+H)+; Anal. calcd for C19H20N4OS: C, 64.75; H, 5.72; N, 15.90. Found C, 64.86; H, 5.38; N, 16.00.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([CH3:22])[NH:5][C:6](=[O:21])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:20])[CH:13]([CH3:19])[CH2:14][S:15]C(=O)C.[OH-].[K+]>>[SH:15][CH2:14][CH:13]([CH3:19])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([NH:5][C@@H:4]([C:3]([OH:23])=[O:2])[CH3:22])=[O:21])=[O:20]
Reactant: COC(=O)[C@@H](C)NC(=O)[C@@H]1CCCN1C(=O)C(C)CSC(C)=O
Agent: [K+]
Agent: [OH-]
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)N[C@H](C)C(=O)O
Reaction time: 2 h
Yield: 62.7 %

Procedure:
(S)-[3-(Acetylthio)-2-methyl 1-oxopropyl]-L-prolyl-D-alanine methyl ester (4 g) is taken into potassium hydroxide/aqueous methanol (3 g of potassium hydroxide in 14 ml of water and 70 ml of methanol) and the solution is kept at room temperature for 2 hours. The product (2.1 g) is isolated using the procedure described in Example 9.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@H:23]3[CH2:27][CH2:26][N:25]([CH3:28])[C:24]3=[O:29])[CH:21]=2)[C:15]([O:17]C)=[O:16])=[N:9][CH:10]=1)=[O:4].CO.[OH-].[Li+].O>C1COCC1>[CH3:1][N:2]([CH3:30])[C:3]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@H:23]3[CH2:27][CH2:26][N:25]([CH3:28])[C:24]3=[O:29])[CH:21]=2)[C:15]([OH:17])=[O:16])=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@H]2CCN(C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)c1cnc(Oc2cc(O[C@H]3CCN(C)C3=O)cc(C(=O)O)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
The methyl 3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 46) (772 mg, 1.86 mmol) was dissolved in THF (9 mL) and methanol (3 mL) and lithium hydroxide solution (1N, 2.2 mL) was added followed by water (25 mL). The resulting mixture was stirred for 1 hour at room temperature. The majority of the organic solvent was removed by distillation under reduced pressure. The remaining aqueous solution was extracted with ethyl acetate (10 mL) then acidified with 2N citric acid and re-extracted with ethyl acetate (5×25 mL), the combined organic extracts were washed with water (10 mL) and brine (20 mL), dried (MgSO4) and evaporated to afford the product (716 mg, 96%). 1H NMR δ (300 MHz, CDCl3) 2.13-2.27 (m, 1H), 2.55-2.69 (m, 1H), 2.96 (s, 3H), 3.17 (d, 6H), 3.35-3.58 (m, 2H), 4.98 (t, 1H), 7.10 (s, 1H), 7.45 (s, 1H), 7.63 (s, 1H), 8.36 (s, 1H), 8.53 (s, 1H); m/z 401 (M+H+).