Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])#[N:2].CC(O)=[O:30]>C(O[Pd]OC(=O)C)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[CH:6]=[C:7]2[C:8]=1[NH:9][C:10]1[CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[CH:17]=[CH:18][C:19]2=1)(=[O:30])[NH2:2]
Reactant: COC(=O)c1cccc(Nc2ccc(-c3cccc(OC)c3)cc2C#N)c1
Reactant: CC(=O)O
Agent: CC(=O)O[Pd]OC(C)=O
Product: COC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3cccc(OC)c3)cc12
Temperature: 130 °C

Procedure:
A mixture of methyl 3-(3-cyano-3′-methoxybiphenyl-4-ylamino)benzoate (3.3 g, 9.21 mmol), diacetoxypalladium (5.17 g, 23.02 mmol), and AcOH (150 mL) in a pressure vessel was heated at 130° C. for 48 h. The sold was separated by filtration and washed with several times with HOAc. The filtrate was taken and the HOAc was removed under reduced pressure. The residue was dissolved in a mixture of DCM and MeOH and mixed with silica gel (12 g). After the removal of solvents, the mixture was loaded to a silica gel column and eluted with DCM containing 0 to 1.5% MeOH to afford 140 mg of methyl 8-carbamoyl-6-(3-methoxyphenyl)-9H-carbazole-2-carboxylate. MS (ESI) m/z 375.2 (M+H). 1H NMR (MeOD) δ ppm 9.28 (1H, d, J=1.53 Hz), 8.18 (1H, d, J=1.53 Hz), 7.86 (1H, d, J=7.32 Hz), 7.78 (1H, d, J=7.93 Hz), 7.46 (1H, t, J=7.78 Hz), 7.32-7.41 (2H, m), 7.31 (1H, d, J=2.14 Hz), 6.88 (1H, dd, J=7.48, 1.98 Hz), 4.04 (3H, s), 3.89 (3H, s).
Reaction SMILES: ClC1C=CC(C(C2C=CC(I)=CC=2)(O)CNCCO)=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([C:35]3[CH:40]=[CH:39][C:38]([C:41]4[CH:42]=[N:43][NH:44][CH:45]=4)=[CH:37][CH:36]=3)[O:34]C[CH2:32][NH:31][CH2:30]2)=[CH:25][CH:24]=1.CN>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:45]=[N:44][NH:43][CH:42]=3)=[CH:37][CH:36]=2)([OH:34])[CH2:30][NH:31][CH3:32])=[CH:25][CH:24]=1
Reactant: Clc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CNCCO2)cc1
Agent: CN
Agent: OCCNCC(O)(c1ccc(Cl)cc1)c1ccc(I)cc1
Product: CNCC(O)(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
By following the procedure described in Example 79A, 79B and 79D but substituting ethanolamine for methylamine, the title compound was obtained. LCMS (PS-A3) Rt 5.28 min [M+H]+328, [M−H2O+H]+310. 1H NMR (Me-d3-OD) δ 2.38 (3H, s), 3.34 (2H, s), 7.28-7.31 (2H, m), 7.41-7.46 (4H, m), 7.51-7.54 (2H, m), 7.92 (2H, s).
Reaction SMILES: [CH3:1][CH:2]([NH2:9])[CH2:3][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.ClC(Cl)C.Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl>>[N:9]([CH:2]([CH3:1])[CH2:3][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)=[C:15]=[O:17]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(N)Cc1cccs1
Solvent: CC(Cl)Cl
Product: CC(Cc1cccs1)N=C=O
Reaction time: 1 h

Procedure:
To a solution of 1-methyl-2-thiophen-2-ylethylamine (2 g, 14.2 mmol) in dichloroethane (30 ml) triethylamine (4.3 g, 42.6 mmol) and triphosgene (2.1 g, 7.1 mmol) were added. The reaction mixture stirred for 1 h and concentrated on rotary evaporator. Diethyl ether is added, and the resulting mixture is filtered. Ether solution is concentrated, and the resulting oil is used in the next step without purification.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7](C=C[C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[O:22]1[CH2:27][CH2:26][O:25]CC1>[Os](=O)(=O)(=O)=O.N1C=CC=CC=1>[OH:22][C@H:27]1[C:14]2[C@:15]([CH3:16])([CH:10]=[CH:11][C:12](=[O:20])[CH:13]=2)[C@@H:17]2[C@H:7]([C@H:6]3[C@@:2]([CH2:19][CH2:18]2)([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]3)[C@H:26]1[OH:25]
Reactant: C1COCCO1
Reactant: C[C@]12C=CC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: O=[Os](=O)(=O)=O
Solvent: c1ccncc1
Product: C[C@]12C=CC(=O)C=C1[C@H](O)[C@H](O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 0.83 g. of 1,4,6-androstatriene-3,17-dione in 15 ml. of dioxane and 0.83 ml. of pyridine add 0.75 g. of osmium tetroxide. Stir the reaction mixture under an atmosphere of nitrogen at room temperature in the absence of light for two days. Isolate the resultant product in a manner similar to that described in Example 1B. Purify by chromatographing on thin layer plates developing with ethyl acetate-chloroform-methanol (4.5:4.5:1). Combine like fractions, elute with ethyl acetate, and evaporate the eluate to a residue comprising 6β,7β-dihydroxy-1,4-androstadiene-3,17-dione. Yield=445 mg. (48% theory). Further purify by recrystallization from methanol; [α]D26° +66.7° (acetone); λmaxmethanol 244 nm (γ=15,300); n.m.r. (dmso-d6 /D2O) δ0.89 (C13 -CH3); 1.37 (C10 -CH3); 3.25(7α-H; d,d J10,3Hz); 4.24 (6α-H; d,J 3.5Hz); 6.11 (C4 -H; d,J 2Hz); 6.11 (C2 -H; d,d J10,2Hz); 7.18 (C1H; d,J 10Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[CH2:11][NH2:12].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:12][CH2:11][CH2:10][NH2:13])=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NCCNCc1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
p-Chlorobenzyl chloride, 32 g. (0.2 mole), was added dropwise to 60 g. (1.0 mole) of ethylenediamine heated at 80°. The solution was stirred at 80° overnight and then the excess amine was distilled in vacuo. The residue was triturated with i-PrOH to yield 32 g. of crude product. This material was dissolved in water, basified with dilute NaOH and the solution extracted with CH2Cl2. The combined extracts were dried (K2CO3) and concentrated in vacuo to an oil. The latter was distilled and the material boiling at 93°-95°/0.06 mm Hg was collected to yield 14.5 g. of the desired product, the identity of which was confirmed by examination of the NMR spectrum.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH:12]([OH:15])[CH2:13][OH:14])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[OH:1][C@H:2]([CH2:11][C@H:12]([OH:15])[CH2:13][OH:14])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5]
Reactant: CC(C)(C)OC(=O)CC(O)CC(O)CO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)CO

Procedure:
The reaction was terminated by the removal of cells by centrifuging at 4000×g for 20 minutes. The pH of the recovered cell-free supernatant was adjusted to 7.5 using 2M NaOH. MgSO4.1.6H2O (15% w/v based on anhydrous) was dissolved in the cell-free supernatant and the resulting solution was extracted twice with an equal volume of 2-pentanone. The solvent phases were collected and the solvent removed under reduced pressure in a rotary evaporator at 45° C. yielding an orange viscous oil. This was re-dissolved in 50 ml dry, distilled 2-pentanone and again the solvent was removed by rotary evaporation to afford t-butyl 3,5,6-trihydroxyhexanoate (5.08 g, 80% isolated yield). Diastereomeric excess was determined as follows; a sample of t-butyl 3,5,6-trihydroxyhexanoate (30 mg) was derivatised by reaction for at least 10 minutes at room temperature in an excess of trifluoroacetic anhydride, excess anhydride was removed under a stream of dry nitrogen and the residual oil diluted with dichloromethane (1 ml). The sample was analysed using a Chiralcel Dex CB column (25 metre) at a temperature of 140° C. (isothermal). The diastereomers eluted at 14.4 minutes (3R,5S diastereomer) and 15.7 minutes (3S,5S diastereomer). The diastereomeric excess of the sample was found by this method to be 99.7%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:16][C:17]([NH2:19])=[O:18])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH2:12][N:13]([CH3:15])[CH3:14])=[CH:5]2.C[O:21][C:22](=O)[C:23]([C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH3:34])[CH:26]=1)=O.[K].CC([O-])(C)C.[K+]>C1COCC1>[Cl:1][C:2]1[C:3]([C:16]2[C:17](=[O:18])[NH:19][C:22](=[O:21])[C:23]=2[C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH3:34])[CH:26]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH2:12][N:13]([CH3:14])[CH3:15])=[CH:5]2
Reactant: COC(=O)C(=O)c1cn(C)c2ccccc12
Reactant: CN(C)Cc1cc2c(CC(N)=O)c(Cl)ccc2cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: C1CCOC1
Product: CN(C)Cc1cc2c(C3=C(c4cn(C)c5ccccc45)C(=O)NC3=O)c(Cl)ccc2cn1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(6-chloro-3-dimethylaminomethyl-isoquinolin-5-yl)-acetamide (47 mg, 0.17 mmol) and (1-methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (56 mg, 0.26 mmol) in anhydrous THF was added dropwise a 1 M solution of potassium t-BuOK in THF (1.8 mL) under an argon atmosphere at 0° C. The resulting deep red reaction mixture was stirred for 1.5 h at 0° C., quenched with a saturated aqueous NH4Cl solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure. Purification by flash column chromatography (silica gel. EtOAc/water/acetic acid 7:1:1) afforded the title compound as its acetate salt (61 mg, 0.12 mmol, 70%). MS (ES+): 445 (M(C25H2135ClN4O2)+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH:10]=O)=[CH:3][CH:2]=1.[CH:12]12[N:18]([C:19](=[O:51])[C:20]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27]([C:32]3[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=3)=[C:26]4[CH2:40][CH2:41][NH:42][CH2:43][CH2:44][C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)([CH3:22])[CH3:21])[CH:15]([CH2:16][CH2:17]1)[CH2:14][CH2:13]2.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH:15]12[N:18]([C:19](=[O:51])[C:20]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27]([C:32]3[CH:33]=[C:34]([CH3:39])[CH:35]=[C:36]([CH3:38])[CH:37]=3)=[C:26]4[CH2:40][CH2:41][N:42]([CH2:10][CH2:9][CH2:8][CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:43][CH2:44][C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)([CH3:21])[CH3:22])[CH:12]([CH2:13][CH2:14]1)[CH2:17][CH2:16]2
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCNCCc2cccnc2)c1
Reactant: O=CCCCc1ccncc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCN(CCCCc2ccncc2)CCc2cccnc2)c1
Reaction time: 17.5 h
Yield: 75.6 %

Procedure:
To a solution of 4-(pyridin-4-yl)butyraldehyde (29 mg in 1.5 mL dry methanol) was added 18 mg of 1-(7-aza-bicyclo[2.2.1]hept-7-yl)-2-(2-(3,5-dimethylphenyl)-3-[2-(2-pyridin-3-yl-ethylamino)-ethyl]-1H-indol-5-yl}-2-methylpropan-1-one followed by 10 mg 3A powdered molecular seives. To this mixture, 13 mg sodium cyanoborohydride was added and the pH adjusted to 5.5 by the addition of 10% methanolic acetic acid. After 17.5 hours, the reaction was quenched by the addition of saturated sodium bicarbonate and the mixture extracted with ethyl acetate. The organic portion was washed successively with saturated ammonium chloride, sodium bicarbonate and brine, then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 90:10) gave the title compound (17 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](#[N:11])[CH:9]=[CH2:10].Cl.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.CCCCCCC>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:9]([CH3:10])[C:8]#[N:11])=[CH:4][CH:3]=1
Reactant: C=CC#N
Reactant: Nc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCCC
Product: CC(C#N)c1ccc(N)cc1
Reaction time: 8 h
Yield: 30.8 %

Procedure:
To 4.95 g aniline (53.128 mmol) are added 2.82 g acrylonitrile (53.128 mmol) and 3.89 ml heptane. A dry HCl gasflow is lead through the solution. Aluminiumchloride (4.10 g; 30.726 mmol) is added portionwise in 2.5 hours. The HCl flow is stopped and the reaction mixture is stored overnight at 0° C. After reflux for 1 hour, the reaction mixture is poured on ice, and dichloromethane is added. The organic phase is washed with 10% aqueous KCl-solution (4x) and, after drying, evaporated. The oil obtained is purified by column chromatography, yielding 2,39 g 4-aminophenylpropionitrile.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl[C:14]1=[C:15]([CH:40]=[CH:41][C:42]2[C:50]([CH3:52])([CH3:51])[C:49]3[C:44](=[CH:45][CH:46]=[C:47]([S:53]([O-:56])(=[O:55])=[O:54])[CH:48]=3)[N+:43]=2[CH2:57][CH2:58][CH2:59][S:60]([O-:63])(=[O:62])=[O:61])[CH2:16][CH2:17][CH2:18]/[C:19]/1=[CH:20]\[CH:21]=[C:22]1/[C:23]([CH3:39])([CH3:38])[C:24]2[C:25](=[N:37]/1)[N:26]([CH2:30][CH2:31][CH2:32][S:33]([O-:36])(=[O:35])=[O:34])[CH:27]=[CH:28][CH:29]=2.[Na+:64].[Na+]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:14]2/[C:15](=[CH:40]/[CH:41]=[C:42]3/[N:43]([CH2:57][CH2:58][CH2:59][S:60]([O-:63])(=[O:62])=[O:61])[C:44]4[C:49]([C:50]/3([CH3:51])[CH3:52])=[CH:48][C:47]([S:53]([O-:56])(=[O:54])=[O:55])=[CH:46][CH:45]=4)/[CH2:16][CH2:17][CH2:18][C:19]=2[CH:20]=[CH:21][C:22]2[C:23]([CH3:39])([CH3:38])[C:24]3[C:25]([N:37]=2)=[N+:26]([CH2:30][CH2:31][CH2:32][S:33]([O-:36])(=[O:35])=[O:34])[CH:27]=[CH:28][CH:29]=3)=[CH:6][CH:5]=1)([OH:3])=[O:2].[Na+:64].[Na+:64]
Reactant: CC1(C)C2=CC=CN(CCCS(=O)(=O)[O-])C2=N/C1=C/C=C1\CCCC(C=CC2=[N+](CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=C1Cl
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: CC1(C)C(/C=C/C2=C(c3ccc(C(=O)O)cc3)/C(=C/C=C3/N(CCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC2)=Nc2c1ccc[n+]2CCCS(=O)(=O)[O-]
Agent: CC1(C)C2=CC=CN(CCCS(=O)(=O)[O-])C2=N/C1=C/C=C1\CCCC(/C=C/C2=[N+](CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=C1Cl
Agent: [Na+]
Product: CC1(C)C(C=CC2=C(c3ccc(C(=O)O)cc3)/C(=C/C=C3/N(CCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC2)=Nc2c1ccc[n+]2CCCS(=O)(=O)[O-]

Procedure:
Compound 17 is prepared analogously to compound 10 (Example 10), except that 4-carboxyphenylboronic acid and compound 16 are used as starting materials.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[O:22][CH2:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[F:31].[C:32]([O:39][CH3:40])(=[O:38])[C:33]#[C:34][CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([F:31])[C:24]=1[CH2:23][O:22][C:16]1[N:15]2[N:14]=[C:34]([CH2:35][CH2:36][CH3:37])[C:33]([C:32]([O:39][CH3:40])=[O:38])=[C:20]2[CH:19]=[C:18]([CH3:21])[CH:17]=1
Reactant: CCCC#CC(=O)OC
Reactant: Cc1cc[n+](N)c(OCc2c(F)cccc2F)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nn2c(OCc3c(F)cccc3F)cc(C)cc2c1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.7 %

Procedure:
0.50 g (1.01 mmol) of 1-amino-2-[(2,6-difluorobenzyl)oxy]-4-methylpyridinium 2,4,6-trimethylbenzenesulphonate from Example 2A were dissolved in 3.3 ml of DMF, and 229 mg (1.82 mmol) of methyl hex-2-ynoate were added. 251 mg (1.82 mmol) of potassium carbonate were added and the mixture was stirred at RT for 3 h. Subsequently, the mixture was poured onto 24 ml of water and stirred briefly, and the precipitated solids were filtered off, washed with water and dried. 169 mg of the title compound were obtained (42% of theory; 95% purity).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH:40]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[CH:7][CH:8]=1)(=[O:40])[NH2:2]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide (0.35 g, 0.62 mmol) prepared in Example 7 in DMSO (7 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (1.05 g, 9.3 mmol), then aqueous solution (1N) of NaOH (3 mL, 3 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (50% to 100% EtOAc in CH2Cl2) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-phenyl)-amide as a white solid (Yield 0.26 g, 72%)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[C:6]2O.P(Br)(Br)[Br:18]>CN(C=O)C>[Br:18][C:6]1[C:7]([N+:13]([O-:15])=[O:14])=[CH:8][N:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]2
Reactant: BrP(Br)Br
Reactant: COc1ccc2ncc([N+](=O)[O-])c(O)c2n1
Solvent: CN(C)C=O
Product: COc1ccc2ncc([N+](=O)[O-])c(Br)c2n1
Temperature: 65 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
The compound of Example 2 (132.3 g, 1 eq.) was suspended in DMF (1200 mL) at 20° C. and PBr3 (68 mL, 1.2 eq.) was added over a period of 15 min. The mixture was stirred at 65° C. for 60 min, cooled to 20° C., poured on ice (800 g) and filtered. The product was slurried in ethanol (500 mL), filtered and dried on a rotary evaporator at 65° C., affording a yellow solid (155.8 g; 92% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH2:19])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH2:19])=[CH:6][CH:5]=1
Reactant: Nc1ncnc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-n2cnc3c(N)ncnc32)cc1
Yield: 89.2 %

Procedure:
In 1,000 mL of methanol, 13.1 g (51 mmol) of [9-(4-nitrophenyl)-9H-purin-6-yl]amine was suspended, and 1.0 g of 10% palladium carbon was added thereto and the mixture suspension was stirred at 60° C. for 22 hours in a hydrogen atmosphere. The palladium carbon was removed by Celite filtration and the filtrate was washed with 3 L of hot methanol. The methanol solution was concentrated under reduced pressure and the formed product was purified by a silica gel column (ethyl acetate:methanol=8:1) to obtain 10.29 g (89%) of a target product as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[C:9]([CH3:21])=[CH:10][C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:19]=1[CH3:20])([CH3:4])([CH3:3])[CH3:2].[Br:23]N1C(=O)CCC1=O.O>C(#N)C>[Br:23][C:10]1[C:11]2[O:15][C:14]([CH3:16])([CH3:17])[C:13](=[O:18])[C:12]=2[C:19]([CH3:20])=[C:8]([NH:7][C:6](=[O:22])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:9]=1[CH3:21]
Reactant: Cc1cc2c(c(C)c1NC(=O)OC(C)(C)C)C(=O)C(C)(C)O2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: Cc1c(Br)c2c(c(C)c1NC(=O)OC(C)(C)C)C(=O)C(C)(C)O2
Temperature: 25 °C
Yield: 72 %

Procedure:
To a solution of tert-butyl(2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Reference Example 60 (4.86 g, 15.9 mmol) in acetonitrile (70 mL) was added N-bromosuccinimide (5.67 g, 31.8 mmol) was heated under reflux for 1.5 hours. The reaction solution was cooled to room temperature, followed by addition of water, which was extracted with ethyl acetate, and the organic layer was washed with water and a saturation brine, dried over anhydrous sodium sulfate, and then was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7), and then was recrystallized with ethyl acetate-hexane to obtain 4.40 g (yield 72%) of the title compound. Melting point: 131-132° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.[C:13]1([N:19]([CH2:23][CH2:24]O)[CH2:20][CH2:21][OH:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12][CH2:24][CH2:23][N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21][OH:22])[N:11]=[C:4]2[N:3]=1
Reactant: OCCN(CCO)c1ccccc1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C)n2nc(SCCN(CCO)c3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
Under a nitrogen atmosphere, 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol (500 mg, 2.78 mmol), N-phenyldiethanolamine (458 mg, 2.53 mmol), tetrahydrofuran (5 mL) and a magnetic stirring bar were added to a 50 mL RBF. Triphenylphosphine (861 mg, 3.28 mmol) was added followed by the slow addition of diisopropylazodicarboxylate (664 mg, 3.28 mmol) via syringe over 15 minutes. The mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by HPLC. The reaction was concentrated then ethyl acetate (40 mL) was added which caused a precipitate to form. The precipitate was removed by filtration and rinsed with ethyl acetate (4 mL). The organic layer was concentrated. The title compound was purified by silica gel column chromatography with a gradient elution of 65-100% ethyl acetate in hexanes. Fractions were combined and concentrated under reduced pressure. The resulting solid was triturated with ethyl acetate (3 mL) and dried to afford the title compound as a white solid (274 mg, 32% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.16 (m, 3H), 6.90 (d, 2H), 6.59 (t, 1H), 4.71 (t, 1H), 3.73 (m, 2H), 3.56 (q, 2H), 3.46 (t, 2H), 3.35 (m, 2H), 2.74 (s, 3H), 2.56 (s, 3H). EM (calc.): 343.1; MS (ESI) m/e: 344.2 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([OH:14])(=[O:13])[C:10]([CH3:12])=[CH2:11]>>[CH:1]([CH2:12][C:10](=[CH2:11])[C:9]([OH:14])=[O:13])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: C=C(C)C(=O)O
Product: C=C(CC=Cc1ccccc1)C(=O)O

Procedure:
In a similar manner to that employed for the copolymer (a-2-1), except that the charged amounts of styrene and methacrylic acid were changed to 70.4% by mass and 9.6% by mass, respectively, a styrene-methacrylic acid copolymer (a-2-3) was obtained.
Reaction SMILES: [C:1]([C:9]1[CH:18]=[CH:17][C:12]2=[N:13][C:14](=[S:16])[N:15]=[C:11]2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Cl:22])[CH:20]=[CH2:21]>C(O)C>[ClH:22].[C:2]1([C:1]([C:9]2[CH:18]=[CH:17][C:12]3[N:13]=[C:14]([S:16][CH2:21][CH:20]=[CH2:19])[NH:15][C:11]=3[CH:10]=2)=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc2c(c1)=NC(=S)N=2
Reactant: C=CCCl
Solvent: CCO
Product: C=CCSc1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Product: Cl

Procedure:
6.55 g (25.76 mmoles) of 5-benzoyl-benzimidazol-2-thione, 2.45 ml of allyl chloride and 40 ml of ethanol are refluxed for 20 hours, thereafter further 2.45 ml of allyl chloride are added and the mixture is refluxed for further 5 hours. The product precipitates upon cooling. The weight (86.7%). M.p.: 182°-183° C. (after recrystallization from isopropanol)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:13])[CH:7]2[CH3:12].[Cl:14][C:15]1[C:16]([O:26][CH2:27][CH3:28])=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=1)[C:20](O)=[O:21]>>[ClH:14].[CH3:12][CH:7]1[C:8]2[C:3](=[C:2]([NH:1][C:20](=[O:21])[C:19]3[CH:23]=[C:15]([Cl:14])[C:16]([O:26][CH2:27][CH3:28])=[CH:17][C:18]=3[O:24][CH3:25])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][N:6]1[CH3:13]
Reactant: CC1c2cccc(N)c2CCN1C
Reactant: CCOc1cc(OC)c(C(=O)O)cc1Cl
Product: CCOc1cc(OC)c(C(=O)Nc2cccc3c2CCN(C)C3C)cc1Cl
Product: Cl

Procedure:
The title compound was prepared in a similar fashion to Example 1 from 5-amino-1,2-dimethyl-1,2,3,4-tetrahydroisoquinoline and 5-chloro-4-ethoxy-2-methoxybenzoic acid. The crude product was recrystallised from methanol and ethyl acetate to afford a pale brown solid (319 mg).