Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1.Cl>ClCCl.C(OCC)(=O)C>[CH2:15]([NH:22][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C1Cc2cc(S(=O)(=O)NCc3ccccc3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
A suspension of 5-chlorosulfonyl-2-oxindole (1.62 g, 7 mmol), benzylamine (0.918 mL, 8.4 mmol) and pyridine (1 mL) in dichloromethane (20 mL) was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate (300 mL) and acidified with 1 N hydrochloric acid (16 mL). The organic layer was then washed with sodium bicarbonate and brine, dried and concentrated. The residue was washed with ethanol (3 mL) and was then purified by chromatography on silica gel eluting with methanol:dichloromethane 1:9 to give 1.4 g (66%) of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid benzylamide.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]([S:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:5]3[CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1.C[Mg+].[Br-].[Li]C(CC)C.[CH:35](=[O:39])[CH:36]([CH3:38])[CH3:37]>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([S:19][C:4]2[C:3]3[C:2]([CH:35]([OH:39])[CH:36]([CH3:38])[CH3:37])=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[N:6]3[CH2:12][CH2:13][CH:14]([CH2:15][C:16]([OH:18])=[O:17])[C:5]=23)=[CH:21][CH:22]=1
Reactant: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Reactant: CC(C)C=O
Agent: C[Mg+]
Agent: [Br-]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)C(O)c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of (+/−)-[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetic acid (Example 7, 100 mg, 0.22 mmol) in THF (4 mL) at −78° C. was added 3M MeMgBr (0.26 mmol) followed by the addition of 1.3M sec-BuLi (0.31 mmol). The reaction mixture was stirred at −78° C. for 20 minutes and an excess of isobutyraldehyde was added. The reaction mixture was slowly warmed to −20° C. over a 30 minute period and quenched with saturated aqueous NH4Cl. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC using a Zorbax column eluted with 10% iPrOH in Hexanes containing 0.2% of AcOH to provide 40 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3](=[O:21])[CH2:4][S:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][CH:9]=1)[CH3:7].[OH:23]O.C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:22][N:2]([CH3:1])[C:3](=[O:21])[CH2:4][S:5]([CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][CH:9]=1)[CH3:7])=[O:23]
Reactant: CC(SCC(=O)N(C)C)c1ccc(-c2ccccc2F)cc1
Reactant: OO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)N(C)C
Yield: 57 %

Procedure:
The difficultly soluble isomer of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid dimethylamide was prepared analogous to Example 51 from [1-(2'-fluoro-4 -biphenylyl)-ethylthio]-acetic acid dimethylamide by oxidation with hydrogen peroxide in glacial acetic acid. Yield: 57% of theory; m.p. 131°-133° C (from toluene)
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].NO.[O:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21]C)=O)[CH:17]=2)[CH:12]=[CH:11][NH:10]1.C(O)(=O)C>CO>[OH:3][NH:2][C:19]([C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[CH:11][NH:10][C:9]2=[O:8])=[CH:14][CH:15]=1)=[O:21]
Reactant: NO
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NO)c1ccc2cc[nH]c(=O)c2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
A mixture of hydroxylamine hydrochloride (2.0 g, 29 mmol) in methanol (10 mL) was heated at 90° C. under a dry nitrogen atmosphere until homogeneous. To this heated solution was added a solution of potassium hydroxide (2.85 g, 50.8 mmol) in methanol (6 mL). A precipitate formed on mixing. After heating at 90° C. for 30 minutes, the mixture was cooled to rt and the solids were allowed to settle. The resulting solution was assumed to contain 1.7 M hydroxylamine.potassium salt and was carefully removed by syringe to exclude solids. An aliquot of the above solution (1.0 mL, 1.7 mmol) was added to a solution of methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (32.5 mg, 0.16 mmol) in methanol (1 mL). After stirring for 1 h at rt, excess reagent was quenched by the addition of acetic acid (0.20 mL, 3.52 mmol). The mixture was concentrated to dryness and the residue was twice co-evaporated with toluene. The crude product was purified by preparative HPLC to afford N-hydroxy-1-oxo-1,2-dihydroisoquinoline-7-carboxamide (12 mg, 37%). LC-MS: (FA) ES+ 205; 1H NMR (300 MHz, MeOD) δ 8.67 (d, J=1.5 Hz, 1H), 8.06 (dd, J=8.3, 1.9 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.26 (d, J=7.1 Hz, 1H), 6.70 (d, J=7.3 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.CO[C:28](OC)([N:30]([CH3:32])[CH3:31])[CH3:29]>CN(C)C=O>[CH3:31][N:30]([CH3:32])[CH:28]([N:1]=[C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=2)[S:3]1)[CH3:29]
Reactant: COC(C)(OC)N(C)C
Reactant: Nc1nc(-c2ccccc2)c(-c2ccnc(Nc3ccccc3)n2)s1
Solvent: CN(C)C=O
Product: CC(N=c1[nH]c(-c2ccccc2)c(-c2ccnc(Nc3ccccc3)n2)s1)N(C)C
Temperature: 140 °C

Procedure:
A suspension of [4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-phenyl-amine (0.28 g, 0.81 mmol) in dimethylacetamide dimethylacetal (0.22 g, 1.62 mmol) and dimethylformamide (10 ml) is heated at 140° C. for 4 hours. After distilling off all volatile compounds the residue is purified by chromatography on silicagel (eluent: ethyl acetate/hexane) to give in form of a yellow powder, m.p. 196–197° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=2[CH:12]=[N:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:2]1.CC(C)([O-])C.[K+].[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1>O1CCCC1.O>[C:15]1([C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:13][CH:12]([CH2:42][C:41]2[CH:44]=[CH:45][C:38]([F:37])=[CH:39][CH:40]=2)[C:11]2[CH:27]=[CH:28][CH:29]=[CH:30][C:10]=2[C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:1][N:2]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: C(=NC(c1ccccc1)c1ccccc1)c1ccccc1-c1noc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(CC(N=C(c2ccccc2)c2ccccc2)c2ccccc2-c2noc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of 2.23 g of 2-(1,2-benzisoxazol-3-yl)-benzaldehyde and 2.6 g of magnesium sulfate in 25 ml of methylene chloride was added 1.7 ml of diphenylmethanamine and the stirring continued overnight. The reaction was filtered through dicalite and the filtrate evaporated to give 3.9 g crude N-[2-(1,2-benzisoxazol-3-yl)-benzylidene]-1,1-diphenylmethanamine as a gum which slowly solidified. A stirred solution of 0.75 g of N-[2-(1,2-benzisoxazol-3-yl)-benzylidene]-1,1-diphenylmethanamine in 15 ml tetrahydrofuran was cooled to -65° C. and 2.5 ml of a 1M solution of potassium tert-butoxide in tetrahydrofuran was added dropwise. The purple coloured solution was stirred for 5 min then 4-fluorobenzyl bromide was added rapidly and the reaction allowed to slowly warm to room temperature. The reaction was diluted with 25 ml of water then extracted with 100 ml then 50 ml of methylene chloride. The combined organic extracts were dried over sodium sulphate then evaporated to give 1.18 g of crude N-(diphenylmethylidene)-2-(1,2-Benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine which was not characterised due to instability. To a solution of 1.1 g of N-(diphenylmethylidene)-2-(1,2-benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine in 20 ml of acetone was added 9 ml of 1 M hydrochloric acid. The solution was stirred overnight then evaporated and 15 ml of 4M sodium hydroxide solution added. The solution was extracted with 100 ml then 50 ml of methylene chloride. The organic extracts were dried and evaporated to an oil which was purified by flash chromatography eluting with a 19:1 mixture of methylene chloride-methanol to yield the pure amine free base which was dissolved in methanol and acidified with a solution of hydrogen chloride in methanol, evaporated and crystalised from methanol-ether to yield 0.18 g of 2-(1,2-benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine hydrochloride, melting at 238-241° C.
Reaction SMILES: Cl.O1CCOCC1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3[CH:20]=[C:21]4[C@:26]([C:28](=[O:39])[C:29]5[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=5)([CH2:27][C:18]=3[CH:17]=[N:16]2)[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C.[CH3:56][N:57]1[CH:61]=[C:60]([S:62](Cl)(=[O:64])=[O:63])[CH:59]=[N:58]1>ClCCl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3[CH:20]=[C:21]4[C@:26]([C:28]([C:29]5[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=5)=[O:39])([CH2:27][C:18]=3[CH:17]=[N:16]2)[CH2:25][N:24]([S:62]([C:60]2[CH:59]=[N:58][N:57]([CH3:56])[CH:61]=2)(=[O:64])=[O:63])[CH2:23][CH2:22]4)=[CH:11][CH:10]=1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2cc(C(F)(F)F)ccn2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C(=O)c3cc(C(F)(F)F)ccn3)C2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
HCl/Dioxane (4M) (25.3 ml, 101 mmol) was added to (R)-tert-butyl 1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (2.75 g, 5.07 mmol) and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo to give an orange gum. This was dissolved in dichloromethane (75 mL) and Hunig's base (4.43 ml, 25.3 mmol) was added followed by 1-methyl-1H-pyrazole-4-sulfonyl chloride (1.099 g, 6.08 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo to give an orange oil. The crude product was purified twice by chromatography on silica gel (gradient: 0-70% ethyl acetate in isohexane, followed by 0-60% ethyl acetate in dichloromethane), to give (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (1.89 g) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.39 min, m+H=587.2.; 1H NMR (400 MHz, CDCl3): δ 8.87 (1H, d, J=5.0 Hz), 8.16-8.15 (1H, m), 7.72-7.70 (1H, m), 7.69-7.66 (2H, m), 7.47-7.42 (2H, m), 7.30 (1H, s), 7.21-7.14 (2H, m), 6.51 (1H, d, J=2.1 Hz), 5.44 (1H, dd, J=12.0, 2.1 Hz), 4.21 (1H, d, J=16.9 Hz), 3.93 (3H, s), 3.80-3.76 (1H, m), 2.94 (1H, J=16.9 Hz), 2.88-2.79 (1H, m), 2.66 (1H, d, J=12.1 Hz), 2.53-2.48 (1H, m), 2.43 (1H, ddd, J=12.6, 10.5, 3.5 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[OH:10])=[C:5]([CH2:18][OH:19])[CH:4]=1)#[N:2].C(N(CC)CC)C.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[OH:10])=[C:5]([CH:4]=1)[CH2:18][O:19][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])#[N:2]
Reactant: N#Cc1ccc(C(O)c2ccc(F)cc2)c(CO)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCc1cc(C#N)ccc1C(O)c1ccc(F)cc1
Reaction time: 1 h
Yield: 95 %

Procedure:
To a stirred solution of (4-cyano-2-hydroxymethylphenyl)(4-fluorophenyl)methanol (9.2 g, 0.037 mol) and triethylamine (4.0 g, 0.04 mol) was added pivaloyl chloride (4.2 g, 0.39 mol). After stirring for 60 minutes the reaction mixture was poured onto ice, extracted with diethyl ether (2×75 mL), dried (MgSO4), and concentrated under reduced pressure to give a colourless oil (12.0 g). The compound was purified by chromatography (eluent hexane/ethyl acetate 1:9 to give the title compound (8.2 g, 70%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[CH2:5][CH2:4][NH:3]1.I[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:21][C:20]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[N:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=2)[C:2]1=[O:1]
Reactant: N#Cc1ccc2c(c1)C(=O)NCC2
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccc(C#N)cc2C1=O
Yield: 38.1 %

Procedure:
Using analogous reaction conditions as described in Example 1, 1-oxo-1,2,3,4-tetrahydro-isoquinoline-7-carbonitrile (I-32c: 120 mg, 0.6976 mmol) was reacted with 3-iodo-4-methyl-pyridine (152.7 mg, 0.6976 mmol), 1,4-dioxane (5 mL), copper iodide (13.2 mg, 0.06976 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (40 mL, 0.2092 mmol) and potassium phosphate (369.7 mg, 1.744 mmol) to afford the crude product. Purification by column chromatography on silica gel (80% ethylacetate in hexane) afforded 70 mg of the product (38.14% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][Cl:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](I)[CH3:24]>>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH2:23][CH3:24])=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][Cl:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CCc1cc(O)c(OCc2ccccc2)c(OCCCCl)c1
Product: CCOc1cc(CC)cc(OCCCCl)c1OCc1ccccc1
Yield: 77 %

Procedure:
1-Benzyloxy-2-[3-chloropropoxy]-4-ethyl-6-ethoxy benzene was prepared in 77% yield as a white solid from 1-Benzyloxy-2-[3-chloropropoxy]-4-ethyl-6-hydroxy benzene and ethyliodide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([CH3:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[CH:4][CH:3]=1.Br[C:18]1[C:19](=[O:44])[N:20]([CH3:43])[CH:21]=[C:22]([C:24]2[C:25]([CH3:42])=[C:26]([NH:30][C:31]([C:33]3[S:37][C:36]4[CH2:38][CH2:39][CH2:40][CH2:41][C:35]=4[CH:34]=3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:14][N:13]1[CH2:12][CH2:11][N:10]([CH3:15])[C:9](=[O:16])[CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:18]2[C:19](=[O:44])[N:20]([CH3:43])[CH:21]=[C:22]([C:24]3[C:25]([CH3:42])=[C:26]([NH:30][C:31]([C:33]4[S:37][C:36]5[CH2:38][CH2:39][CH2:40][CH2:41][C:35]=5[CH:34]=4)=[O:32])[CH:27]=[CH:28][CH:29]=3)[N:23]=2)=[CH:7][CH:6]=1
Reactant: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c(Br)n1
Reactant: CN1CCN(C)C(c2ccc(N)cc2)C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c(Nc2ccc(C3C(=O)N(C)CCN3C)cc2)n1
Temperature: 25 °C
Yield: 36.3 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 4 (160 mg, 0.73 mmol), 11 (304 mg, 0.66 mmol), cesium carbonate (475 mg, 1.46 mmol) and 1,4-dioxane (10 mL). After bubbling nitrogen through the resulting solution for 30 minutes, Xantphos (32 mg, 0.056 mmol) and tris(dibenzylideneacetone)dipalladium(0) (30 mg, 0.033 mmol) were added and the reaction mixture was heated at reflux for 16 h. After this time the reaction was cooled to room temperature and concentrated under reduced pressure. The resulting residue was absorbed onto silica gel and purified by flash chromatography to give a residue, which was further purified by preparative reverse phase HPLC to afford a 30% yield (143 mg) of 12 as a yellow solid: mp 155-156° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.43 (s, 1H), 8.08 (d, 2H, J=7.5 Hz), 7.68 (s, 1H), 7.32 (d, 2H, J=7.5 Hz), 7.27-7.32 (m, 3H), 7.24 (s, 1H), 4.88 (bs, 1H), 3.42-3.75 (m, 4H), 3.59 (s, 3H), 2.95 (s, 3H), 2.76 (m, 2H), 2.61 (m, 5H), 2.28 (s, 3H), 1.78 (m, 4H); MS (ESI+) m/z 597 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]=[C:14]=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[ClH:16].Cl.[Cl:18][C:19]1[CH:36]=[CH:35][C:22]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][SH:34])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:18].[ClH:16].[CH3:12][O:11][C:7]1[CH:6]=[C:5]([NH:13][C:14](=[SH:34][CH2:33][CH2:32][CH2:31][N:28]2[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C:22]3[CH:21]=[CH:20][C:19]([Cl:18])=[CH:36][CH:35]=3)[CH2:26][CH2:27]2)[OH:15])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Reactant: SCCCN1CCN(CCc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(O)=[SH]CCCN2CCN(CCc3ccc(Cl)cc3)CC2)cc(OC)c1OC
Yield: 46.4 %

Procedure:
The procedure described in Example 2 was followed, using 2.5 g of 3,4,5-trimethoxyphenyl isocyanate, 4.4 g of 3-[4-(4-chlorophenethyl)piperazin-1-yl]propanethiol dihydrochloride, 1.2 g of triethylamine and 50 ml of methylene chloride, to give 1.6 g (23% of theory) of N-(3,4,5-trimethoxyphenyl)-S-{3-[4-(4-chlorophenethyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 239°-241° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][C:22]([CH3:25])([OH:24])[CH3:23])[C@H:12]([CH3:26])[NH:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=1[CH2:45][C:46](O)=[O:47].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][C:22]([OH:24])([CH3:25])[CH3:23])[C@H:12]([CH3:26])[N:11]1[C:46](=[O:47])[CH2:45][C:38]1[CH:39]=[C:40]([O:43][CH3:44])[CH:41]=[CH:42][C:37]=1[Cl:36])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H]1N[C@@H](CO[Si](C)(C)C(C)(C)C)Cc2c(CCC(C)(C)O)cccc21
Reactant: COc1ccc(Cl)c(CC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)c(CC(=O)N2[C@@H](CO[Si](C)(C)C(C)(C)C)Cc3c(CCC(C)(C)O)cccc3[C@@H]2C)c1

Procedure:
Dissolve 4-[(1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-butan-2-ol (0.36 g, 0.95 mol in dichloromethane (9.5 mL). Add diisopropylethylamine (499 μL, 2.86 mmol). Add 2-(2-chloro-5-methoxy-phenyl)acetic acid (229.5 mg, 1.14 mmol). Add O-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (561 mg, 1.40 mmol) and stir at ambient temperature overnight. Dilute the reaction mixture with dichloromethane and wash with water and brine, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a brown oil. Purify the residue by silica gel chromatography, eluting with acetone: hexanes (gradient, 0-20%) to give the title compound as an opaque oil (0.46 g, 0.82 mmol). MS (m/z): 560.2 (M+1).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]([O:27][CH2:28][C:29]3([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:20]=[N:21][C:22]=2[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH2:37](OCC)C>C(Cl)Cl>[ClH:1].[ClH:1].[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[C:19]([O:27][CH2:28][C:29]3([OH:35])[CH2:34][CH2:33][N:32]([CH3:37])[CH2:31][CH2:30]3)[N:20]=[N:21][C:22]=2[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOCC
Reactant: CCCCc1nnc(OCC2(O)CCNCC2)cc1-c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nnc(OCC2(O)CCN(C)CC2)cc1-c1ccc(OCc2ccccc2)cc1

Procedure:
A suspension of 4-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-piperidin-4-ol dihydrochloride (0.1 mmol) aqueous formaldehyde (37%, 0.3 mmol) and molecular sieves in anhydrous DCM may be stirred for 20 minutes. To this suspension at room temperature may be added sodium triacetoxyborohydride (0.3 mmol). The reaction mixture may be monitored by LCMS until the reaction is complete. The reaction may be quenched with saturated NaHCO3 and the layers may be separated. The organic layer may be dried and the solvent may be removed under reduced pressure. The crude product may be purified by flash chromatography using with 1-5% (2N ammonia in MeOH) in DCM to give 4-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-1-methyl-piperidin-4-ol. The neutral amine may be treated with 2N HCl in diethyl ether and DCM. The volatiles may be removed under reduced pressure and the salt triturated with diethyl ether and filtered to provide the title compound. LCMS: m/z 463 [M+1]. 1H NMR (400 MHz, CDCl3) δ 7.32-7.49 (5H, m), 7.19-7.25 (2H, m), 7.02-7.09 (2H, m), 6.78 (1H, bs), 5.12 (2H, s), 4.58-4.83 (1H, m), 4.32 (2H, s), 2.54-2.69 (3H, m), 2.40-2.51 (2H, m), 2.27-2.36 (3H, m), 1.71-1.83 (2H, m), 1.59-1.70 (2H, m), 1.18-1.51 (5H, m), 0.81 (3H, t).
Reaction SMILES: [OH:1][CH2:2][C@@:3]([C:6]1[CH:25]=[CH:24][C:9]([C:10]([NH:12][C:13]2[N:18]=[CH:17][C:16]3[CH:19]=[CH:20][N:21]([CH2:22][CH3:23])[C:15]=3[CH:14]=2)=[O:11])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[Cl:26]N1C(=O)CCC1=O.CCOCC>CN(C=O)C.[Cl-].[Na+].O>[Cl:26][C:19]1[C:16]2[CH:17]=[N:18][C:13]([NH:12][C:10](=[O:11])[C:9]3[CH:24]=[CH:25][C:6]([C@:3]([OH:5])([CH3:4])[CH2:2][OH:1])=[CH:7][CH:8]=3)=[CH:14][C:15]=2[N:21]([CH2:22][CH3:23])[CH:20]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCn1ccc2cnc(NC(=O)c3ccc([C@@](C)(O)CO)cc3)cc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(Cl)c2cnc(NC(=O)c3ccc([C@@](C)(O)CO)cc3)cc21
Temperature: 60 °C
Yield: 64 %

Procedure:
In a 200 mL pear flask was added (R)-4-(1,2-dihydroxypropan-2-yl)-N-(1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide (13, 3.2 g, 7.1 mmol) in anhydrous DMF (45 ml) to give a brown suspension. At room temperature, N-chlorosuccinimide (0.94 g, 7.1 mmol) was added, and the mixture was heated to 60° C. for 4 hours. An additional 0.2 equivalent of N-chlorosuccinimide was added at room temperature. After an additional 1.5 hours of heating at 60° C., the mixture was cooled to room temperature. Brine was added, and the mixture was extracted with ethyl acetate twice. Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated until a precipitate was formed. Ether was added and the red solid was collected on a fritted filter, while the filtrate was concentrated. The oil was then purified by column chromatography (SiO2, 75-100% EtOAc/hexanes+0.25% MeOH). The product-containing fractions were combined and concentrated. The residue was combined with the red solid collected earlier and the mixture was resuspended in hot EtOAc/methanol mixture. After cooling, the much lighter-colored solid was collected on a fritted-glass filter under nitrogen, and washed with Et2O to remove most of the colored impurities to give the title compound (R)-N-(3-chloro-1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide (14, 1.7 g, 64% yield) as a light-pink solid. 1H NMR (DMSO-d6) d: 10.68 (s, 1 H), 8.60 (s, 1 H), 8.38 (s, 1 H), 8.01 (d, J=8.3 Hz, 2 H), 7.69 (s, 1 H), 7.58 (d, J=8.6 Hz, 2 H), 5.05 (s, 1 H), 4.76 (t, J=5.8 Hz, 1 H), 4.19 (q, J=7.2 Hz, 2 H), 3.40-3.50 (m, 2 H), 1.42 (s, 3 H), 1.38 (t, J=7.3 Hz, 3 H); ESI-MS: m/z 374 (M+H)+; m.p. 224.4-225.1° C.