Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[CH2:8]([S:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[C:18]([Cl:23])[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>CN(C=O)C.CCOC(C)=O>[CH2:8]([S:15][C:16]1[N:21]=[C:20]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:19]=[C:18]([Cl:23])[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1cc(Cl)nc(SCc2ccccc2)n1
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc(Cl)nc(SCc2ccccc2)n1
Reaction time: 1 h

Procedure:
To methane sulphonamide (1.47 g) in DMF (30 ml) was added 60% sodium hydride (0.59 g) at room temperature and stirred for 1 h. To this mixture was then added the subtitle product of step ii) and the mixture stirred at room temperature for 6 h. To the reaction mixture was added EtOAc (50 ml) and aqueous hydrochloric acid (50 ml, 1M). The organic layer was separated and washed with brine (20 ml), combined, dried (MgSO4) and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (20 to 50% EtOAc/iso-hexane) to afford the subtitle compound as a yellow oil. Yield: 1.60 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:10][C:11]1[CH:12]=[C:13]2[C:18]3=[C:19]([CH2:21][CH2:22][N:17]3[CH2:16][C@@H:15]3[CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][C@H:14]23)[CH:20]=1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH3:9])=[CH:3][C:2]=1[NH:10][C:11]1[CH:12]=[C:13]2[C:18]3=[C:19]([CH2:21][CH2:22][N:17]3[CH2:16][C@@H:15]3[CH2:23][NH:24][CH2:25][C@H:14]23)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCc4cc(N)cc(c43)[C@H]2C1
Reactant: Cc1ccc(Cl)c(Br)c1
Product: Cc1ccc(Cl)c(Nc2cc3c4c(c2)[C@H]2CNC[C@H]2CN4CC3)c1

Procedure:
Using 3-bromo-4-chlorotoluene and following the procedures described in EXAMPLE 17, Parts B and C, (±)-cis tert-butyl 2-amino-4,5,7a,8,10,10a-hexahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline-9(7H)-carboxylate was converted into (±)-cis-N-(2-chloro-5-methylphenyl)-4,5,7,7a,8,9,10,10a-octahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinolin-2-amine, bis-trifluoroacetic acid salt, after HPLC purification (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA). This material was free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to the title compound of EXAMPLE 117 as the free base. 1H NMR (CDCl3) δ: 7.18 (d, 1H, J=8.0 Hz), 6.91 (s, 1H), 6.71 (app s, 2H), 6.52 (dd, 1H, J=8.0, 1.4 Hz), 5.83 (s, 1H), 3.79 (dd, 1H, J=11.4, 8.1 Hz), 3.63 (dd, 1H, J=11.5, 7.1 Hz), 3.54 (q, 1H, J=7.5 Hz), 3.37-3.22 (m, 3H), 3.15 (dd, 1H, J=11.3, 8.4 Hz), 3.08-2.92 (m, 4H), 2.85 (dd, 1H, J=10.4, 7.5 Hz). LRMS (ES)+: 340.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13](=O)[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH3:16][C:17]([S@:20]([NH:22][CH:13]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[C:2]([CH3:1])[CH:3]=1)[CH3:14])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OC(F)(F)F)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)ccc1OC(F)(F)F
Yield: 66 %

Procedure:
The title compound is prepared in 66% yield (971 mg, colorless oil) from 1-(3-methyl-4-(trifluoromethoxy)phenyl)ethanone (1.00 g, 4.58 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide (833 mg, 6.88 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1.I([O-])(=O)(=O)=[O:32].[Na+]>CO>[CH3:1][S:2]([C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1)=[O:32]
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(SC)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(C)=O)c1
Reaction time: 1.5 h

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-methylsulfanyl-pyridin-4-yl)-propyl]-amide (0.10 mg, 0.24 mmol) in MeOH (5 mL) was added an aqueous solution of sodium periodate (51 mg, 0.24 mmol). After 1.5 hours, a solid precipitated and additional MeOH (3 mL) was added. After 5 days, mixture was concentrated and partitioned between water (5 mL) and EtOAc (50 mL). The organic phase was separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by reversed-phase HPLC (Sunfire PrepC18 OBD 5 mM 30×150 mm column) eluting with a gradient of 15-75% acetonitrile in water (0.1% TFA). The fractions from the column were concentrated to remove acetonitrile, made basic with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated to afford the title compound as a white solid.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>C(O)C>[N:20]1([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7](=[O:15])[C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:31][CH2:30]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C(CCN1CCCC1)CC1CCNCC1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Solvent: CCO
Product: O=C1Nc2ccccc2N(C(=O)N2CCC(CCCCN3CCCC3)CC2)c2ncccc21
Yield: 72 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 4-[4-(1-pyrrolidinyl)butyl]piperidine in a yield of 72% of theory. Colourless crystals, m.p. 193°-195° C. (ethanol).
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[CH2:21]([N:23]([CH2:37][CH3:38])[C:24](=[O:36])[NH:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)[CH3:22]>>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:32]([C:29]2[CH:28]=[CH:27][C:26]([NH:25][C:24]([N:23]([CH2:37][CH3:38])[CH2:21][CH3:22])=[O:36])=[CH:31][CH:30]=2)(=[O:34])=[O:33])[C:3]1=[O:12]
Reactant: COc1ccccc1C1(N)C(=O)Nc2ccc(Cl)cc21
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3OC)c3cc(Cl)ccc32)cc1

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 0.266 g of 3-amino-5-chloro-1,3-dihydro-3-(2-methoxyphenyl)indol-2-one and 0.280 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride. The expected product is obtained after crystallization from a DCM/iso ether mixture. m=0.160 g. M.p.=214°-217° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[C:21]1([CH2:27][CH2:28][NH2:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=1>>[C:21]1([CH2:27][CH2:28][NH:29][C:2]2[N:3]=[C:4]([NH2:20])[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NCCC1=CCCCC1
Product: Nc1nc(NCCC2=CCCCC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 140 °C
Reaction time: 6 h

Procedure:
A mixture of 2-chloroadenosine (0.30 g) and 2-(1-cyclohexenyl)-ethylamine (0.63 g) is stirred under nitrogen for 6 hours at 140° C. The solution is concentrated to dryness at reduced pressure; the residue is dissolved in ethanol, treated with propylene oxide (2 ml) and stirred at room temperature for 16 hours. The mixture is concentrated to dryness at reduced pressure and flash chromatographed through a 25×150 mm column of silica gel using methylene chloride and methanol saturated with ammonia (9:1) as eluent. Fractions containing the desired product are combined, concentrated to dryness at reduced pressure; the residue is redissolved in hot ethanol, the solution is decolorized with charcoal and then concentrated to dryness. The residual solid is triturated with ethanol (2 ml) and collected to afford 2-[2-(1-cyclohexenyl)-ethylamino]adenosine, m.p. 135°-38°.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]([O:19][C:20](=[O:31])[NH:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1)([CH3:18])([CH3:17])[CH3:16].C([O-])(O)=O.[Na+]>CC(O)C>[C:15]([O:19][C:20](=[O:31])[NH:21][CH2:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][NH:30][C:2]2[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:27][CH2:28]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CN)CC1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CN(C)c1nc(NC[C@H]2CC[C@H](CNC(=O)OC(C)(C)C)CC2)nc2ccccc12

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine (15.2 g, 73.3 mmol) and trans-(4-aminomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (14.8 g, 61.0 mmol) in 2-propanol (80 mL) was stirred at reflux for 4 days, poured into saturated aqueous NaHCO3, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 33% EtOAc in hexane) to give trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-carbamic acid tert-butyl ester (20.4 g, 81%) as a pale yellow solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:21]2[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=2[C:23](N(CC)CC)=O)=[C:16]([CH3:43])[CH:15]=1.C1C[O:47]CC1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]2[N:20]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[C:21]3[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=3[CH2:23][C:43](=[O:47])[C:16]=2[CH:15]=1
Reactant: C1CCOC1
Reactant: CCN(CC)C(=O)c1ccccc1N(Cc1ccc(OC)cc1)c1ccc(Cl)cc1C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: COc1ccc(CN2c3ccccc3CC(=O)c3cc(Cl)ccc32)cc1
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
To a mixture of diisopropylamine (1.09 mL, 7.8 mmol) and N,N,N,N-tetramethylenediamine (1.17 mL, 7.8 mmol) in dry THF (19 mL) at −20° C. was added n-BuLi (5.54 mL, 1.4 M in hexane) and the resulting mixture was stirred at −20° C. for 5 minutes. Then a mixture of 2[(4-chloro-2-methylphenyl>(4-methoxybenzyl)-amino]-N,N-diethylbenzamide (189JO26) (1.36 g, 3.1 mmol) in dry THF (38 mL) was added and the resulting mixture was stirred at −20° for 4 h. The reaction was quenched by addition of saturated aqueous NH4Cl-solution. The mixture was diluted with EtOAc, washed with water, dried (Na2SO4), concentrated, and flash chromatographed (SiO2, toluene:heptane, 7:1-1:0) to give 665 mg (59%) of the title compound (189JO27). 1H NMR (CDCl3) δ 8.15 (dd, 1 H, J=1.8, 8.0 Hz), 7.43 (m, 1 H), 7.24 (m, 4 H), 7.17 (d, 1 H, J=8.6 Hz), 7.12 (dd, 1 H, J=2.4, 8.6 Hz), 7.00 (dt, 1 H, J=0.8, 7.0 Hz), 6.81 (m, 2 H), 5.09 (s, 2 H), 4.00 (s, 2 H), 3.75 (s, 3 H); 13C NMR (CDCl3) δ 190.3, 159.1, 149.5, 146.2, 134.1, 132.4, 131.3, 131.1, 129.1, 129.0, 128.6, 127.3, 126.4, 123.4, 121.0, 118.5, 114.2, 55.5, 19.3. MS (ESI) 364 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[C:7]([CH:18]2[O:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:39])(=O)=O)=CC=1.[NH4+].[Cl-]>C1COCC1.CCCCCC>[C:1]([C:5]1[CH:10]=[C:9]([F:39])[C:8]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[C:7]([CH:18]2[O:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)COC(c2ccc(C(C)(C)C)cc2C2OCCCO2)=N1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)COC(c2c(F)cc(C(C)(C)C)cc2C2OCCCO2)=N1
Temperature: -17 °C
Reaction time: 3 h
Yield: 33.1 %

Procedure:
To a solution of 101e (20 g, 63 mmol) in anhydrous THF (400 mL) was added 2.4 M solution of n-butyllithium in hexane (65 mL) at −78° C. under N2 atmosphere. The clear yellow solution was stirred at −17° C. for 3 hr, when it showed a deep red-orange color. The reaction solution was re-cooled to −78° C., stirred rapidly and a solution of N-fluorobenzenesulfonimide (29 g, 92 mmol) in anhydrous THF (100 mL) was added in dropwise over 10 min. The reaction mixture was stirred at −78° C. for 5 min, −20° C. for 30 min, then room temperature for 1 h. The reaction mixture was poured into 150 mL of 50% aqueous NH4Cl and extracted with 300 mL of EtOAc. The separated organic phase was washed with 150 mL of water and 150 mL of brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a residue which was purified by silica gel chromatography using EtOAc/CH2Cl2=1:5 as eluent to afford 101f (7 g, 33%) as yellow solid. LCMS (ESI) m/z 336 (M+H)+. 1HNMR (300 MHz, CDCl3) δ 7.53 (d, J=1.6 Hz, 1H), 7.08 (dd, J=2.0, 12.0 Hz, 1H), 5.90 (s, 1H), 4.24 (dd, J=5.2, 10.8 Hz, 2H), 4.06 (s, 2H), 3.98-3.91 (m, 2H), 2.26-2.19 (m, 1H), 1.45-1.42 (m, 1H), 1.42 (s, 6H), 1.30 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>CO.O>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
Methyl 8-[(4,5-diphenyl-2-oxazolyl)thio]octanoate (2.0 g, 4.9 mol) was dissolved in methanol (30 mL). A solution of lithium hydroxide monohydrate (0.41 g, 9.8 mmol) in water (8 mL) was added and the mixture heated to reflux for 1 hour. After cooling to room temperature, the methanol was removed in vacuo, the residue diluted with water and acidified to about pH 2 using dilute hydrochloric acid solution. The mixture was extracted with EtOAc, the combined extracts dried over MgSO4 and concentrated. The residue was chromatographed on a column of silica gel using CH2Cl2 /MeOH (95/5) as eluent to give 8-[(4,5-diphenyl-2-oxazolyl)thio]octanoic acid (1.70 g, 88%).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>O.C(O)C>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:2][OH:3])=[CH:14][CH:13]=1
Reactant: NO
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(-c2ccccn2)cc1
Temperature: 80 °C
Yield: 57.5 %

Procedure:
Add hydroxylamine hydrochloride (0.379 g, 5.458 mmol) and a solution of NaOH (0.327 g, 8.187 mmol) in water (2 mL) to a solution of 4-(2-pyridyl)-benzaldehyde (0.5 g, 2.729 mmol) in ethanol (10 mL). Heat the mixture at 80° C. for 2 h. Cool to ambient temperature and remove the solvent in vacuo. Partition the residue between EtOAc and water. Separate and day the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 4:1) to obtain the desired intermediate (311 mg, 58%). GC-MS m/z: 198 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH2:11])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CCC(=O)Cl
Reactant: NC1(c2ccc(Br)cc2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)NC1(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 79.2 %

Procedure:
To a solution of 1-(4-bromophenyl)-cyclopropylamine (Intermediate 116, 84 mg, 0.4 mmol) in 4 mL CH2Cl2 at room temperature was added propionyl chloride (43.0 mg, 0.47 mmol) and pyridine (56.0 mg, 0.71 mmol). After stirring 17 hours at room temperature the reaction was quenched by the addition of H2O and extracted with EtOAc. The combined extracts were washed with 10% aqueous HCl, saturated aqueous NaHCO3, and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound 85.0 mg (67%), was isolated by column chromatography (20-50% EtOAc-hexanes) as a colorless solid.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12]1[S:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)=[N:15][N:16]=1)C1C=CC=CC=1>Br.C(O)(=O)C.C(OCC)C>[NH2:10][CH2:11][C:12]1[S:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[N:15][N:16]=1
Reactant: O=C(NCc1nnc(-c2ccc(OCc3ccccc3)cc2)s1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: NCc1nnc(-c2ccc(O)cc2)s1

Procedure:
A solution of benzyl((5-(4-(benzyloxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)carbamate (7.4 g, 17.1 mmol) in 33% HBr in acetic acid (100 mL) and was stirred for 2 h. The resulting mixture was diluted with diethyl ether and the precipitate was collected and washed with diethyl ether to yield 4-(5-(aminomethyl)-1,3,4-thiadiazol-2-yl)phenol (MS m/z=408 MH+).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[O:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[CH:36]=[C:35]1[CH:43]=O.C([O-])(O)=O.[Na+]>ClCCl>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([N:28]([CH2:43][C:35]2[O:34][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[CH:36]=2)[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=Cc1cc2ccccc2o1
Reactant: CC(C)CCNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CCN(Cc1cc2ccccc2o1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.4 %

Procedure:
Sodium triacetoxyborohydride (0.88 g, 4.16 mmol) is added to a stirred solution of 4-(3-methyl-butylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.75 g, 2.77 mmol), benzofuran-2-carboxaldehyde (0.50 g, 3.46 mmol), and dichloromethane (14 ml). The reaction is stirred overnight at room temperature under nitrogen. The reaction is poured into aqueous saturated NaHCO3 (50 ml) and extracted with dichloromethane (25 ml×3). The organic layer is washed with aqueous saturated NaHCO3 and dried over Na2SO4, and filtered. The crude product is concentrated on a rotary evaporator and purified by flash chromatography on silica gel eluting with 0-30% (1:2 (10% NH4OH in methanol):ethanol) to yield (1.17 g) of 4-{[(benzofuran-2-yl)methyl]-(3-methylbutyl)-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=401 (M+1); 1H NMR (CDCl3): δ=7.57-7.41 (2H, m), 7.30-7.16 (2H, m), 6.55 (1H, s), 4.15 (2H, brs), 3.81 (2H, s), 2.75-2.56 (6H, m), 1.80 (2H, brd), 1.63-1.53 (3H, m), 1.46 (9H, s), 1.42-1.33 (1H, m), 0.92-0.85 (6H, m).
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:10]([NH:12]CC)[CH3:11].C(O)(=O)C.[OH-].[Na+]>C(Cl)Cl>[CH:1]1([CH2:7][NH:12][CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCCCC1
Reactant: CCNCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNCC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
Cyclohexanecarboxaldehyde (38 g), diethylamine hydrochloride (55 g) and acetic acid (29 ml) are dissolved in methylene chloride (500 ml) and thereto is added triacetoxy sodium borohydride (71.8 g) at room temperature and the mixture is stirred at room temperature overnight. To the reaction solution are added a 2N-aqueous sodium hydroxide solution and methylene chloride, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and the mixture is concentrated under reduced pressure to give cyclohexylmethyl-ethyl-amine (40.1 g) as a crude product. MS (m/z): 142 [M+H]+
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[Na+].CO>[Pd].C(OCC)(=O)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reaction time: 15 h
Yield: 77.1 %

Procedure:
A mixture of 208 mg of 1-Bromo-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (0.5 mmol), 49 mg of sodium acetate (0.6 mmol), 50 mg of 10 wt % palladium on charcoal, 10 ml of methanol, and 5 ml of ethyl acetate was stirred under hydrogen at 1 atm for 15 h. Then the mixture was filtered by suction through a pad of celite and was concentrated in vacuo. The residue was partitioned between 2 ml of half concentrated aqueous bicarbonate solution and 8 ml of ethyl acetate. The organic phase was dried over MgSO4. Evaporation in vacuo gave 130 mg of the title compound; 1H NMR (CDCl3): δ=11.89 (bs, 1H), 8.61 (s, 1H), 8.36 (d, 1H), 7.10 to 7.53 (m, 7H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]([F:24])([F:23])[F:22])=[CH:11][C:12]=2[S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[OH:25]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([C:21]([F:23])([F:22])[F:24])=[CH:11][C:12]=2[S:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:25])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cc(Sc2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: O=S(c1ccc(Cl)cc1)c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Yield: 65.6 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-[(p-chlorophenyl)thio]-5-(trifluoromethyl)pyrrole (2.57 g, 6.6 mmol) and 30% hydrogen peroxide solution (0.83 g, 7.3 mmol) in acetic acid is stirred at room temperature overnight and poured into water. The resultant aqueous mixture is filtered to obtain a solid. A solution of the solid in methylene chloride is washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and a 1:3 ethyl acetate/hexanes solution gives the title product as a white solid (1.75 g, mp 174°-176° C.)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2]
Reactant: [H][H]
Reactant: CCCCCC(C(=O)OCC)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCC(C(=O)OCC)c1cccc(N)c1
Yield: 97.5 %

Procedure:
A solution of 2-(3-nitro-phenyl)-heptanoic acid ethyl ester (4.451 g, 15.9 mmole) in 150 mL of ethyl acetate containing 1.69 g of 10% palladium on carbon was subjected to atmospheric pressure of hydrogen for 15 hours. The mixture was filtered through a Celite/SiO2 pad and the volatiles were removed in vacuo to yield 3.866 g of 2-(3-amino-phenyl)-heptanoic acid ethyl ester as a pale yellow oil.