Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10](=[O:51])/[C:11](/[NH:30][C:31](=[O:50])[C:32]1[CH:37]=[CH:36][C:35]([C:38]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([OH:48])[CH:43]=2)=[O:39])=[CH:34][C:33]=1[Cl:49])=[CH:12]/[C:13]1[S:17][C:16]([NH:18]C(OC(C)(C)C)=O)=[N:15][C:14]=1[C:26]([F:29])([F:28])[F:27].FC(F)(F)C(O)=O>ClCCl>[CH3:8][O:9][C:10](=[O:51])/[C:11](/[NH:30][C:31](=[O:50])[C:32]1[CH:37]=[CH:36][C:35]([C:38]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([OH:48])[CH:43]=2)=[O:39])=[CH:34][C:33]=1[Cl:49])=[CH:12]/[C:13]1[S:17][C:16]([NH2:18])=[N:15][C:14]=1[C:26]([F:29])([F:28])[F:27]
Reactant: COC(=O)/C(=C/c1sc(NC(=O)OC(C)(C)C)nc1C(F)(F)F)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)/C(=C/c1sc(N)nc1C(F)(F)F)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Triethylsilane (0.15 mL, 0.94 mmol) was added to a solution of (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[2-(1,1-dimethylethoxycarbonyl)amino-4-trifluoromethylthiazol-5-yl]propenoic acid methyl ester (130 mg, 0.198 mmol) in dichloromethane (1 mL). Trifluoroacetic acid (1 mL, 13.0 mmol) was added and the solution was stirred at room temperature for 2 h and then the solvents were removed under reduced pressure. NMR indicated that the reaction had not gone to completion, so the crude residue was re-dissolved in dichloromethane and treated with triethylsilane and trifluoroacetic acid as before. After the solution was stirred at room temperature for 3 h, the solvents were removed in vacuo and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was dried (Na2SO4), filtered and evaporated to give (Z)-3-(2-amino-4-trifluoromethylthiazol-5-yl)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]propenoic acid methyl ester (100 mg, 91% yield) as a yellow foam.
Reaction SMILES: [ClH:1].CO[C:4](=O)[CH:5]([NH2:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12].[N:15]#[C:16][NH2:17]>>[ClH:1].[CH2:6]([C:5]1[N:13]=[C:16]([NH2:17])[NH:15][CH:4]=1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12]
Reactant: N#CN
Reactant: C#CCCCCCC(N)C(=O)OC
Agent: Cl
Product: C#CCCCCCc1c[nH]c(N)n1
Yield: 53 %

Procedure:
2-Amino-non-8-ynoic acid methyl ester hydrochloride (2.02 g, 9.20 mmol) was treated to an Akabori reduction followed by a cyanamide condensation employing conditions previously reported to produce 4-Hept-6-ynyl-1H-imidazol-2-ylamine hydrochloride (1.04 g, 53%) as a pale yellow solid (Olofson et al., Journal of Organic Chemistry 1997, 62, (23), 7918-7919). 1H NMR (300 MHz, CD3OD) δ 6.17 (s, 1H), δ 2.19 (t, 2H), δ 1.90 (t, 1H), δ 1.86 (m, 2H), δ 1.24-1.13 (m, 6H) ppm; 13C NMR (75 MHz, CD3OD) δ 147.5, 128.3, 108.8, 83.8, 65.5, 28.4, 28.3, 28.2, 24.5, 17.8 ppm; HRMS (ESI) calcd for C10H16N3 (M+) 178.1338. Found 178.1337.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.C1C=CC2N(O)N=NC=2C=1.O[NH:26]/[C:27](=[N:46]/[H])/[C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[NH:35][CH:34]=[C:33]2[CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:46]=[C:27]([C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[C:36]=3[NH:35][CH:34]=[C:33]4[CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[N:26]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: [H]/N=C(/NO)c1cccc2c(CCCCC(=O)OCC)c[nH]c12
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCOC(=O)CCCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.4 %

Procedure:
To a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (279 mg) in tetrahydrofuran (40 mL) stirred at room temp was added EDC (479 mg) and HOBT (363 mg). The reaction mixture was stirred at room temperature for 2 h. Then ethyl 5-{7-[(E)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}pentanoate (D55) (390 mg) was added. The reaction mixture was stirred at 60° C. for 1 h, and then TBAF (1.0 mol/L in THF, 5 mL) was added. The reaction solution was concentrated and transferred to a microwave vessel. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 145° C. for 3 h. After cooling the reaction, the solvent was removed and the residue was purified by Mass Directed AutoPrep to afford ethyl 5-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]pentanoate (D56) (120 mg) as a yellow solid. δH (CDCl3, 400 MHz): 1.25 (3H, t), 1.45 (6H, d), 1.75-1.78 (4H, m), 2.37 (2H, t), 2.84 (2H, t), 4.14 (2H, q), 4.68-4.74 (1H, m), 7.05 (1H, d), 7.14-7.15 (1H, m), 7.25 (1H, t), 8.08 (1H, dd), 8.09 (1H, dd), 8.27 (1H, d), 9.58 (1H, s). MS (ES): C26H28ClN3O4 requires 481; found 482.2 (M+H+).
Reaction SMILES: [C:1]1([NH:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26].CC(C)([O-])C.[Na+]>C(O)CCC>[CH3:26][N:25]([CH3:27])[CH2:24][CH2:23][CH2:22][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[S:9][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:12][CH:11]=2)=[CH:18][CH:17]=1
Reactant: CN(C)CCCCl
Reactant: Oc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Temperature: 100 °C

Procedure:
A mixture of 4-(2-phenylamino-thiazol-5-yl)-phenol (35 mg, 0.130 mmol), 1-chloro-3-dimethylaminopropane hydrochloride (27 mg, 0.170 mmol, 1.3 equiv), and sodium tert-butoxide (29.6 mg, 0.299 mmol, 2.3 equiv) in 1-butanol (0.2 mL) is heated to 100° C. (using a preheated oil bath) for 3.5 h. The reaction mixture is allowed to cool to RT and concentrated in vacuo. Purification of the crude material by silica gel (10 g) column chromatography (CH2Cl2/MeOH, 90/10→80/20) affords the title compound as a reddish solid: ES-MS: 354.0 [M+H]+; single peak at tR=6.27 min (System 1); Rf=0.09 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:15][C:14](=[O:16])[CH:13]([CH3:17])[CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH:27]([F:29])[F:28])[CH:21]=1>>[F:29][CH:27]([F:28])[O:26][C:22]1[CH:21]=[C:20]([CH2:19][N:15]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH:13]([CH3:17])[C:14]2=[O:16])[CH:25]=[CH:24][N:23]=1
Reactant: FC(F)Oc1cc(CBr)ccn1
Reactant: COc1cccc(OC)c1C1CC(C)C(=O)N1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccnc(OC(F)F)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one with 4-(bromomethyl)-2-(difluoromethoxy)-pyridine. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.83 min.; [M+H]+: 393.19 g/mol.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([NH:22][CH3:23])=[O:21])[O:19][C:15]=2[C:14](F)=[C:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]=1[CH3:31])#[N:10].C(N(CC)CC)C>CS(C)=O>[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([NH:22][CH3:23])=[O:21])[O:19][C:15]=2[C:14]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]=1[CH3:31])#[N:10]
Reactant: CNC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Reaction time: 0.83 h

Procedure:
A dimethyl sulfoxide (1.5 ml) solution of (3S)-3-(dimethylamino)pyrrolidine (57 μl, 446 μmol) was added to a dimethyl sulfoxide (6 ml) solution of 4-cyano-7-fluoro-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-113) (115 mg, 372 μmol) and triethylamine (67 μl, 484 μmol) at 150° C., followed by stirring at the same temperature for 50 minutes under nitrogen atmosphere.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18](NC3SC=CN=3)=O)[CH2:13][CH2:12]2)[C:5]([Br:26])=[CH:4][N:3]=1.BrC1C(Cl)=C([N+]([O-])=O)C(N)=NC=1.CCN(C(C)C)C(C)C.C(N1CCNCC1)C>C(O)(C)C>[Br:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: CCN1CCNCC1
Agent: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Yield: 54 %

Procedure:
This was prepared using the same procedure as for 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide, but here using 5-bromo-4-chloro-3-nitropyridin-2-amine (300 mg, 1.19 mmol), DIPEA (1.1 eq, 1.31 mmol, 0.23 mL), isopropanol (7 mL) and 1-ethylpiperazine (1.1 eq, 1.31 mmol, 0.17 mL). After 18 h the precipitate was filtered and washed with cold water (2×3 mL) to give the product (212 mg, 54%) as a yellow solid; 1H-NMR (500 MHz, DMSO-d6) 1.04 (t, J=7.0 Hz, 3H, CH2CH3), 2.46-2.58 (2 m, 6H, CH2CH3 and piperazine N(CH2)2), 3.08 (br s, 4H, piperazine N(CH2)2), 6.98 (br s, 2H, NH2), 8.16 (s, 1H, pyridine H-6);
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.[C:43]1([CH2:49][CH2:50][CH2:51][NH2:52])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl>[C:43]1([CH2:49][CH2:50][CH2:51][NH:52][C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N:6]=2)=[O:10])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(O)c1ccc(O)cn1
Reactant: NCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(NCCCc1ccccc1)c1ccc(O)cn1
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
To a solution of 5-hydroxypyridine-2-carboxylic acid (0.103 g, 0.74 mmol) in dichloromethane was added diisopropylethylamine (0.279 mL, 1.6 mmol), followed by 1-hydroxybenzotriazole monohydrate (0.012 g, 0.8 mmol) and EDCl (0.153 g, 0.8 mmol). The resulting mixture was stirred for 15 minutes and 3-phenyl-1-propylamine (0.108 g, 0.8 mmol) was added. After stirring for 22 h, the reaction mixture was diluted with dichloromethane (80 mL), washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by column chromatography afforded 5-hydroxypyridine-2-carboxylic acid (3-phenylpropyl)amide as white crystals (0.116 g, 61% yield). MS (ES+) m/z 257.2 (M+1).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[S:17](=[O:20])(=[O:19])=[O:18]>S(=O)=O.[Pd]>[CH:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1.[C:8]1([S:17]([OH:20])(=[O:19])=[O:18])[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)=O
Agent: [Pd]
Agent: O=C1c2ccccc2C(=O)c2ccccc21
Agent: O=S=O
Product: O=C1c2ccccc2C(=O)c2c1cccc2S(=O)(=O)O
Yield: 76 %

Procedure:
New catalysts which promote selectively the α-sulfonation of anthraquinone in liquid sulfur dioxide as a solvent are taught addressed in, "Palladium-Catalyzed α-Monosulfonation of Anthraquinone by Sulfur Trioxide in Liquid Sulfur Dioxide" by Yasuziro Kawabata, et al., appearing in Journal of the Chemical Society of Japan, 1980, (3), p. 322-326, wherein the use of liquid sulfur dioxide and palladium containing compounds in the sulfonation reaction resulted in about 100% conversion of anthraquinone and 76% yield of 1-anthraquinonesulfonic acid with 99% α-selectivity. Further, Kawabata, et al. disclose a process of reprecipitation of the solubilized palladium on carbon by hydrogen treating, in which the pH value of the reaction mixture was adjusted to >7, and then 20 atm hydrogen was introduced to deposit the solubilized Pd on carbon. However, the conversion of anthraquinone was found to have decreased to 70% as the recovered Pd-carbon was recycled. Additionally, air or oxygen was introduced into the mixture after the Pd-carbon had been removed in order to precipitate a salt of the monoanthraquinonesulfonic acid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>>[OH:25][CH2:24][CH2:26][NH:27][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NCCO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCO)cn1
Yield: 81 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using ethanolamine instead of methylamine, to the title compound (92 mg, 81%) which was obtained as a white solid. MS: m/e=354.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].Cl>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1nc(OCc2ccccc2)c2[nH]cnc2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2,6-dichloropurine (0.30 g, 1.6 mmol) is added to a mixture of benzyl alcohol (0.19 g, 1.8 mmol) and 60% sodium hydride (0.13 g, 3.3 mmol) in DMF (8 ml) at room temperature (RT). After 1 hr, the reaction is heated to 60° C. for 18 hr, cooled to RT and dilute HCl is added to adjust the pH to 5. The mixture is extracted with EtOAc/THF 1:1, and the organic layer is dried over sodium sulfate, filtered and concentrated to give a solid. This is recrystallized from EtOAc/hexane to give the title compound, mp. 195°-196° C.
Reaction SMILES: O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[C:14]1(=[O:27])[C:22]2[C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19][C:18]=2[CH2:17][CH2:16][CH2:15]1.[CH3:28][C:29]1[N:33](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:32]=[N:31][C:30]=1[CH:53]=O.S(=O)(=O)(O)O>C1COCC1.FC(F)(F)C(O)=O>[CH3:28][C:29]1[NH:33][CH:32]=[N:31][C:30]=1/[CH:53]=[C:15]1/[C:14](=[O:27])[C:22]2[C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19][C:18]=2[CH2:17][CH2:16]/1
Reactant: O=C1CCCc2sc3ccccc3c21
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]cnc1/C=C1\CCc2sc3ccccc3c2C1=O
Reaction time: 1.5 h
Yield: 44.5 %

Procedure:
Lithium diisopropylamide mono(tetrahydrofuran) (1.5M in cyclohexane; 3.6 ml) was added dropwise to a solution of 3,4-dihydro-1(2H)-dibenzothiophenone (1.0 g) in dry THF (30 ml) at -65°. The resultant solution was stirred at -65° for 1 h and 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (1.9 g) was then added. The reaction mixture was stirred for a further 1.5 h, whilst it was allowed to warm to 0°. The solution was quenched with acetic acid (6 ml) and the resultant suspension was treated with water (10 ml) and p-toluenesulphonic acid (10.2 g). The reaction mixture was heated at reflux for 17 h, added cautiously to 8% aqueous sodium bicarbonate (300 ml), and extracted with dichloromethane (2×120 ml). The combined organic extracts were dried and evaporated to give an oil which was heated at reflux in a mixture of trifluoroacetic acid (60 ml) and concentrated sulphuric acid (0.3 ml) for 40 min. The reaction mixture was concentrated in vacuo to ca. 10 ml, added cautiously to 8% aqueous sodium bicarbonate (300 ml) and the resultant suspension was extracted with dichloromethane (2×120 ml). The combined organic extracts were dried and evaporated to give a foam which was purified by FCC eluting with System A (100:5:0.5) to give the title compound (648 mg) as a solid, m.p. 220°-223°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH2:13][NH:12][C:11](=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].OS(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CC(CCOC2CCCCO2)(c2ccc(Cl)c(Cl)c2)CN1
Agent: O=S(=O)(O)O
Product: Clc1ccc(C2(CCOC3CCCCO3)CCNC2)cc1Cl

Procedure:
Prepare according to the method of example 1.3.2 using 4-(3,4-dichloro-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy)ethyl ]-pyrrolidin-2-one (as prepared in example 11.3) (3 mmol), LiA1H4 (18 mmol) H2SO4 (99.999%) (9 mmol). Purify to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][CH:21]=3)([OH:17])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+].O>C(O)C.O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=3)([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(CCN2CCC(O)(COc3ccc(C=O)cc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(CCN2CCC(O)(COc3ccc(CO)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
The compound (0.20 g) obtained in Step 1 was dissolved in a mixture of ethanol (3 mL) and tetrahydrofuran (2.75 mL) and to this solution was added sodium borohydride (0.016 g) under cooling with ice-water and the mixture was stirred at the same temperature for two hours under nitrogen atmosphere. After adding water (15 mL) and stirring, to the mixture was added salt until it was saturated, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (Chromatorex NH™) (eluent; ethyl acetate:methanol=99:1 to 9:1) to obtain the titled compound (0.16 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7].[I-].[K+].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1>[N:31]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]2[CH:21]=[CH:20][C:19]3[S:18][C:17]4[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:15][CH:16]=4)[CH2:11][C:10]=3[CH:9]=2)=[O:7])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCNCC1
Reactant: O=C(CCCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCCl)ccc1S2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCCN3CCCCC3)ccc1S2
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture of 20 g of 2,7-bis(5-chlorovaleryl)thioxanthene, 2 g of potassium iodide, 70 ml of piperidine and 150 ml of tetrahydrofuran was heated in a Paar bomb at 100°C. with stirring for 48 hours. Upon cooling, the solvent was evaporated, and the remaining material was poured into water then filtered. The residue was recrystallized several times from heptane to give the desired product. M.P. 98.5°-99.5°C.
Reaction SMILES: [C:1](=[O:15])([O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[O:2][CH2:3]Cl.[I-:16].[Na+]>CC(C)=O>[C:1](=[O:15])([O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[O:2][CH2:3][I:16]
Reactant: O=C(OCCl)Oc1ccc([N+](=O)[O-])cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(OCI)Oc1ccc([N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
Chloromethyl p-nitrophenyl carbonate (52) (100 g, 0.43 moles), sodium iodide (228 g, 1.30 moles) and 50 g of dried molecular sieves (4 Å) were added to 2 L of acetone under nitrogen with mechanical stirring. The resulting mixture was stirred at 40° C. for 5 hours (monitored by 1H NMR). Upon completion, the solid materials were removed by filtration and the solvent was removed under reduced pressure. The residue was redissolved in dichloromethane (1 L) and washed twice with saturated aqueous sodium carbonate (300 mL) followed by water (300 mL). The organic layer was separated and dried over anhydrous sodium sulfate. Removal of solvent gave 123.6 g (89%) of the title compound (53) as a solid upon standing. The compound was found to be unstable to LC-MS. 1H NMR (CDCl3, 400 MHz): 6.06 (s, 2H), 7.42 (d, J=9 Hz, 2H), 8.30 (d, J=9 Hz, 2H). 13C NMR (CDCl3, 100 MHz): 155.1, 151.0, 146.0, 125.8, 125.7, 121.9, 33.5.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:20]=2[NH:19][C:18]([C:21](O)=[O:22])=[CH:17]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[N:25](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:20]=2[NH:19][C:18]([C:21]([NH2:25])=[O:22])=[CH:17]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)Nc2cccc3cc(C(=O)O)[nH]c23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Nc2cccc3cc(C(N)=O)[nH]c23)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 66 %

Procedure:
To a mixture of 7-{[(4-methylphenyl)sulfonyl]amino}-1H-indole-2-carboxylic acid (105 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (58 mg) and N,N-dimethylformamide (5 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (80 mg) at 4° C., and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (69 mg, yield 66%) as pale-yellow crystals. melting point 312-313° C.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[Cl:12][C@@H:13]([CH3:17])[CH2:14][CH2:15][OH:16].[CH2:18]([C:24]1[CH:25]=[N:26][C:27]([C:30]2[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=2)=[N:28][CH:29]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:12][C@@H:13]([CH3:17])[CH2:14][CH2:15][O:16][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[N:26]=[CH:25][C:24]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:29][N:28]=2)=[CH:35][CH:34]=1
Reactant: C[C@H](Cl)CCO
Reactant: CCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCc1cnc(-c2ccc(OCC[C@H](C)Cl)cc2)nc1
Reaction time: 24 h

Procedure:
26.3 g of (S)-3-chlorobutyl-1-tosylate, preparable from p-toluenesulfonyl chloride and (S)-3-chlorobutan-1-ol, and 27.2 g of 4-(5-n-hexylpyrimidin-2-yl)phenol are added to a suspension of 40 g of potassium carbonate in 200 ml of acetone. After 24 hours' boiling under reflux, the reaction mixture is filtered, the filtrate is free from solvent and the residue is twice recrystallized from ethanol. (S)-2-[p-(3-Chlorobutyloxy)phenyl]-5-n-hexylpyrimidine is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:22][C:23]1[C:28]([Cl:29])=[CH:27][C:26]([NH:30][CH2:31][CH2:32][NH2:33])=[CH:25][C:24]=1[Cl:34]>>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:33][CH2:32][CH2:31][NH:30][C:26]3[CH:25]=[C:24]([Cl:34])[C:23]([NH2:22])=[C:28]([Cl:29])[CH:27]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: NCCNc1cc(Cl)c(N)c(Cl)c1
Reactant: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCCl)CC2
Product: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCNCCNc1cc(Cl)c(N)c(Cl)c1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl)-propyl chloride and 2-(4-amino-3,5-dichlorophenylamino)-ethylamine analogously to Example 6.