Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:17][CH2:18][CH3:19])=[CH:8][C:9]2[O:14][C:13](=[O:15])[CH:12]=[CH:11][C:10]=2[CH:16]=1.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO.C([O-])(=O)/C=C/C([O-])=O>C(O)C>[CH2:18]([O:17][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)=[CH:16][C:10]2[CH:11]=[CH:12][C:13](=[O:15])[O:14][C:9]=2[CH:8]=1)[CH3:19]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOc1cc2oc(=O)ccc2cc1OCCCCl
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CO
Solvent: CCO
Product: CCOc1cc2oc(=O)ccc2cc1OCCCN1CCN(c2ccccc2)CC1
Yield: 57 %

Procedure:
Method A (26 h at 60° C.); starting materials: 6-(3-chloropropoxy)-7-ethoxy-2H-1-benzopyran-2-one (see example 70) and 1-phenylpiperazine; yield 57%; fusion point 151° to 153° (from methanol and ethanol). Fumarate: method E; yield 78%; fusion point 170° to 173° C. (from ethanol).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][C:3]=1[C:15](=[O:30])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=1.[OH-].[K+].Cl>CO>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][C:3]=1[C:15](=[O:30])[CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:22][CH:23]=1
Reactant: COC(=O)COc1ccc(CCC(=O)c2ccc(OC)c(CCC(C)C)c2O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)CCc2ccc(OCC(=O)O)cc2)c(O)c1CCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
Then, 20.6 g of 1-(2-hydroxy-4-methoxy-3-isopentylphenyl)-3-(4-methoxycarbonylmethoxyphenyl)-1-propanone was dissolved in 100 ml of methanol, and 100 ml of a 5% aqueous solution of potassium hydroxide was added to the solution and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction mixture was made acidic by dilute hydrochloric acid, and the formed precipitate was recovered by filtration and recrystallized from benzene to obtain 15.2 g (yield=96.8%) of 1-(2-hydroxy-4-methoxy-3-isopentylphenyl)-3-(4-carboxymethoxyphenyl)-1-propanone in the form of a colorless grain.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1Cl)(=[O:6])=[O:5].[C:17]1([NH2:24])[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1>CO>[OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[NH:23][C:20]1[CH:21]=[CH:22][C:17]([NH2:24])=[CH:18][CH:19]=1)(=[O:6])=[O:5]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)CCO)c1
Reactant: Nc1ccc(N)cc1
Solvent: CO
Product: Nc1ccc(Nc2ccc([N+](=O)[O-])cc2S(=O)(=O)CCO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
132.85 g of 2-chloro-5-nitrophenyl hydroxyethyl sulfone are added at 65° C. under nitrogen to a solution of 118.8 g of 1,4-phenylenediamine in 500 ml of methanol in the course of 30 minutes. The reaction solution is stirred at this temperature for a further 4 hours and is then allowed to cool down to room temperature, and the reaction product is crystallized by addition of 1 l of ice-water. Filtering with suction and drying gives 168 g of 2-(4-aminophenylamino)-5-nitrophenyl hydroxyethyl sulfone having a melting point of 147°-149° C. and a purity of >99%, which corresponds to a yield of 99% of theory, relative to starting 2-chloro-5-nitrophenyl hydroxyethyl sulfone.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH:8]1[CH2:12][CH2:11][O:10][CH2:9]1.Br[CH2:14][C:15]1[C:16]([Cl:28])=[C:17]([CH:21]=[CH:22][C:23]=1[S:24]([CH3:27])(=[O:26])=[O:25])[C:18]([OH:20])=[O:19].Cl>CN(C=O)C>[Cl:28][C:16]1[C:15]([CH2:14][O:7][CH:8]2[CH2:12][CH2:11][O:10][CH2:9]2)=[C:23]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: OC1CCOC1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1CBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1COC1CCOC1
Temperature: -15 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
At 0° C., 25 ml of DMF and 3.25 g (28 mmol) of potassium tert-butoxide were initially charged and mixed with 2.5 g (27.5 mmol) of 3-hydroxytetrahydrofuran. The solution was cooled to −15° C., and 4.7 g (140 mmol) of 3-bromomethyl-2-chloro-4-methylsulfonylbenzoic acid were added. The mixture was then stirred at 15-20° C. for one hour. The reaction was poured into 45 g of ice/water, acidified with 2N HCl and extracted with EA. The organic phases were dried with MgSO4, filtered and concentrated. This gave 5.41 g of a viscous oil of a purity of about 66% according to HPLC. Yield about 60%
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C@H:12]3[NH:15][CH2:16][CH2:17][C@:6]4([C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)[C:5]=2[CH:4]=[C:3]([C:18](=[O:20])[CH3:19])[CH:2]=1.C(N(CC)CC)C.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[C:18]([C:3]1[CH:2]=[CH:1][C:14]2[CH2:13][C@H:12]3[N:15]([C:34]([CH2:33][C:29]4[O:28][CH:32]=[CH:31][CH:30]=4)=[O:35])[CH2:16][CH2:17][C@@:6]4([C:5]=2[CH:4]=1)[C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)(=[O:20])[CH3:19]
Reactant: O=C(Cl)Cc1ccco1
Reactant: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)Cc1ccco1)CC3
Temperature: 25 °C
Yield: 90 %

Procedure:
To a mixture of 1.5 g, (-)-1-(morphinan-3-yl)ethanone, 1.7 g of triethylamine and 15 ml of methylene chloride at ice-bath temperature was added a solution of 1.3 g of 2-furyl acetyl chloride in 10 ml of methylene chloride over a period of 1 hour. After the mixture had been refluxed for 4 hours, it was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in 100 ml ether and the ether solution was washed with 1 N hydrochloric acid (2×15 ml) then with water and dried over magnesium sulfate. Removal of the solvent gave 1.9 g (90%) of crude (-)-3-acetyl-N-[(2-furylmethyl)carbonyl]morphinan. For analysis, a sample of this compound was distilled, bp 235°-245° (0.05 mm), [α]25D-160.43° (c 0.94, MeOH).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22]C)[CH:18]=2)[CH2:13]1)[CH3:2].Cl.[N:25]1([CH2:32][CH2:33][O:34][C:35]2[CH:43]=[CH:42][C:38]([C:39](Cl)=O)=[CH:37][C:36]=2[F:44])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:32][CH2:33][O:34][C:35]2[CH:43]=[CH:42][C:38]([CH2:39][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:37][C:36]=2[F:44])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCCC2)c(F)c1
Agent: Cl
Product: Oc1ccc2c(c1)CCC(c1ccc(O)cc1NCCCc1ccc(OCCN3CCCCCC3)c(F)c1)C2
Yield: 49.7 %

Procedure:
Synthesized from ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (400 mg) and 4-(2-azepan-1-ylethoxy)-3-fluorobenzoyl chloride hydrochloride (560 mg) according to an analogous synthetic method to Example 187, the title compound (340 mg) was obtained.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1.CCN(CC)CC>CC#N>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:35][C:34]4[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=4)[CH2:26][CH2:25]3)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NCC1CCNCC1
Reactant: Fc1ccc(CBr)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NCC1CCN(Cc2ccc(F)cc2)CC1

Procedure:
A solution of 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (1.50 g, 3.49 mmol), 4-fluorobenzyl bromide (0.478 mL, 3.84 mmol), and Et3N (1.47 mL, 10.5 mmol) in CH3CN (200 mL) was stirred at room temperature for 13 h and concentrated. Column chromatography (SiO2, 10% CH3OH/CH2Cl2) afforded 4-[{N-(9fluorenylmethyloxycarbonyl)glycyl}aminomethyl]-1(4-fluorobenzyl)piperidine
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.O>CN(C=O)C>[O:18]=[C:17]1[C:16]2[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](=[O:19])[N:1]1[CH:2]([C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NC(CC(=O)O)c1ccc(F)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CC(c1ccc(F)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 135 °C
Reaction time: 0.5 h

Procedure:
2.0 g of rac-3-amino-3-(4-fluorophenyl)propanoic acid (10.92 mmol) and 1.62 g of phthalic anhydride (10.92 mmol) were dissolved in 9 ml of DMF and heated at reflux at 135° C. overnight. The reaction solution was added to about 200 ml of water. The solid formed was stirred at RT for about 30 min and then filtered off, washed with water and dried under high vacuum. This gave 3.43 g of the title compound (86% of theory, purity about 86%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)(=[O:19])=[O:18])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CCCC[N+](CCCC)(CCCC)CCCC.[I-].CN(C=O)C.C(OCC)(=O)C>[C:7]([C:6]1[C:5]([CH3:9])=[C:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)(=[O:19])=[O:18])[N:3]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:2]=1[CH3:1])#[N:8]
Reactant: Cc1[nH]c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C)c1C#N
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(C)c(C#N)c(C)c1Cc1ccccc1S(=O)(=O)N1CCCC1
Temperature: 60 °C
Yield: 44.7 %

Procedure:
A mixture of 2,4-dimethyl-5-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrole-3-carbonitrile (513.6 mg, 1.495 mmol), TBAI (55.2 mg, 0.150 mmol), cesium carbonate (1462 mg, 4.49 mmol), and ethyl bromoacetate (250 μl, 2.243 mmol) in DMF (7.5 ml) was heated at 60° C. for 4 hours. The mixture was diluted in ethyl acetate (100 ml) and washed with water (50 ml×3). The organic layer was dried, filtered, and evaporated to give an oil. This oil was purified by column chromatography (0 to 40% ethyl acetate in hexanes) to give ethyl 2-(3-cyano-2,4-dimethyl-5-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (286.9 mg, 0.668 mmol, 44.7% yield). 1H NMR (CDCl3/400 MHz) δ (ppm) 7.92-7.88 (m, 1H), 7.44-7.38 (m, 1H), 7.35-7.29 (m, 1H), 6.96-6.92 (m, 1H), 4.36 (s, 2H), 4.28 (s, 2H), 3.94 (q, 2H), 3.38-3.30 (m, 4H), 2.27 (s, 3H), 2.13 (s, 3H), 1.98-1.92 (m, 4H), 1.11 (t, 3H). MS m/z: 430.3 (M+1).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[C:12](=[O:13])[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]4[CH:25]=[C:24]([NH:26][C:27]5[CH:31]=[C:30]([CH:32]6[CH2:34][CH2:33]6)[NH:29][N:28]=5)[C:23](=[O:35])[N:22](COCC[Si](C)(C)C)[N:21]=4)[C:15]=3[CH3:44])[CH2:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O>ClCCl.FC(F)(F)C(O)=O>[C:1]([C:5]1[S:6][C:7]2[C:12](=[O:13])[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]4[CH:25]=[C:24]([NH:26][C:27]5[CH:31]=[C:30]([CH:32]6[CH2:34][CH2:33]6)[NH:29][N:28]=5)[C:23](=[O:35])[NH:22][N:21]=4)[C:15]=3[CH3:44])[CH2:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(-c2cc(Nc3cc(C4CC4)[nH]n3)c(=O)n(COCC[Si](C)(C)C)n2)cccc1N1Cc2nc(C(C)(C)C)sc2C1=O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1c(-c2cc(Nc3cc(C4CC4)[nH]n3)c(=O)[nH]n2)cccc1N1Cc2nc(C(C)(C)C)sc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a mixture of 2-tert-butyl-5-(3-(5-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-3-yl)-2-methylphenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one 111b in dichloromethane (5 mL) and trifluoro-acetic acid (5 mL) was added anisole (0.11 mL, 1.0 mmol) and trifluoromethanesulfonic acid (0.054 mL, 0.61 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated. The residue was purified by reverse phase HPLC: C-18 column eluted with 20 to 60% acetonitrile in water with 1% ammonium hydroxide to afford 2-tert-butyl-5-(3-(5-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)-2-methylphenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one 111 (50 mg, 50%). M+1 502.2. 1H NMR (400 MHz, DMSO) δ 12.94 (s, 1H), 12.02 (s, 1H), 9.06 (s, 1H), 7.82 (s, 1H), 7.50 (dd, J=5.8, 3.5, 1H), 7.38 (dd, J=8.0, 5.6, 2H), 5.87 (d, J=2.0, 1H), 4.96 (s, 2H), 2.13 (s, 3H), 1.84 (td, J=8.4, 4.2, 1H), 1.47 (s, 9H), 0.98-0.82 (m, 2H), 0.71-0.59 (m, 2H).
Reaction SMILES: [Br-].[Br-].C[N+]([CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][N+](C)(C)C)(C)C.Cl[P:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[C:35]1([P:34]([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]=2[CH2:28][P:34]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[N+](C)(C)Cc1ccc2ccccc2c1-c1c(C[N+](C)(C)C)ccc2ccccc12
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CN(C)C=O
Product: c1ccc(P(Cc2ccc3ccccc3c2-c2c(CP(c3ccccc3)c3ccccc3)ccc3ccccc23)c2ccccc2)cc1
Yield: 78.4 %

Procedure:
The procedure of Example 7 is repeated, but using an electrolyte comprising 5.58 g (0.010 mol) of 2,2'-bis[(trimethylammonio)methyl]-1,1'-binaphthyl dibromide, 6.62 g (0.030 mol) of chlorodiphenylphosphine and 50 ml of dimethyl formamide (max. 0.1% of water) in the electrolysis. The amount of charge is 0.96 Ah. Workup gives 5.1 g of 2,2'-bis[(diphenylphosphino)methyl]-1,1'-binaphthyl ("naphos"). This corresponds to a yield of 78% based on 2,2'-bis[(trimethylammonio)methyl]-1,1'-binaphthyl dibromide used.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].O.NN>CO.O1CCCC1>[NH2:3][O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CON
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of tert-butyl 2-(1,3-dioxoisoindolin-2-yloxy)acetate (Compound XXIII-1) (13.86 g, 50 mmol) in methanol:tetrahydrofuran (2:3, 150 ml) was added hydrazine monohydrate (7.28 ml, 150 mmol) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (300 ml) and the mixture was washed with sat. NaHCO3 aq. (300 ml). The organic layer was washed with brine (300 ml), dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to obtain the title compound (6.40 g, 87%).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:32][S:29]([N:16]([CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][C:6]([OH:33])=[O:5])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[CH:22][CH:23]=1)(=[O:30])=[O:31]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(C)(=O)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1ccc(-c2nccs2)cc1)Cc1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
A solution of (3-{[methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-acetic acid tert-butyl ester (0.074 g) in 2 mL CH2Cl2 was cooled to 0° C. and 2 mL trifluoroacetic acid was added. The reaction was stirred at room temperature for 2 hours. The solvent was removed by evaporation azeotroping with CH2Cl2 to afford the title compound (40 mg). 1H NMR (400 MHz, CDCl3) δ 9.94 (bs, 1H), 8.14 (s, 1H), 7.81 (d, 2H), 7.55 (s, 1H), 7.37 (d, 2H), 7.18 (m, 1H), 6.90 (d, 1H), 6.80 (d, 1H), 6.63 (s, 1H), 4.58 (s, 2H), 4.35 (s, 2H), 4.29 (s, 2H), 2.93 (s, 3H); MS 431 (M−1).
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[N:22][C:21]([NH2:24])=[C:20]4[O:25][C:26](Cl)=[CH:27][C:19]=34)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)(C)(C)C.[CH3:31][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][C:39]=2B(O)O)[CH:34]=[N:33]1>>[NH2:24][C:21]1[N:22]=[CH:23][C:18]([C:16]2[CH:15]=[N:14][N:13]([C@H:10]3[CH2:9][CH2:8][C@H:7]([OH:6])[CH2:12][CH2:11]3)[CH:17]=2)=[C:19]2[CH:27]=[C:26]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]4[C:40]=3[N:32]([CH3:31])[N:33]=[CH:34]4)[O:25][C:20]=12
Reactant: Cn1ncc2cccc(B(O)O)c21
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Product: Cn1ncc2cccc(-c3cc4c(-c5cnn([C@H]6CC[C@H](O)CC6)c5)cnc(N)c4o3)c21

Procedure:
The title compound was prepared in 69% yield from 4-{1-[4-(tert-butyldimethyl-silanyloxy)-cyclohexyl]-1H-pyrazol-4-yl}-2-chlorofuro[2,3-c]pyridin-7-ylamine and 1-methylindazole-7-boronic acid by a procedure analogous to Example 229. The material was further purified by preparative TLC (5% 7 N ammonia/MeOH:ethyl acetate) instead of trituration. 1H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1H), 8.23 (s, 1H), 8.03 (s, 1H), 7.98 (dd, J=0.76, 8.08 Hz, 1H), 7.92 (s, 1H), 7.71 (dd, J=1.01, 7.07 Hz, 1H), 7.56 (s, 1H), 7.29 (dd, J=7.20, 7.96 Hz, 1H), 6.41 (br s, 2H), 4.67 (d, J=4.29 Hz, 1H), 4.15 (tt, J=3.95, 11.59 Hz, 1H), 3.91 (s, 3H), 3.46-3.57 (m, 1H), 2.04 (d, J=12.13 Hz, 2H), 1.79-1.98 (m, 4H), 1.30-1.43 (m, 2H); MS (ESI): 428.94 [M+H]+; HPLC tR=2.63 min (ZQ3: polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.C(O)C.C(OCC)(OCC)OCC.S(=O)(=O)(O)O>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOC(OCC)OCC
Solvent: CCO
Product: Cc1cc(Cl)ccc1CO
Yield: 97 %

Procedure:
A sample of 4-chloro-2-methylbenzoic acid was converted to the ethyl ester using ethanol/triethyl orthoformate/sulfuric acid in >95% yield. Reduction of the ester with LiAiH4/tetrahydrofuran gave 4-chloro-2-methylbenzyl alcohol in 97% yield as a colorless oil. Subsequent treatment with thionyl chloride/pyridine/CH2Cl2 gave the substituted benzyl chloride. The latter, on treatment with 40% excess sodium cyanide in DMF at 90° C. for 20 min. and normal work-up and crystallization from hexane/butyl chloride (2 crops) gave 4-chloro-2-methylbenzyl cyanide in 80% overall yield.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[K].[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20]>CC(N(C)C)=O>[CH3:10][C:4]1[CH:3]=[C:2]([O:20][C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[Cl:12])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Oc1ccc(F)cc1Cl
Reactant: Cc1cc(Cl)ccc1C#N
Agent: [K]
Solvent: CC(=O)N(C)C
Product: Cc1cc(Oc2ccc(F)cc2Cl)ccc1C#N
Yield: 96.8 %

Procedure:
A stirred solution of 4-chloro-2-methylbenzonitrile (4.7 g., 0.03 mole) and the potassium salt of 2-chloro-4-fluorophenol (5.54 g., 0.03 mole) in 40 ml of dimethyl acetamide was heated for 48 hours at 150° C. The cooled reaction mixture was diluted with 200 ml. of water to precipitate a brown oil. An ether extract yielded 7.6 g of 2-methyl-4-(2'-chloro-4'-fluorophenoxy)benzonitrile as a brown oil in about 90% purity.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].Cl[C:9]1[N:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([O:19]C)=[CH:14][CH:15]=2)[N:10]=1>C(Cl)Cl>[CH2:1]([S:3][C:9]1[N:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=2)[N:10]=1)[CH3:2]
Reactant: COc1ccc2cnc(Cl)nc2c1
Reactant: CCS
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCSc1ncc2ccc(O)cc2n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a solution of ethanthiol (30 ml) in DCM (50 ml) was added AlCl3 (6 eq). The reaction mixture was cooled to 0° C. and stirred for 10 min under N2 atmosphere. A solution of 2-chloro-7-methoxyquinazoline (1 eq) in DCM (20 ml) was added dropwise to it. The reaction mixture was warmed to room temperature and stirred for 2 h. The solvent was evaporated and residue was partitioned between EtOAc and satd. NaHCO3. The insoluble material was filtered, washed and dried to provide title product as a yellow solid (yield, 60%). The ethyl acetate layer was separated from basic layer, washed with brine and dried over sodium sulfate. Filtration, evaporation and drying under vacuum provide additional amount of product. (yield, 38%). ES/MS m/z 207.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:29])[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[CH3:19][N:20]([CH3:29])[C:21]([N:23]1[CH2:24][CH2:25][N:26]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN(C)C(=O)N1CCNCC1
Product: CN(C)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 from Example 3 and piperazine-1-carboxylic acid dimethylamide using General Procedure Z yielded 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid dimethylamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([OH:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][CH:4]=1.[CH2:31]([C:35]1([CH2:73][CH3:74])[CH2:41][S:40](=[O:43])(=[O:42])[C:39]2[CH:44]=[CH:45][C:46]([N:48]([CH3:50])[CH3:49])=[CH:47][C:38]=2[CH:37]([C:51]2[CH:52]=[C:53]([NH:57][C:58]([CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][O:67][CH2:68][C:69](O)=[O:70])=[O:59])[CH:54]=[CH:55][CH:56]=2)[CH:36]1[OH:72])[CH2:32][CH2:33][CH3:34]>ClCCl.CO>[CH2:31]([C:35]1([CH2:73][CH3:74])[CH2:41][S:40](=[O:43])(=[O:42])[C:39]2[CH:44]=[CH:45][C:46]([N:48]([CH3:50])[CH3:49])=[CH:47][C:38]=2[CH:37]([C:51]2[CH:52]=[C:53]([NH:57][C:58]([CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][O:67][CH2:68][C:69]([NH:1][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH:9]4[CH:10]([CH2:21][CH2:22][CH:23]([OH:30])[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:11](=[O:20])[N:12]4[C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)=[CH:5][CH:4]=3)=[O:70])=[O:59])[CH:54]=[CH:55][CH:56]=2)[CH:36]1[OH:72])[CH2:32][CH2:33][CH3:34]
Reactant: NCc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: CCCCC1(CC)CS(=O)(=O)c2ccc(N(C)C)cc2C(c2cccc(NC(=O)COCCOCCOCC(=O)O)c2)C1O
Solvent: ClCCl
Solvent: CO
Product: CCCCC1(CC)CS(=O)(=O)c2ccc(N(C)C)cc2C(c2cccc(NC(=O)COCCOCCOCC(=O)NCc3ccc(C4C(CCC(O)c5ccccc5)C(=O)N4c4ccc(F)cc4)cc3)c2)C1O

Procedure:
Preparation analogous to example II, starting from 83 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-(3-hydroxy-3-phenylpropyl)azetidin-2-one and 130 mg of [2-(2-{[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenylcarbamoyl]methoxy}ethoxy)ethoxy]acetic acid; chromatography: SiO2, dichloromethane/methanol=20:1; product of melting point 120° C. and molecular weight 1021.3 (C57H67FN4O10S); MS (ESI+): 1021 (M+H+).