Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][N:21]=1>>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccnc1Br
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Product: COc1cccnc1NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (3.97 g) and 2-bromo-3-methoxypyridine (1.50 g) were heated with stirring at 100° C. for 48 hours. The cooled residue was partitioned between chloroform and water. The aqueous layer was further extracted with chloroform and the combined chloroform layers were washed with water, dried and evaporated to dryness. The brown residue was dissolved in aqueous acetic acid to pH 4 and extracted with ether to remove unreacted 2-bromo-3-methoxypyridine. The aqueous solution was basified with potassium carbonate to pH 9-10 and then extracted with chloroform. The combined chloroform extracts were washed, dried and evaporated to dryness. The residue was subjected to column chromatography on silica with chloroform as eluant to afford the title compound as an oil. This was treated with maleic acid in isopropanol to give as a white solid, 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-3-methoxypyridine dimaleate (0.82 g), m.p. 111°-112° C. (recrystallised from acetone - ethyl acetate).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[CH3:10][NH:11][NH2:12]>C(O)CC>[NH2:6][C:5]1[N:11]([CH3:10])[N:12]=[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])[CH:4]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CNN
Solvent: CCCO
Product: Cn1nc(C(C)(C)C)cc1N
Temperature: 25 °C
Yield: 65.3 %

Procedure:
To a solution of 12.5 g (0.1 mol) of 4,4-dimethyl-3-oxopentanenitrile in 50 cm3 of n-propanol were added, at room temperature, 4.6 g (0.1 mol) of methylhydrazine. The reaction medium was maintained at reflux for 1 hour and then cooled to room temperature. The white solid obtained was filtered off on a sinter funnel and then washed with isopropyl ether. After drying under vacuum at 40° C., 10 g of the expected product were obtained in the form of a beige solid, the melting point of which was 157° C.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:13]([O:14][Si](C(C)(C)C)(C)C)[C@@H:12]([CH2:22][O:23][CH3:24])[O:11][C@H:10]1[N:25]1[CH:33]=[N:32][C:31]2[C:26]1=[N:27][C:28]([CH2:49][O:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)=[N:29][C:30]=2[NH:34][CH2:35][CH:36]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[C:43]1([CH:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:35][NH:34][C:30]2[N:29]=[C:28]([CH2:49][O:50][CH2:51][CH2:52][N:53]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)[N:27]=[C:26]3[C:31]=2[N:32]=[CH:33][N:25]3[C@H:10]2[C@H:9]([OH:8])[C@H:13]([OH:14])[C@@H:12]([CH2:22][O:23][CH3:24])[O:11]2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COCCN4CCCCC4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COCCN4CCCCC4)nc32)[C@H](O)[C@@H]1O
Yield: 30.4 %

Procedure:
The title compound was prepared by a similar method to example 38 using N-(9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-2-{[2-(1-piperidinyl)ethoxy]methyl}-9H-purin-6-yl)-N-(2,2-diphenylethyl)amine (100 mg, 0.12 mmol) (preparation 29), and a 1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (0.5 ml, 0.5 mmol). The compound was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (95:5:0.5) to give the title compound (22 mg) as a gum. MS: 604 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[C:17]1([CH3:24])[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:17]1([CH3:24])[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=1[O:23][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccccc1O
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccccc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 63.7 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added o-cresol (20 mg, 0.185 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-(4-o-tolyloxymethyl-phenyl)-isoxazole-5-carboxylic acid amide (21 mg, 64%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 8.00 (br. s., 1H), 7.92 (d, J=8.1 Hz, 2H), 7.53-7.67 (m, 3H), 7.05-7.20 (m, 2H), 6.99 (d, J=7.7 Hz, 1H), 6.74-6.90 (m, 1H), 5.19 (s, 2H), 2.21 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][CH2:28][O:29][C:22]=3[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][CH2:28][O:29][C:22]=4[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc4c(c3)OCCO4)c2c1C
Reactant: c1c[nH]cn1
Product: Cc1sc2nc(-n3ccnc3)nc(NCc3ccc4c(c3)OCCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6-dimethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6-dimethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:4]([C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=1)[C:5](=O)[NH:6]2.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>P(Cl)(Cl)(Cl)=O>[Cl:20][C:5]1[N:4]2[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=[C:3]2[C:2]2[C:7](=[CH:8][CH:9]=[CH:10][CH:1]=2)[N:6]=1
Reactant: O=c1[nH]c2ccccc2c2nc3ccccc3n12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nc2ccccc2c2nc3ccccc3n12

Procedure:
A mixture of 23.5 g (100 mmol) of benzimidazo[1,2-c]quinazolin-6(5H)-one [16367-99-0], 22.9 g (110 mmol) of phosphorus pentachloride and 250 ml of phosphoryl chloride is heated under reflux for 24 h. The excess phosphoryl chloride is removed in vacuo, 1000 ml of dichloromethane are added to the residue, the mixture is hydrolysed by addition of 1000 g of ice, rendered weakly alkaline by addition of 10% by weight sodium hydroxide solution, the organic phase is separated off, dried over sodium sulfate, and the dichloromethane is then removed in vacuo. Yield: 24.1 g (94 mmol), 94%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17](Br)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[CH2:21]([Sn](CCCC)(CCCC)CCCC)[CH:22]=[CH2:23]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH2:23][CH:22]=[CH2:21])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 160 °C
Yield: 54.3 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.300 g, 0.844 mmol), allyltributyl tin (0.414 mL, 1.350 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.097 g, 0.084 mmol) were combined in DMF (7 mL), purged with nitrogen, and heated at 160° C. in a microwave reactor for 30 min. The reaction mixture was filtered through Celite, diluted with EtOAc, and washed four times with dilute aqueous NaHCO3. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted successively with EtOAc followed by 0 to 10% CH3OH/DCM to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(2-propen-1-yl)benzonitrile (0.145 g, 0.458 mmol, 54.3% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.45-7.53 (m, 2H), 7.42 (s, 1H), 7.22 (s, 1H), 7.13 (s, 1H), 5.87-6.00 (m, 1H), 5.04-5.14 (m, 2H), 3.76 (s, 2H), 3.41 (d, J=6.59 Hz, 2H), 2.18-2.46 (br. s., 2H). LC-MS (ES−) m/z 315.20, 317.08 [M−1]. LC-MS (ES+) m/z 317.31, 319.31 [M+H].
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:19]2[O:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:22]4[NH:26][N:25]=[N:24][N:23]=4)[CH:16]=3)[C:11](=[O:27])[C:10]=2[CH:9]=1)(=O)C.[OH-].[Na+].Cl>O>[OH:4][CH2:5][CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:19]2[O:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:22]4[NH:26][N:25]=[N:24][N:23]=4)[CH:16]=3)[C:11](=[O:27])[C:10]=2[CH:9]=1
Reactant: CC(=O)OCCOc1ccc2oc3cc(-c4nnn[nH]4)ccc3c(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1c2ccc(-c3nnn[nH]3)cc2oc2ccc(OCCO)cc12

Procedure:
2-(2-Acetoxyethoxy)-6-(5-tetrazolyl)xanthone (1.0 g) was boiled under reflux with a solution of sodium hydroxide (2.0 g) in water (20 ml) for 2.5 h. The solution was cooled and poured into excess aqueous hydrochloric acid and the precipitated product filtered off, washed with water, and dried. Recrystallisation from dimethylformamide gave the title compound, m.p. 270° C. (decomposes).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([SH:11])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[OH-].[Na+].[CH3:17]OS(OC)(=O)=O>O>[CH3:17][S:11][C:5]1[CH:6]=[C:7]([CH:8]([CH3:9])[CH3:10])[C:2]([Br:1])=[CH:3][C:4]=1[CH:12]([CH3:14])[CH3:13]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)c1cc(Br)c(C(C)C)cc1S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1cc(C(C)C)c(Br)cc1C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
A mixture of 78.4 g of 4-bromo-2,5-diisopropylbenzenethiol and 12.8 g of sodium hydroxide was stirred together in 200 ml of water while 50.4 g of dimethylsulfate was added at a rate to maintain the reaction temperature between 45°-55°C. After stirring for 3 hours at ambient temperature, the reaction mixture was extracted with ether. The ether solution, washed with half saturated sodium chloride solution and dried over sodium sulfate, was concentrated to an oil which was distilled to give 64 g of 4-bromo-2,5-diisopropylphenyl methyl sulfide, boiling at 91°-93°C at 0.15-0.1 mm Hg; ND23 1.5714.
Reaction SMILES: O[CH2:2][C:3]1[N:4]([CH:18]([CH3:20])[CH3:19])[S:5](=[O:17])(=[O:16])[C:6]2[S:11][C:10]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9][C:7]=2[CH:8]=1.C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:39]([NH2:42])[C:40]#[CH:41]>C1COCC1>[CH3:19][CH:18]([N:4]1[C:3]([CH2:2][NH:42][CH2:39][C:40]#[CH:41])=[CH:8][C:7]2[CH:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:6]=2[S:5]1(=[O:17])=[O:16])[CH3:20]
Reactant: C#CCN
Reactant: CC(C)N1C(CO)=Cc2cc(S(N)(=O)=O)sc2S1(=O)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCNCC1=Cc2cc(S(N)(=O)=O)sc2S(=O)(=O)N1C(C)C
Reaction time: 18 h
Yield: 39 %

Procedure:
To a solution of the product from Example 15, Step E (1.40 g, 4.14 mmol) and triethylamine (1.26 g, 12.4 mmol) in anhydrous THF (80 mL) at 0° C. was added p-toluenesulfonyl chloride (1.18 g, 6.21 mmol) and the mixture was maintained at this temperature for 20 h. Propargylamine (3 mL) was added to the reaction mixture which was stirred for an additional 18 h. The reaction mixture was evaporated to a residue which was mixed with 2N HCl (60 mL) and this mixture was extracted with ethyl acetate (2×50 mL). The aqueous layer was separated and adjusted to pH 7.5 by the addition of a saturated aqueous solution of sodium bicarbonate (100 mL) followed by extraction with ethyl acetate (2×60 mL). The combined extracts were dried (MgSO4), filtered, and evaporated to a residue which was purified by column chromatography (silica, 50% to 75% ethyl acetate/hexane) to give an oil which crystallized from methylene chloride/hexane to provided an off-white solid (0.61 g, 39%): mp 133°-135° C. Analysis: Calculated for C13H17N3O4S3 : C, 41.58; H, 4.60; N, 11.11. Found: C, 41.42; H, 4.60;0N, 11.11.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:11]([OH:13])=O)[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH2:64])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[S:28]1[C:32]([C:33]2[CH:34]=[CH:35][C:36]([CH2:39][N:40]([NH:64][C:11](=[O:13])[C@H:7]([CH:8]([CH3:9])[CH3:10])[NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:37][CH:38]=2)=[CH:31][N:30]=[CH:29]1
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1)C(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C)C(C)C

Procedure:
Analogously to Example 7, 213 mg (1.13 mmol) of N-ethoxycarbonyl-(L)-valine, 431 mg (2.25 mmol) of EDC and 304 mg (2.25 mmol) of HOBT in 18 ml of DMF and 627 μl (4.5 mmol) of TEA are reacted with 0.75 mmol of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane (Example 7b) to form the title compound: m.p: 243-244° C.; HPLC20-100 : tRet =14.0; FAB MS (M+H)+ =697.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(N(CC)CC)C>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([C:33]([O:32][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:34])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1
Reactant: Nc1sc2c(c1C(=O)c1ccc(-c3ccccc3)cc1)CCNC2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Product: Nc1sc2c(c1C(=O)c1ccc(-c3ccccc3)cc1)CCN(C(=O)OCc1ccccc1)C2

Procedure:
2-Amino-3-(4-phenylbenzoyl)-4,5,6,7-tetrahydrothieno(2,3-c)pyridine was reacted with benzyloxycarbonyl chloride and triethylamine to afford the title compound as a solid (mp 83-85° C.). 1H NMR (CDCl3) 2.05 (m, 2H); 3.45 (m, 2H); 4.46 (s, 2H); 5.15 (s, 2H); 6.72 (bs, 2H) 7.35-7.66 (m, 14H)
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[F:5][C:6]1[CH:7]=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([OH:12])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:12][C:10]1[CH:11]=[C:6]([F:5])[CH:7]=[CH:8][C:9]=1[N+:13]([O-:15])=[O:14])[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(F)ccc1[N+](=O)[O-]
Yield: 74.7 %

Procedure:
Allyl bromide (3.4 g, 28 mmol, 1.5 eq) was added to a mixture of 5-fluoro-2-nitro-phenol (3.0 g, 19 mmol, 1 eq) and potassium carbonate (5.2 g, 38 mmol, 2 eq) in anhydrous acetonitrile (25 ml) and the mixture was heated to reflux for 6 hr. The reaction mixture was filtered and washed with acetonitrile and the filtrate concentrated to dryness to give 2-allyloxy-4-fluoro-1-nitro-benzene (2.8 g, 75%). The crude compound was used in the next stage without purification.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([S:8][CH3:9])=[N:6][N:7]=1.[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23])=[O:15]>O1CCOCC1>[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH:25][C:26](=[O:27])[NH:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([S:8][CH3:9])=[N:6][N:7]=1)(=[O:23])=[O:24])=[O:15]
Reactant: CSc1nnc(N)c(=O)n1C
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nnc(SC)n(C)c1=O
Yield: 73.1 %

Procedure:
3.42 g of 6-amino-4-methyl-3-methylthio-1,2,4-triazin-5-one are suspended in 100 ml of absolute dioxane, and 4.99 g of 2-methoxycarbonylphenylsulfonyl isocyanate are added at room temperature. The reaction proceeds slightly exothermically. After a reaction time of one hour at room temperature, the reaction has ended. The precipitate which has separated out is filtered off and washed with a small amount of dioxane. After drying, 6.0 g of 6-[3-(2-methoxycarbonylphenylsulfonyl)-ureido]-4-methyl-3-methylthio-1,2,4-triazin-5-one with a melting point of 186° C. are thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[OH-].[Na+].O.Cl[CH2:14][CH:15]([OH:19])[CH2:16][CH2:17][Cl:18]>C(O)(C)C>[Cl:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: OC(CCl)CCCl
Reactant: COc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: COc1ccccc1OCC(O)CCCl

Procedure:
To a mixture of 2 moles (248.26 g.) of 2-methoxyphenol, 4 moles (160 g.) of sodium hydroxide, 250 ml. of water and 1 liter of isopropanol was added with stirring 2.2 moles (314.64 g.) of 1,4-dichloro-2-butanol. The mixture was refluxed gently overnight. The reaction mixture was extracted with 1 liter of isopropyl ether, dried over sodium sulfate and distilled under reduced pressure. The distillate which was collected at 136°-138° C./0.015 mm. (396.8 g.) solidified to a white crystalline solid which melted at 48°-50° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[N:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)[CH:11]=1.CCN=C=NCCCN(C)C.Cl.[NH2:44][CH2:45][C@H:46]([OH:49])[CH2:47][OH:48]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[OH:49][C@H:46]([CH2:47][OH:48])[CH2:45][NH:44][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:18]=[N:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][N:14]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29]
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: NC[C@H](O)CO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C(=O)NC[C@H](O)CO)[nH]2)c1
Reaction time: 25 h
Yield: 53.5 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulfonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.07 g, 2.39 mmol) synthesized in Example (97e) was dissolved in methylene chloride (20 mL), and WSCI.HCl (732 mg, 3.82 mmol), (S)-(−)-3-amino-1,2-propanediol (500 mg, 5.49 mmol) and 4-dimethylaminopyridine (146 mg, 1.19 mmol) were added at room temperature, followed by stirring for 25 hours under nitrogen atmosphere. The reaction solution was diluted with ethyl acetate (50 mL), washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired product (666 mg, 54%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH2:18])[CH2:3]1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:25]=1>N1C=CC=CC=1.O>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH:18][S:30]([C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)(=[O:32])=[O:31])[CH2:3]1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C(F)(F)F)cc21
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2cccnc2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,4-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)aniline (150 mg, 0.47 mmol) in pyridine (2 mL) was added pyridine-3-sulfonyl chloride (100 mg) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by HPLC to give pyridine-3-sulfonic acid [2-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide LC/MS m/e obsd. (ESI+) [(M+H)+] 462.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([N:25]=[C:26]=[S:27])(=O)C1C=CC=CC=1.CO.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:26]([NH2:25])=[S:27])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(NC(N)=S)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3 g (13.5 mmol) (4-Amino-benzyl)-carbamic acid tert-butyl ester and 1.81 ml (13.5 mmol) benzoyl isothiocyanate in 60 ml THF was stirred at room temperature for 1 h and afterwards evaporated under reduced pressure. 80 ml MeOH and 5.6 g (40.5 mmol) potassium carbonate in 80 ml water were added and the mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layers were washed with saturated NaHCO3 solution and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica eluting with a gradient of hexane/ethyl acetate to yield after evaporation of the product fractions 3.67 g (97%) of the title compound as yellow amorphous solid.