Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[O:6][C:5]([C:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=O)[CH2:18][CH2:17]4)[S:11][CH:12]=2)([CH3:7])[CH2:4][O:3]1.Cl.[NH2:26][OH:27]>>[CH3:1][C:2]1([CH3:24])[O:6][C:5]([C:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)/[C:19](=[N:26]/[OH:27])/[CH2:18][CH2:17]4)[S:11][CH:12]=2)([CH3:7])[CH2:4][O:3]1
Reactant: CC1(C)OCC(C)(c2csc(Sc3ccc4c(c3)CCC4=O)c2)O1
Reactant: NO
Agent: Cl
Product: CC1(C)OCC(C)(c2csc(Sc3ccc4c(c3)CC/C4=N\O)c2)O1
Yield: 60 %

Procedure:
Using an analogous procedure to that described in Example 68, 5-[4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thien-2-ylthio]indan-1-one was reacted with hydroxylamine hydrochloride to give (E)-5-[4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thien-2-ylthio]indan-1-one oxime in 60% yield as a foam.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([OH:13])=[O:12].[OH-].[K+]>CCO>[O:10]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[CH:18][C:17]1[CH:20]=[CH:21][C:14]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=C1CCc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C=C2Cc3ccccc3C2=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To a suspension of indanone (2.00 g, 15.1 mmol) and 4-carboxybenzaldehyde (1.89 g, 12.6 mmol) in EtOH (10 ml) was added KOH (1.77 g, 31.5 mmol) at 0° C. The reaction mixture was stirred 30 min at 0° C. then at room temperature for 16 h. The solvent was evaporated and the residue was dissolved in water, acidified to pH 5 with HCl 1 M. The precipitate was filtered and rinsed with water to afford the title compound 273 (2.27 g, 57%) as a yellow solid. LPMS: 264.1 (Calc.); 265.0 (found).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=O)[CH3:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[NH4+:15].CO>[Ni].Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([NH2:15])[CH3:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc2c(c1)OCCO2
Reactant: [NH4+]
Agent: [Ni]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CC(N)c1ccc2c(c1)OCCO2
Yield: 66 %

Procedure:
A mixture of 1-(2,3-dihydro-1,4-benzodioxin-6-yl)acetaldehyde, oxime, (Preparation 5, 10.74 g, 0.0556 mole), and Raney nickel (1 mL) in ammonium hydroxide/methanol (20 mL/200 mL) was hydrogenated (H2, 50 psi) for 48 hours. The reaction mixture was filtered through Celite and the resultant filtrate was concentrated in vacuo. The residual oil obtained was diluted with HCl (1N). The aqueous layer was washed with EtOAc (1×250 mL). The aqueous layer was then made basic with NaOH (1N), and extracted with EtOAc (3×200 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the resultant filtrate was concentrated in vacuo to provide the title product (7.1 g, 66%) as a clear oil.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([NH2:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.CC(N=[C:38]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][NH:39]1)C1C=CC(CCC2C=CC=CC=2)=CC=1>>[ClH:1].[CH3:2][CH:3]([N:19]=[C:38]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][NH:39]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(N=C1CCCCCN1)c1ccc(CCc2ccccc2)cc1
Reactant: CC(N)c1ccccc1OCCc1ccccc1
Agent: Cl
Product: CC(N=C1CCCCCN1)c1ccccc1OCCc1ccccc1

Procedure:
Substituting this amine for the α-methyl-ρ-phenethylbenzylamine of Example IV results in the formation of hexahydro-2-[α-methyl-o-(2-phenylethoxy)benzylimino]azepine hydrochloride, having a M.P. of 189°-90° C. (dec.)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.[CH:21](=[O:25])[CH:22]([CH3:24])[CH3:23].O>O1CCCC1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]2[C:5]=1[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:22]([CH3:24])([CH3:23])[CH:21]2[OH:25])=[O:20]
Reactant: CC(C)C=O
Reactant: COC(=O)c1cc(F)ccc1N=Cc1cccc(Br)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(F)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2O
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a mixture of 2-{[1-(3-bromo-phenyl)-methylidene]-amino}-5-fluoro-benzoic acid methyl ester (50 g, 59.8 mmol) and ytterbium(III) triflate hydrate (3.7 g, 5.95 mmol) in dry tetrahydrofuran (30 mL) at 25° C. was added isobutyraldehyde (4.3 g, 59.5 mmol) and water (1.1 mL, 59.5 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-6-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (24.3 g, 100%) as a light yellow oil: LC/MS m/e calcd for C19H19BrFNO3 M+: 408.3, observed: 408.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[C:16]=2[C:17]#[N:18])[CH:13]=1.[BH4-].[Na+].O>CO>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:9][NH:10][C:11]2[N:12]([N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[C:16]=2[C:17]#[N:18])[CH:13]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2cc(-c3ccccc3N)cnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(c1ccccc1N)=C2
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a solution of 6-(2-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (320 mg, 0.79 mmol) in MeOH (20 mL) was added NaBH4 (86 mg, 2.28 mmol). The solution was stirred at it for 30 min then was poured into water (50 mL) and extracted with EA (50 mL×3). The organic combined layers were dried over Na2SO4 and concentrated to give the crude product (240 mg, 75%) as a yellow solid. MS (ESI, m/e) [M+1]+ 406.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11]([C:13]1(Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12].[Cl-].[Li+].CN(C)C=O>O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11]([C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1)=[O:12]
Reactant: COc1ccc(C(=O)C2(Br)CCCCC2)c(Cl)c1Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C2=CCCCC2)c(Cl)c1Cl

Procedure:
1-Bromocyclohexyl (2,3-dichloro-4-methoxyphenyl) ketone (47.3 g., 0.13 mole), lithium chloride (16.5 g., 0.39 mole) and dimethylformamide (200 ml.) are heated at 90°C. for two hours, then poured into water (1 l.) to give 36.5 g. of 1-cyclohexenyl (2,3-dichloro-4 -methoxyphenyl) ketone which melts at 126°-129°C. after drying at 60°C. under vacuum for 16 hours.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:39]([F:42])([F:41])[F:40])=[C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][O:26][CH:25]([CH2:28][C:29]([O:31]CC5C=CC=CC=5)=[O:30])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[O:8])[N:6]=1>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH3:1][C:2]1[O:3][C:4]([C:39]([F:42])([F:40])[F:41])=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH:22]4[CH2:27][O:26][CH:25]([CH2:28][C:29]([OH:31])=[O:30])[CH2:24][CH2:23]4)=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)=[O:8])[N:6]=1
Reactant: Cc1nc(C(=O)Nc2ccc(-c3ccc(C4CCC(CC(=O)OCc5ccccc5)OC4)cc3)cc2)c(C(F)(F)F)o1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1nc(C(=O)Nc2ccc(-c3ccc(C4CCC(CC(=O)O)OC4)cc3)cc2)c(C(F)(F)F)o1
Yield: 80 %

Procedure:
Benzyl 2-(5-(4′-(2-methyl-5-(trifluoromethyl)oxazole-4-carboxamido)-[1,1′-biphenyl]-4-yl)tetrahydro-2H-pyran-2-yl)acetate was dissolved in EtOAc and hydrogenated with 10% Pd(OH)2/C under H2 balloon for 30 min. The reaction mixture was filtered off to remove the catalyst and the filtrate was concentrated. The residue was purified by reverse HPLC (8 to 50% ACN-water (0.1% NH40H) with X-bridge C8 column) to give the title compound 93 mg (yield 80%) as a mixture of cis/trans isomer (ratio of 1:3). After chiral SFC separation (CL2-20×250 mm, isocratic 45% MeOH in CO2, 75% g/min flow, 220 nM UV) afforded the cis and trans enantiomes:
Reaction SMILES: [CH2:1]([O:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]CC3C=CC=CC=3)=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O1CCCC1>[Pd].CO>[CH2:1]([O:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOC(C)c1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCOC(C)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 76.6 %

Procedure:
1.03 g (2.8 mmol) of VII-15, 0.1 g of 5% Pd-C, 15 ml of tetrahydrofuran and 5 ml of methanol were mixed and the mixture was subjected to catalytic hydrogenation under normal pressure. When the hydrogen absorption reached 66 ml, the reaction was stopped and the catalyst was filtered away. The filtrate was concentrated and purified by column chromatography to obtain 0.76 g (98% yield) of (+)-4'-(1-octyloxyethyl)-4-biphenylcarboxylic acid. [α]D25 =+67.5° (c=1, CHCl3), m.p.=139°-140° C.
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl.N1C=CC=CC=1>[F:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([CH:6]3[CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:7]3)=[CH:13][CH:12]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(CCCF)cc1
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(CCCF)cc3)cc2)C1
Yield: 19.7 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (100 mg, 0.52 mmol) in CH2Cl2/pyridine 1:1 (12 ml) was treated with 4-(3-fluoro-propyl)-benzenesulfonyl chloride (161 mg, 0.68 mmol). Purification of the crude product by chromatography on reversed phase silica gel (H2O+0.1% acetic acid:CH3CN+0.1% acetic acid, 75:25) provided the title compound (40 mg, 20%) as a colourless gum.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH:10]=2)=[O:5])C.[NH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31]>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([NH:17][C:11]2[CH:10]=[C:9]3[C:14]([C:15]([OH:16])=[C:6]([C:4]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])[N:7]=[CH:8]3)=[CH:13][CH:12]=2)=[O:26])=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1ncc2cc(NC(=O)c3ccc(F)cc3)ccc2c1O
Reactant: NCCC(=O)O
Product: O=C(O)CCNC(=O)c1ncc2cc(NC(=O)c3ccc(F)cc3)ccc2c1O

Procedure:
3-{[7-(4-Fluoro-benzoylamino)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-propionic acid was prepared from 7-(4-Fluoro-benzoylamino)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester under conditions analogous to Example 116(b) using beta-alanine. MS ESI(−) m/e: 395.9953 (M−1).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]=1[OH:15])[CH:2]=[CH2:3].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:2]=[CH2:3]
Reactant: ClCc1ccccc1
Reactant: C=CCc1cccc(C2CCCC2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1cccc(C2CCCC2)c1OCc1ccccc1
Yield: 91.7 %

Procedure:
90 g (0.44 mol) of 2-allyl-6-cyclopentylphenol, 62 g (0.49 mol) of benzyl chloride and 124 g (0.9 mol) of potassium carbonate are heated under reflux in 800 ml of acetone for 70 h. The cooled reaction mixture is filtered, and the filtrate is concentrated. The residue is taken up in petroleum ether, and the solution is washed three times with 2N sodium hydroxide solution and then once each with water and saturated brine. The organic phase is dried over sodium sulfate and concentrated in vacuo. The residue is distilled in vacuo. 118 g (92% of theory) of 1-allyl-2-benzyloxy-3-cyclopentylbenzene are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:10](N(CC)CC)[CH3:11].C(OC(=O)C)(=O)C>ClCCl>[CH2:10]([NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:11]
Reactant: NCCN1CCCCC1
Reactant: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCNCCN1CCCCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 79 %

Procedure:
To a solution of 1-(2-aminoethyl)piperidine(5.01 g) in dichloromethane (100 ml) were added triethylamine(11 ml) and acetic anhydride(4.4 ml) and then the mixture was stirred at room temperature for 40 minutes. The reaction solution was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated under a vacuum. The residue was dropped into a suspension of lithium aluminium hydride (3.46 g) in tetrahydrofuran(100 ml). After being refluxed with heating for 1 hour, the reaction mixture was filtrated. The filtrate was concentrated, thereby yielding 4.43 g(79%) of 1-[2-(ethylamino)ethyl]piperidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[CH:11][C:10]([C:23]([O:25]CC)=[O:24])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)=[CH:11][C:10]([C:23]([OH:25])=[O:24])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2ccc(F)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2ccc(F)cc2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
4.50 g (11.9 mmol) of the compound of Example 37A are provided in 107 ml of 1,4-dioxane, 107 ml (214 mmol) of a 2N solution of lithium hydroxide in water are added, and the mixture is stirred at 70° C. for 2 h. The mixture is concentrated, a 2N aqueous hydrogen chloride solution is subsequently added to the residue until the pH is acidic, the mixture is extracted with dichloromethane, and the organic phase is dried over magnesium sulfate, filtered and concentrated. 4.11 g (99% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:15](=O)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][NH:18][CH3:19]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:14][CH:13]2[CH:15]([N:18]([CH3:19])[CH3:17])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C2CCC1CN(Cc1ccccc1)C2
Reactant: CNC
Solvent: ClCCl
Product: CN(C)C1C2CCC1CN(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of 3-benzyl-3-azabicyclo[3.2.1]octan-8-one (107 mg, 0.50 mmol) in DCM (2 ml) was added dimethylamine (2 ml, 1M in THF) and the resulting reaction mixture was stirred at room temperature for 1H. Na(AcO)3BH (316 mg, 1.49 mmol) was added and the reaction mixture was stirred at room temperature overnight. When TLC shows completion reaction mixture was diluted with DCM and washed with water and brine. Combined aqueous layers were backextracted with DCM. Combined organic layers were dried over Na2SO4, filtered, concentrated and purified by column chromatography which gave 3-benzyl-N,N-dimethyl-3-azabicyclo[3.2.1]octan-8-amine (80 mg) in 67% yield. 1H NMR (400 MHz, MeOD) δ ppm 7.47-7.23 (m, 5H) 3.86 (s, 2H) 2.88 (d, J=11.62 Hz, 2H) 2.72 (dd, J=12.38, 3.28 Hz, 2H) 2.52 (s, 7H) 2.35 (br. s., 2H) 1.90-1.73 (m, 4H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:9]1[C:10]([F:11])=[C:2]([Cl:1])[C:3]([F:12])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Product: O=C(O)c1cc([N+](=O)[O-])c(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An amount of 1 g of 3-chloro-2,4-difluorobenzoic acid is added to a mixture of 1 ml of fuming nitric acid and 1.3 ml of sulfuiric acid at 0° C. The suspension is then stirred at room temperature for 30 minutes and poured on ice. Filtration affords the desired product.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH3:32][N:33]1[CH:37]=[C:36](B(O)O)[C:35]([CH3:41])=[N:34]1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:36]3[C:35]([CH3:41])=[N:34][N:33]([CH3:32])[CH:37]=3)[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cc1nn(C)cc1B(O)O
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cc1nn(C)cc1-c1nc(C(=O)Nc2cnn(C)c2[C@@H]2CC[C@@H](N)[C@H](F)CO2)cs1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (1,3-dimethyl-1H-pyrazol-4-yl)boronic acid gave 241. 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.28 (s, 1H), 8.24 (s, 1H), 7.84 (s, 1H), 4.95-4.83 (m, 1H), 4.83-4.62 (m, 1H), 4.42-4.28 (m, 1H), 4.24-4.05 (m, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.48 (dd, J=17.3, 8.4 Hz, 1H), 2.47 (s, 3H), 2.15-2.06 (m, 1H), 1.87 (d, J=14.4 Hz, 4H). LCMS (ES+) m/z 434 (M+1).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:21]2[CH2:20][CH2:19][N:18]([CH3:22])[CH2:17][CH2:16][C:15]=2[C:14]([N+:23]([O-:25])=[O:24])=[CH:13][CH:12]=1>CN(C)C=O>[CH3:22][N:18]1[CH2:17][CH2:16][C:15]2[C:14]([N+:23]([O-:25])=[O:24])=[CH:13][CH:12]=[C:11]([S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:21]=2[CH2:20][CH2:19]1
Reactant: Sc1ccccc1
Reactant: CN1CCc2c(Cl)ccc([N+](=O)[O-])c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(Sc3ccccc3)ccc([N+](=O)[O-])c2CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 11.0 g. (0.1 mole) of thiophenol in 200 ml. of dimethylformamide at 0°-10° C., under an atmosphere of nitrogen, is added cautiously, in portions, 4.65 g. (0.11 mole) of a 57% dispersion of sodium hydride in mineral oil. The resulting solution is stirred for 15 minutes at 25° C. and then a solution of 24.1 g. (0.1 mole) of 6-chloro-3-methyl-9-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine in 50 ml. of dimethylformamide is added dropwise. The reaction mixture is heated at 100° C. for 2 hours, then it is cooled to 25° C. and poured into ice/water. The resulting solid is filtered, air-dried and recrystallized from ethyl acetate-hexane to give 3-methyl-9-nitro-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:23]([F:26])([F:25])[F:24])=[CH:11][C:12]=2[S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[Br:27]Br.C([O-])(=O)C.[Na+].O>C(O)(=O)C.BrBr>[Br:27][C:11]1[C:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)(=[O:14])=[O:15])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[NH:9][C:10]=1[C:23]([F:25])([F:24])[F:26]
Reactant: BrBr
Reactant: O=S(=O)(c1ccc(Cl)cc1)c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(Cl)cc1)c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-[(p-chlorophenyl)sulfonyl]-5-(trifluoromethyl)pyrrole (2.15 g, 5.12 mmol), bromine (0.29 mL, 5.63 mmol) and sodium acetate (0.46 g, 5.63 mmol) in acetic acid is stirred at room temperature for 4 hours, treated with additional bromine (3 drops), stirred overnight at room temperature and poured into water. The resultant aqueous mixture is filtered to obtain a solid. Flash column chromatography of the solid using silica gel and a 1:5 ethyl acetate/hexanes solution gives the title product as a white solid (1.88 g, mp >230° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([S:14]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:5]=[CH:4][C:3]1=2.[Li+].[OH-].CO>O1CCCC1>[CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([S:14]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=3)(=[O:16])=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(S(=O)(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(S(=O)(=O)c3ccc(C(=O)O)cc3)ccc21
Temperature: 55 °C
Yield: 93.4 %

Procedure:
To a solution of 95 mg (0.23 mmol) of ethyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylsulfonyl)benzoate (Compound 4) in 4.0 mL of tetrahydrofuran was added 1.0 mL of LiOH (2.6N aqueous solution) and 1.4 mL of MeOH. The solution was heated at 55° C. for 2.5 h, cooled to room temperature and concentrated in vacuo. The residue was diluted with brine, acidified to pH=1 using 10% HCl and extracted with ether (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and the solvents were removed in vacuo to give the title compound as a white solid (80 mg, 91%):
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:50](C)=O.[Na+]>ClC(Cl)C>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH3:50])[CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=3)(=[O:33])=[O:34])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCN(C)CC5)nc4)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To the solution of 3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.16 mmol) and paraformaldehyde (10 mg, 0.32 mmol) in dichloroethane was added Na(OAc)3BH (68 mg, 0.32 mmol) and stirred at RT overnight. Distilled off the solvent to get 95 mg (95.0% yield) of the titled compound after purification by column (Silica gel 60/120) using 5% methanol in dichloromethane as eluent. MS: m/z=640.2 (M+1).