Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:9]([CH:10]=O)=[CH:8][N:7]([CH2:12][C:13]([NH:15][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2[C:25]([NH2:27])=[O:26])=[O:14])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:29][NH:30][CH3:31].CN(C=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[C:1]([C:5]1[C:9]([CH2:10][N:30]([CH3:31])[CH3:29])=[CH:8][N:7]([CH2:12][C:13]([NH:15][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2[C:25]([NH2:27])=[O:26])=[O:14])[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CNC
Reactant: CC(C)(C)c1nn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN(C)Cc1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(C)(C)C
Reaction time: 1 h

Procedure:
2-[2-(3-Tert-butyl-4-formylpyrazol-1-yl)-acetylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (50 mg, 0.13 mmol) and dimethylamine hydrochloride (20 mg, 0.23 mmol) were mixed with DMF (0.3 mL) and acetic acid (0.3 mL). Sodium triacetoxyborohydride (70 mg, 0.33 mmol) was added and the mixture stirred for 1 h. The reaction was quenched with MeOH and water and directly purified by preparative reverse phase HPLC. The clean product was passed down an SCX cartridge and the volatiles were blown off under a nitrogen atmosphere (2.1 mg, 5 μmol, 4%).
Reaction SMILES: CO.C([O:11][CH2:12][C@@H:13]([O:39][CH2:40][O:41][CH3:42])[C@@H:14]([CH2:25][CH2:26][CH2:27][O:28]S(C1C=CC(C)=CC=1)(=O)=O)[CH2:15]OC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CC(C)([O-])C.[K+].O>O1CCCC1.C(OCC)(=O)C>[O:28]1[CH2:27][CH2:26][CH2:25][C@H:14]([C@H:13]([O:39][CH2:40][O:41][CH3:42])[CH2:12][OH:11])[CH2:15]1
Reactant: COCO[C@H](COC(=O)c1ccccc1)[C@@H](CCCOS(=O)(=O)c1ccc(C)cc1)COC(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCO[C@H](CO)[C@H]1CCCOC1
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
In 600 ml of tetrahydrofuran, containing 3.3 ml methanol were dissolved 47.3 g (82.3 mmol) of (2S,3S)-2-(methoxymethyl)oxy-3-(3-tosyloxypropyl)-1,4-butanediol dibenzoate and the solution was chilled in an ice-bath. To the solution were added, portionwise, 20.65 g (184 mmol) of potassium t-butoxide and the reaction mixture was stirred at room temperature for 2.5 hours. Then, an additional 2.46 g (22 mmol) of potassium t-butoxide and 150 μl of water were added and the reaction was stirred for an additional 30 minutes. Finally, 6 ml of water was added and the mixture was further stirred for 2 hours. The reaction mixture then was poured into a mixture of water and ethyl acetate. The aqueous phase was extracted four times with ethyl acetate and twice with 10% isopropanol-methylene chloride. The organic extracts were combined, dried over magnesium sulfate, carefully concentrated and purified by medium pressure column chromatography using silica gel and 72% ethyl acetate/hexane, 100% ethylacetate. The resulting compound, (2S)-2-[(3S)-tetrahydropyran-3-yl]-2-(methoxymethyl)oxyethanol, was found to be volatile. Thus, evaporation of the solvent was carefully carried out with an aspirator below room temperature. Pure fractions were collected and combined to yield 9.82 g of (2S)-2-[(3S)-tetrahydropyran-3-yl]-2-(methoxymethyl)oxyethanol contaminated with ethyl acetate (34%) as judged by 270 MHz 1H-NMR.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].[Br:7][C:8]1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][C:14](Cl)=[N:15]2)=[CH:10][CH:9]=1>CN(C=O)C>[Br:7][C:8]1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][C:14]([O:5][CH2:4][CH2:3][OH:6])=[N:15]2)=[CH:10][CH:9]=1
Reactant: Clc1cnc2ccc(Br)cc2n1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCOc1cnc2ccc(Br)cc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
Suspend sodium hydride (310 mg, 13 mmol) in a solution of ethylene glycol (800 mg, 13 mmol) in DMF (50 mL) at 0° C. After stirring for 30 min at room temperature, 7-bromo-2-chloro-quinoxaline (Preparation 26; 610 mg, 2.5 mmol) is added. Stir for 2 h at room temperature and dilute with 3:1 chloroform/isopropyl alchol. Wash the organic phase with brine and purify by FCC to give the title compound (564 mg, 85%). MS m/e (268, M+1). 1H NMR (400 MHz, CDCl3) δ 8.5 (s, 1H), 8.0 (d, J=2.0 Hz), 7.90 (dd, J=8.8, 2.0 Hz, 1H), 7.7 (d, J=8.8 Hz, 1H), 4.6 (t, d=4.8 Hz, 2H), 43.9 (t, J=4.8 Hz, 2H).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH2:40])[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1.Cl[C:42]1[N:47]=[C:46]([O:48][C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=2)[CH:45]=[C:44]([CH3:56])[N:43]=1.ClCCl>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:55][C:52]1[CH:53]=[CH:54][C:49]([O:48][C:46]2[CH:45]=[C:44]([CH3:56])[N:43]=[C:42]([NH:40][C:30]3[CH:31]=[CH:32][C:33]([N:34]4[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]4)=[C:28]([O:27][CH3:26])[CH:29]=3)[N:47]=2)=[CH:50][CH:51]=1
Reactant: Cc1cc(Oc2ccc(F)cc2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(Nc2nc(C)cc(Oc3ccc(F)cc3)n2)ccc1-n1cnc(C)c1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
Palladium acetate (7 mg, 0.03 mmol) and 2-(dicyclohexylphosphino)biphenyl (22 mg, 0.06 mmol) were dissolved in 2.5 mL of dioxane and stirred at 20° C. under argon for 10 minutes. Sodium tert-butylate (57 mg, 0.59 mmol) was added, followed by 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (80 mg, 0.39 mmol) and 2-chloro-4-(4-fluoro-phenoxy)-6-methyl-pyrimidine (115 mg, 0.48 mmol). The resulting mixture was heated in the microwave oven for 20 minutes at 200° C. Dichloromethane was added, insoluble material filtered off and the resulting solution purified by chromatography on silica gel using ethyl acetate as a solvent. The title compound was isolated as a yellow solid (50 mg, 31%). MS ISP (m/e): 406.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.58 (d, 1H), 7.46 (d, 1H), 7.17 (s, 1H), 7.15-7.05 (m, 4H), 7.04 (d, 1H), 6.91 (dxd, 1H), 6.80 (s, 1H), 6.23 (s, 1H), 3.62 (s, 1H), 2.40 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[NH:10]1[CH2:20][CH2:19][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11]1.O>C1(C)C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([O:16][C:14]([CH:13]1[CH2:19][CH2:20][N:10]([C:2]2[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=2)[CH2:11][CH2:12]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1ccc(Cl)nn1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2ccc(OC)nn2)CC1
Temperature: 100 °C
Yield: 40.2 %

Procedure:
A mixture of 4.33 g (30 mmol) 3-chloro-6-methoxypyridazine, 5.66 g (36 mmol) ethyl isonipecotate, 3.46 g (36 mmol) sodium tert.-butylate, 0.56 g (0.9 mmol) BINAP amd 0.55 g (0.5 mmol) Pd2 dba3 in 60 mL toluene was heated to 100° C. for 90 min. After cooling to room temperature water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried with Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated to yield 3.2 g (34%) of the title compound as orange solid. MS m/e: 266.3 [M+H]+.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]2[C:43]([CH3:44])=[CH:42][S:41][CH:40]=2)[CH:38]=1)[C:33](O)=[O:34])=[O:5])C.[CH3:45][NH:46][CH3:47]>>[C:4]([CH2:6][CH2:7][C:8]1[C:9]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:38]=[C:37]([C:39]3[C:43]([CH3:44])=[CH:42][S:41][CH:40]=3)[CH:36]=[C:32]([C:33](=[O:34])[N:46]([CH3:47])[CH3:45])[CH:31]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([OH:3])=[O:5]
Reactant: CNC
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cscc3C)c2)c1CCC(=O)OCC
Product: Cc1cscc1-c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(C(=O)N(C)C)c1

Procedure:
The title compound was prepared according to the general procedure described in Example 74 starting from 3-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-(4-methyl-thiophen-3-yl)-benzoic acid and dimethylamine (27% yield after two steps).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[NH:12][C:11](=[O:16])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](N)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C1OCCOC1>[O:16]=[C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[CH:3]=[C:2]([NH:1][S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[CH:15]=[CH:14][C:13]=2[NH:12]1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)Nc2ccc3[nH]c(=O)c4ccccc4c3c2)cc1
Reaction time: 30 h
Yield: 93 %

Procedure:
Prepared from 2-amino-6(5H)-phenanthridinone 3 and 4-methyl benzenesulfonamide according to General Procedure A. P-dioxane was used as solvent and the reaction was run at 40° C. for 30 hours. Purification of compound by crystallization in dioxane gave a brown solid (93% yield). mp 199-203° C. 1H-NMR (400 MHz, DMSO-d6), 10.20 (s, 1H), 8.30 (d, J=8.0 Hz, 1H), 8.15 (d, J=8.1 Hz, 1H), 7.95 (s, 1H), 7.88 (t, J=7.6, 1H), 7.65 (m, 3H), 7.33 (d, J=8.2 Hz, 2H), 7.19 (m, 2H). Anal. (C20H16N2O3S), C H N.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[F:14][C:15]1[CH:28]=[CH:27][C:18]2[S:19][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:21]([CH3:22])[C:17]=2[CH:16]=1>ClCCl.CN(C1C=CN=CC=1)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][S:23]([C:20]3[S:19][C:18]4[CH:27]=[CH:28][C:15]([F:14])=[CH:16][C:17]=4[C:21]=3[CH3:22])(=[O:25])=[O:24])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccc(-c2ccncc2)cc1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
To a solution of (4-pyridine-4-yl)aniline (CAS: 13296-04-3, 0.290 g) in dichloromethane (12.0 ml) was added 5-fluoro-3-methylbenzo[b]thiophene-2-sulphonyl chloride (0.440 g) and DMAP (0.305 g). The reaction mixture was stirred at rt for 16 h, diluted with dichloromethane (12 ml) and chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain the title compound (0.205 g) as an off-white solid. MS (ISN): 397.1 (M−H)−
Reaction SMILES: Cl[N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:9]1([CH:15]([SH:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:16][CH:15]([S:17][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(S)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(SN1C(=O)CCC1=O)c1ccccc1
Yield: 36.8 %

Procedure:
To a suitable reactor equipped with temperature controlling means and stirring means, there are charged, while maintaining the temperature at about room temperature, N-chlorosuccinimide (about 0.30 mole) in 400 ml of benzene and 1-phenylethanethiol (about 0.30 mole) in 50 ml of benzene. After stirring the reaction mixture 10 minutes, triethylamine (0.32 mole) in 50 ml of benzene is added dropwise. The benzene mixture is stirred one hour and then filtered. The filtrate is washed three times with 250 ml portions of water and then subjected to vacuum with heating to strip off volatile components. A crystalline residue is recrystallized from ethanol to give 26 grams of N-(α-methylbenzylthio)succinimide, m.p. 121-125°C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH:13]1[O:15][CH2:14]1.[NH2:16][CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>>[CH:17]1([NH:16][CH2:14][CH:13]([OH:15])[CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: NC1CCCc2ccccc21
Reactant: c1ccc2cc(OCC3CO3)ccc2c1
Product: OC(CNC1CCCc2ccccc21)COc1ccc2ccccc2c1

Procedure:
Following the general procedure of Example 98, but starting from 1-(2-naphthyloxy)-2,3-epoxypropane (4.5 g) and 1-aminotetralin (2.95 g), N-(1,2,3,4-tetrahydronaphth-1-yl)-2-hydroxy-3-(2-naphthyloxy)propanamine free base is obtained as an oily product which is dissolved in an isopropyl ether/isopropanol 1/1 mixture (40 ml) and acidified with HC1/isopropanol. The corresponding hydrochloride is thus obtained which is crystallized from isopropanol (20 ml). Yield: 2.2 g; m.p. 135°-137° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].CO.[N+](=[CH2:18])=[N-]>C1COCC1>[CH3:18][O:5][C:4](=[O:6])[C:3]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:2]=1[F:1]
Reactant: O=C(O)c1c(F)cccc1[N+](=O)[O-]
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a stirred solution of 2-fluoro-6-nitro-benzoic acid (2.15 g, 0.0116 mol) in THF (25 mL)/methanol (10 mL) under nitrogen was added diazomethane (5.8 mL) dropwise. The reaction mixture was stirred at room temperature overnight. HPLC indicated complete conversion to product. The reaction solvent was removed in vacuo to give a tannish yellow solid 2-Fluoro-6-nitro-benzoic acid methyl ester (2.2 g, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, 1H, J=7.6 Hz), 7.88 (m, 2H), 3.92 (s, 3H).
Reaction SMILES: [C:1](=[O:11])(SC)[S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CN=[CH:13]1>C(O)CO>[C:3]1([S:2][CH:1]([OH:11])[CH3:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CSC(=O)Sc1ccccc1
Reactant: c1c[nH]cn1
Solvent: OCCO
Product: CC(O)Sc1ccccc1
Temperature: 160 °C
Yield: 90 %

Procedure:
S-phenyl S-methyl dithiocarbonate prepared as described in Example 3 (5 g), ethylene glycol (5 ml), and imidazole (0.1 g) were placed in a stirred flask and heated to 160° C. for 10 hours. At this time, the major component (excepting ethylene glycol) was identified by g.c. comparison with an authentic sample as phenylmercaptoethanol (g.c. suggested over 90 percent yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>>[NH:10]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)[NH2:11]
Reactant: NN
Reactant: Clc1ccc(Cl)nc1
Solvent: O
Product: NNc1ccc(Cl)cn1

Procedure:
5 g of 2,5-dichloropyridine were reacted in the manner described in Example 22 with 2.2 ml of hydrazine hydrate. 1.6 g of 2-hydrazino-5-chloropyridine were obtained.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:35])=[C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:27]3[CH:28]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]=3[CH3:35])[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Cc1ccc(Cl)cc1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cc(Cl)ccc3C)CC2)c(OC)nc1C
Yield: 63 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(5-chloro-2-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH2:15])=[N+:2]=[N-:3].[C:16]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][O:18][CH2:17]1.O.C(#N)C>ClCCl>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:20](=[O:21])[CH2:19][O:18][CH2:17][C:16]([OH:23])=[O:22])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCCOCCOCCN
Reactant: O=C1COCC(=O)O1
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: [N-]=[N+]=NCCOCCOCCOCCNC(=O)COCC(=O)O
Reaction time: 8 h

Procedure:
To a solution of 11-azido-3,6,9-trioxaundecanamine (10.9 g, 50.0 mmol) in dichloromethane (100 ml) was added diglycolic anhydride (6.38 g, 55.0 mmol). The reaction mixture was stirred overnight. HPLC analysis (column Vydac 218TP54; solvents: A=water/0.1% TFA and B=acetonitrile/0.1% TFA; gradient 4-16% B over 20 min; flow 1.0 ml/min; UV detection at 214 and 284 nm), showed complete conversion of starting material to a product with retention time 18.3 min. The solution was concentrated to give quantitative yield of a yellow syrup. The product was analysed by LC-MS (ES ionisation) giving [MH]+ at 335 as expected. 1H (500 MHz) and 13C (125 MHz) NMR spectroscopy was in agreement with structure The product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18](Cl)=[O:19]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:18](=[O:19])[CH2:17][O:9][C:3]=2[CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(F)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: O=C1COc2cc(F)ccc2N1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
To a suspension of 2-amino-5-fluorophenol (Alfa, 15.00 g, 118 mmol), K2CO3 (48.9 g, 354 mmol) and tetrabutyl-ammonium bromide (3.80 g, 11.80 mmol) in MeCN (200 mL) was added 2-chloroacetyl chloride (14.66 g, 130 mmol) dropwise at 0° C. The reaction mixture was warmed to rt and then heated at reflux overnight. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The solid was collected, washed with water (100 mL) and dried in vacuo to give 7-fluoro-4H-benzo[1,4]oxazin-3-one as a pale solid (17.2 g, 87%). 1H NMR (DMSO-d6, 400 MHz): δ10.71 (s, 1H), 6.84-6.88 (m, 2H), 6.76-6.81 (m, 1H), 4.57 (s, 2H).
Reaction SMILES: [O:1]([C:9]1[CH:10]=[C:11]([C@H:23]([OH:28])[CH2:24][N+:25]([O-])=O)[CH:12]=[CH:13][C:14]=1[O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H][H]>CO.[Pd]>[O:1]([C:9]1[CH:10]=[C:11]([C@H:23]([OH:28])[CH2:24][NH2:25])[CH:12]=[CH:13][C:14]=1[O:15][Si:16]([C:19]([CH3:21])([CH3:20])[CH3:22])([CH3:18])[CH3:17])[Si:2]([C:5]([CH3:8])([CH3:6])[CH3:7])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H](O)C[N+](=O)[O-])cc1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H](O)CN)cc1O[Si](C)(C)C(C)(C)C
Yield: 93.3 %

Procedure:
98 mg of (S)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol obtained in example 10 was dissolved in 10 ml of methanol, and 10 mg of 10% Pd/C was added to the solution, after which the mixture was reacted at 20° C. under the hydrogen pressure of 0.3 MPa for 5 hours, so as to obtain 85 mg of the intended compound.
Reaction SMILES: [I:1][CH2:2][C:3]1([CH3:21])[O:20][C:6]2=[C:7]([CH3:19])[C:8]3[CH2:9][C:10]([CH3:18])([CH3:17])[N:11](C=O)[C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1.Cl.C(=O)([O-])O.[Na+].O.C(OCC)(=O)C>CO>[I:1][CH2:2][C:3]1([CH3:21])[O:20][C:6]2=[C:7]([CH3:19])[C:8]3[CH2:9][C:10]([CH3:17])([CH3:18])[NH:11][C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1
Reactant: Cc1c2c(c(C)c3c1OC(C)(CI)C3)N(C=O)C(C)(C)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c2c(c(C)c3c1NC(C)(C)C3)OC(C)(CI)C2
Yield: 97.8 %

Procedure:
To a solution of 2,3,6,7-tetrahydro-2-(iodomethyl)-2,4,6,6,8-pentamethyl-5H-furo[2,3-f]indole-5-carbaldehyde (2.42 g, 6.06 mmol) in methanol (10 ml) was added concentrated hydrochloric acid (3 ml), and heated under reflux for 2.5 hours under nitrogen atmosphere. The reaction mixture was added dropwise to a mixture of sodium hydrogen carbonate (3.7 g, 44 mmol) with water-ethyl acetate, neutralized and extracted three times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 2.20 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:4]=1[CH3:13].C(Cl)(Cl)(Cl)Cl.[Br:19]Br>CC(O)=O>[Br:19][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:13])[C:5]=1[C:9]([F:10])([F:11])[F:12]
Reactant: COc1cccc(C(F)(F)F)c1C
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc(Br)c(C(F)(F)F)c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask, was placed 1-methoxy-2-methyl-3-(trifluoromethyl)benzene (700 mg, 3.68 mmol, 1.00 equiv), CCl4 (3.0 mL). The mixture was cooled to 0° C. Br2 (698 mg, 4.37 mmol, 1.19 equiv) and AcOH (0.5 mL) were added. The resulting solution was stirred for 1 h at 30° C. The reaction process was monitored by TLC (Petroleum ether). The reaction was then quenched by the addition of 10 mL of saturated sodium bicarbonate. The resulting solution was extracted with 3×10 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether. This resulted in 0.7 g (71%) of 1-bromo-4-methoxy-3-methyl-2-(trifluoromethyl)benzene as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]1[CH2:12][C:11](=O)[CH2:10]1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:11]2[CH2:12][O:9][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C1COC1
Reactant: Nc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Clc1ccc(NC2COC2)cc1
Temperature: 40 °C
Reaction time: 5 h
Yield: 29.4 %

Procedure:
4-Chloroaniline (0.26 g, 2.0 mmol) was dissolved in methanol (25 ml). Then 3-oxetanone (0.22 g, 3 mmol) and zinc chloride (1.09 g, 8.0 mmol) were added and the reaction mixture was cooled with an ice bath. After adding sodium cyanoborohydride (0.377 g, 6.0 mmol) the mixture was allowed to stir at 40° C. for 5 hours. After cooling, the reaction mixture was poured onto ammonium chloride/ice and extracted with ethyl acetate (3 times 20 ml). The organic layer was dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography (heptane/ethyl acetate=95:5) to yield a light yellow liquid (108 mg, 29%); 1H-NMR (CDCl3): 4.14 b, 1H(NH); 4.55 m, 3H(CHO, CHN); 5.00 t, 2H(CHO), 6.43 d, 2H (aryl-H) and 7.15 d, 2H (aryl-H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]([O-])=[O:19])[S:17][C:10]=12.[Li+]>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:18]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[Cl:8])[CH:15]=2)=[O:19])[CH:3]=1
Reactant: Nc1cccnc1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: O=C(Nc1cccnc1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 3-aminopyridine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 290/292 (MH+), HPLC Rf: 4.72 min.; HPLC purity 95%.