Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17])C(O)=O>C(O)(=O)C>[CH3:19][O:18][C:14]1[CH:13]=[C:9]([N+:1]([O-:4])=[O:2])[CH:8]=[C:7]([O:6][CH3:5])[C:15]=1[O:16][CH3:17]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a solution of nitric acid (20.0 mL) and acetic acid (40.0 mL) under 10° C. was added 3,4,5-trimethoxybenzoic acid (10.0 g, 47.0 mmol) in portions. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was then poured into ice-water. The resulting precipitate was collected by filtration and washed with water, which was then recrystallized from ethanol to afford the product 1,2,3-trimethoxy-5-nitrobenzene (6.64 g, yield 66.1%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.51 (s, 2H), 3.87 (s, 6H), 3.77 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[C:35]([CH3:37])[N:34]=[C:33]2[CH3:38])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:38][C:33]1[N:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:39])[NH:21][C:9]4[CH:10]=[C:11]([C:14]5[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[CH:36]=[C:35]([CH3:37])[N:34]=1
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)c2)c(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cn(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)c(C)n1

Procedure:
Prepared from (3-{3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K59) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (54 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[NH:14][C:13](=[O:15])[CH2:12][S:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].[C:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:20])[CH3:19]>C1COCC1>[F:8][C:6]1[CH:5]=[C:4]([C@@H:9]2[CH2:10][S:11][CH2:12][C:13](=[O:15])[N:14]2[CH2:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1CSC[C@@H](c2cc(F)cc(F)c2)N1
Reactant: CC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CN1C(=O)CSC[C@H]1c1cc(F)cc(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of (5R)-5-(3,5-difluorophenyl)thiomorpholin-3-one (247 mg, 1.08 mmol, prepared by analogy to Intermediate 2) in THF (8.0 mL) was added sodium hydride (38 mg, 1.5 mmol, 95% by weight). After 5 minutes, the ice bath was removed and the reaction was allowed to warm to ambient temperature. Once hydrogen gas evolution had ceased, as judged by an oil bubbler, the reaction mixture was cooled to 0° C., prior to the introduction of benzyl acetate (272 mg, 1.19 mmol). After 5 minutes, the ice bath was removed and the reaction was stirred for 15 hours. The bulk of the THF was removed under reduced pressure. The residue was then diluted with water and ether. The aqueous layer was extracted once with ether and the combined organics were washed with saturated brine. The organics were then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of MeOH:DCM—0.5:99.5 to 5:95, to give the title compound. MS: m/z=378 (M+1).
Reaction SMILES: Cl[C:2]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]([C:5]2[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=2[F:12])O1.[NH2:18][C:19]([NH2:21])=[S:20].C([O-])([O-])=O.[K+].[K+]>CCO>[NH2:21][C:19]1[S:20][C:4]([C:5]2[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=2[F:12])=[C:2]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:18]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C1(Cl)OC1c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1nc(N)sc1-c1c(F)cccc1F
Temperature: 0 °C

Procedure:
To a solution of ethyl 2-chloro-3-(2,6-difluorophenyl)oxirane-2-carboxylate in EtOH was added thiourea, followed by heating under reflux for 4 hours. To the reaction mixture was added ice-water, followed by addition of K2CO3 to make it basic. The solid precipitated was collected by filtration and washed with water to obtain ethyl 2-amino-5-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].O>N1C=CC=CC=1>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:16](=[O:17])[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Nc1cnc(-c2ccc(O)cc2)cn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cnc(-c2ccc(O)cc2)cn1)Oc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 2-amino-5-(4-hydroxyphenyl)pyrazine (283 mg) in pyridine (20 mL) was added under ice-cooling phenyl chloroformate (199 μL) and the mixture was stirred for 1 hour. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the solvent left a crystal residue, which was washed with diethyl ether (10 mL) to give the subject compound (314 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Br:9]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)cn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CBr)nc1
Reaction time: 5 h
Yield: 58.1 %

Procedure:
A suspension of 5-chloro-2-methylpyridine (Reference Example 52, Step A, 6.4 g, 50 mmol) and N-bromosuccinimide (12.5 g, 70 mmol) in 100 mL carbon tetrachloride was heated to gentle reflux (bath temperature 90° C.), and 2,2′-azobisisobutyronitrile (0.74 g) was added in several portions over 30 min. After stirring at this temperature for 5 h, the reaction mixture was concentrated. The resulting slurry was diluted with EtOAc (100 mL) and was washed with water (100 mL), saturated aqueous sodium bicarbonate/saturated aqueous sodium thiosulfate, and brine. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 2 to 15% ether in CH2Cl2/hexane (1:1) to afford 2-bromomethyl-5-chloropyridine (6.0 g, 60%), which was used immediately for the ensuing reaction. Thus, to a vigorously stirred solution of 2-bromomethyl-5-chloropyridine (6.0 g, 29 mmol) and 3-bromophenyl acetone (Step A, 6.0 g, 28 mmol) and tetrabutylammonium iodide (20 mg) in 30 mL CH2Cl2 at −78° C. was added cesium hydroxide monohydrate (10 g, 60 mmol), and the reaction was allowed to slowly warm to room temperate overnight. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 5 to 40% EtOAc in hexane to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 8.44 (d, 1H), 7.66 (dd, 1H), 7.46-7.41 (m, 2H), 7.24 (t, 1H), 7.22 (d, 1H), 7.15 (d, 1 h), 4.42 (dd, 1H), 3.54 (dd, 1H), 3.07 (dd, 1H), 2.12 (s, 3H). LC-MS: m/e 338 (M+H)+ (3.0 min).
Reaction SMILES: [N:1]1([C:13](=[O:14])[C:12]2[N:10]([CH3:11])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].S(=O)(=O)(O)O.[F:20][C:21](I)([F:23])[F:22].OO>[Fe].CS(C)=O>[F:20][C:21]([F:23])([F:22])[C:9]1[N:10]([CH3:11])[C:12]2[C:13](=[O:14])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=2[N:8]=1
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: FC(F)(F)I
Agent: [Fe]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CS(C)=O
Product: Cn1c(=O)c2c(nc(C(F)(F)F)n2C)n(C)c1=O
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 37 %

Procedure:
0.19 g (1.0 mmol) of caffeine was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 0.016 g (0.3 mmol) of iron powder, 2.0 ml of dimethyl sulfoxide, 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide and 0.2 ml of a 30% hydrogen peroxide aqueous solution. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 8-trifluoromethylcaffeine (19F-NMR yield: 37%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[CH:15]/[CH:16]=[CH:17]/[CH:18]=[O:19])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:20]([O:26][CH3:27])(=[O:25])[CH2:21][C:22]([CH3:24])=[O:23]>>[CH:11]1[C:12]2[C:13](=[CH:15]/[CH:16]=[CH:17]/[CH:18]([OH:19])[CH2:24][C:22](=[O:23])[CH2:21][C:20]([O:26][CH3:27])=[O:25])[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C/C=C/C=C1c2ccccc2Sc2ccccc21
Reactant: COC(=O)CC(C)=O
Product: COC(=O)CC(=O)CC(O)/C=C/C=C1c2ccccc2Sc2ccccc21

Procedure:
By the method of Example 1, (E)-4-(thioxanthen-9-ylidene)-2-butenal (1.94 g, 7.34 mmol) was reacted with methyl acetoacetate to form present title product, 1.43 g.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Na+].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12]([O-:14])=[O:13])[CH:7]=1>CN(C=O)C>[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12]([CH2:2][C:3]#[N:4])(=[O:14])=[O:13])[CH:7]=1
Reactant: O=S([O-])c1cccnc1
Reactant: N#CCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCS(=O)(=O)c1cccnc1
Reaction time: 1 h
Yield: 67.4 %

Procedure:
2.1 ml (33.4 mmol) of chloroacetonitrile were added to a solution of 4.6 g (42 mmol) of pyridine-3-sulphinic acid sodium salt in 50 ml of DMF and stirred at 90° for 1 hr. The reaction solution was evaporated, the residue was partitioned between H2O and CH2Cl2. The aqueous phase was washed three times with CH2Cl2. The combined organic phases were washed once with H2O, dried (MgSO4) filtered and evaporated. Chromatography (SiO2, AcOEt/hexane 2:1) yielded 4.1 g (80%) of (pyridine-3-sulphonyl)-acetonitrile as a beige solid.
Reaction SMILES: CC(C)([O-])C.[K+].[I:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:14][CH:15]=2)[NH:10][CH:9]=1.Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[CH:28][N:27]=1>CN(C=O)C.O>[F:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:29]1[CH:30]=[N:31][C:26]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:12]=3)[C:8]([I:7])=[CH:9]2)=[N:27][CH:28]=1
Reactant: O=C(c1ccc2c(I)c[nH]c2c1)N1CCOCC1
Reactant: Fc1ccccc1-c1cnc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(I)cn(-c3ncc(-c4ccccc4F)cn3)c2c1)N1CCOCC1
Temperature: 25 °C

Procedure:
Potassium tert-butoxide (236 mg, 2.106 mmol, 1.5 eq), compound 354a) (500 mg, 1.404 mmol, 1.0 eq) and 2-chloro-5-(2-fluorophenyl)pyrimidine (292 mg, 1.404 mmol, 1.0 eq) in DMF (10 mL) were stirred at 120° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography [100-200 mesh silica; ethyl acetate/pet ether=7:3]. Yield: 400 mg (53% of theory).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](C4C=C5C(=CC=4)C=C(N4C(=O)C(=C)SC4=O)C=C5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[C:38]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:39]=1[CH:40]=[CH:41][CH:42]=[C:43]2[CH:48]=[O:49]>>[C:1]12([C:11]3[CH:12]=[C:13]([C:38]4[CH:47]=[CH:46][CH:45]=[C:44]5[C:39]=4[CH:40]=[CH:41][CH:42]=[C:43]5[CH:48]=[O:49])[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: C=C1SC(=O)N(c2ccc3cc(-c4ccc(OC)c(C56CC7CC(CC(C7)C5)C6)c4)ccc3c2)C1=O
Reactant: O=Cc1cccc2c(Br)cccc12
Product: COc1ccc(-c2cccc3c(C=O)cccc23)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
The intermediate 5-[3-(1-adamantyl)-4-methoxyphenyl]-1-naphthaldehyde was prepared in a similar manner as described herein using 3-(1-adamantyl)-4-methoxyphenyl boronic acid (see Example 8) and 5-bromo-1-naphthaldehyde.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.Br[C:40]1[CH:41]=[C:42]([S:46]([NH2:49])(=[O:48])=[O:47])[CH:43]=[N:44][CH:45]=1.CCCCCCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:17]([F:18])([F:19])[C:15]1[CH:14]=[C:13]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:40]3[CH:41]=[C:42]([S:46]([NH2:49])(=[O:48])=[O:47])[CH:43]=[N:44][CH:45]=3)[N:7]=[CH:8]2)[CH:16]=1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1cncc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.503 g, 0.7 mmol), commercially available 5-bromo-pyridine-3-sulfonic acid amide (0.183 g, 0.77 mmol), tetrakis(triphenylphosphine)palladium (0.040 g, 0.030 mmol) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (258 mg, 72%). MS (ISP) 514.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:44][O:45][NH:46][CH3:47]>CN(C=O)C>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([N:46]([O:45][CH3:44])[CH3:47])=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-Amino-5-bromonicotinic acid (1 g, 4.6 mmol) in DMF (15 ml) is added EDC hydrochloride (1.06 g, 5.53 mmol), HOBt (0.747 g, 5.53 mmol), diisopropylethylamine (2 ml, 11.5 mmol) and N-methoxy-N-methylamine hydrochloride (0.54 g, 5.53 mmol), and the resulting solution is stirred at room temperature overnight. The reaction is concentrated in vacuo, and the residue is dissolved in EtOAc, washed with sat. aq. NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (SiO2, 0-10% ethanol in DCM) yields 2-Amino-5-bromo-N-methoxy-N-methyl-nicotinamide.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]O.C(N(CC)C(C)C)(C)C.S(Cl)([Cl:26])=O>C(OCC)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][Cl:26]
Reactant: COCOc1c(CO)cccc1OC
Reactant: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COCOc1c(CCl)cccc1OC
Reaction time: 0.25 h

Procedure:
2.34 g (11.8 mmol) of 2-methoxymethoxy-3-methoxybenzyl alcohol was dissolved in 20 ml of diethyl ether, and the resultant solution was added with 1.53 g (11.8, mmol) of N,N-diisopropylethylamine. To the obtained solution was fed dropwise 1.40 g (11.8 mmol) of thionyl chloride and diethyl ether (15 ml) in a manner of spending 15 min. while cooling the solution with ice. The temperature of the resultant mixture was then brought back to a room temperature, and the mixture was stirred all night. The insoluble materials therein are removed by filtration, and the filtrate was condensed under reduced pressure to thereby obtain a crude product of 2-methoxymethoxy-3-methoxybenzyl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)#[CH:2].Br[C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15].C1(C)C=CC=CC=1>C(N(CC)CC)C>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:24]2[CH:25]=[CH:11][CH:12]=[C:13]([C:14](=[O:15])[C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:23]=2)=[CH:4][CH:5]=1
Reactant: O=C(c1ccc(F)cc1)c1cccc(Br)c1
Reactant: C#Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)c1cccc(C#Cc2ccc(F)cc2)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Thus a reaction mixture is formed by dissolving appropriate amounts of 1-ethynyl-4-fluorobenzene, 3-bromo-4′-fluorobenzophenone, and tetrakis(triphenylphosphine)palladium[0] in a de-aerated aprotic solvent, for example, triethylamine. Alternatively, toluene can be used as a first solvent and triethylamine added as a cosolvent in a stoichiometric equivalent to 3-bromo-4′-fluorobenzophenone. The reaction mixture is heated to 80° C. with stirring under an inert atmosphere, e.g. argon, for approximately three hours. The reaction mixture is then allowed to cool to ambient while stirring is continued for approximately 16 hours. A white precipitate of triethylamine hydrobromide is removed by filtration and the aprotic solvents employed are removed by evaporation. The resulting solids are dissolved in a solvent, e.g. dichloromethane, or preferably toluene due to its relatively higher environmental friendliness, and then washed with water, an aqueous 2% HCl solution, brine, and then dried. After solvent evaporation, a good yield of white crystalline 4-fluoro-3′-(4-fluorobenzoyl)tolane, melting at approximately 127-128° C. is obtained. Purification by recrystallization from acetone results in a material with a melting point of 130-131° C. Alternatively, recrystallization from toluene provide a crystalline material in the form of rhombic fine needles with a melting point of 135-136° C.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12](Cl)(=[O:14])=[O:13])=[CH:7][CH:6]=1)#[N:4]>O1CCCC1>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([NH:2][CH3:1])(=[O:14])=[O:13])=[CH:7][CH:6]=1)#[N:4]
Reactant: CN
Reactant: N#Cc1ccc(CS(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: CNS(=O)(=O)Cc1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
Gaseous methylamine was introduced into a solution of 0.8 g (3.71 mMol) of 4-cyanobenzenemethanesulphonic acid chloride in 20 ml of tetrahydrofuran until a distinctly alkaline reaction was obtained. The mixture was stirred for a further hour at ambient temperature, the excess methylamine together with the solvent was distilled off in vacuo and the residue was triturated with diethylether. The crystals formed were suction filtered and dried. 420 mg (54% of theory) of colourless crystals were obtained, Mp. 151-152° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([O:41][CH:42]([CH2:45][CH3:46])[CH2:43][CH3:44])[CH2:14][C@@H:15]([OH:40])[C@@H:16]([NH:32]C(=O)OC(C)(C)C)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:32][C@@H:16]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:23]=1)[C@H:15]([OH:40])[CH2:14][N:13]([O:41][CH:42]([CH2:43][CH3:44])[CH2:45][CH3:46])[S:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)(=[O:11])=[O:12]
Reactant: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)ON(C[C@@H](O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 5 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
To an ice cold solution of tert-Butyl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl) (1-ethylpropoxy)amino]-1-[4-(benzyloxy)benzyl]-2-hydroxypropylcarbamate (1.5 g, 2.3 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (10 mL). After stirring at 5° C. for 3 h, the reaction was concentrated in vacuo, taken up in ethyl acetate (80 mL), washed with saturated sodium bicarbonate (2×50 ml), dried (magnesium sulfate) and concentrated in vacuo to afford the title compound (1.27 g, quant.) as an off-white foam. 1H NMR (DMSO-d6): δ 0.77 (6H, dt), 1.07-1.72 (4H, m), 1.82 (2H, br), 2.28 (1H, t), 2.58-3.05 (4H, m), 3.43-3.53 (1H, m), 3.95-4.03 (1H, m), 4.86 (1H, br s), 5.01 (2H, s), 6.16 (2H, s), 6.86 (2H, d), 7.03 (2H, d), 7.12-7.40 (8H, m);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:19][CH2:18][N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([C:16]#N)[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:20]=1.CC(C[AlH]CC(C)C)C.CC[O:32]C(C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:19][CH2:18][N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([CH:16]=[O:32])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:20]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: O=Cc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Temperature: -78 °C
Reaction time: 6 h
Yield: 40 %

Procedure:
To a solution of 2-chloro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-11-carbonitrile (500 mg, 1.77 mmol) in toluene (10 mL) was added DIBAL-H (505 mg, 3.55 mmol) in portion under nitrogen at −78° C. and then the mixture was stirred at −78° C. for 6 hours. The reaction mixture was quenched with ice water and extracted with EtOAc. Then the combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo to provide the 2-chloro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-11-carbaldehyde (200 mg, yield: 40%) through the column chromatography (petroleum ether:EtOAc=5:1˜2:1). 1H-NMR (CDCl3, 400 MHz) δ 10.29 (s, 1H), 8.03 (s, 1H), 7.69 (dd, J1=0.8 Hz, J2=7.2 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 6.05 (s, 2H). MS (M+H)+: 285/287.
Reaction SMILES: NC[C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9]C2C=NC=CC=2)=[O:8])=[CH:5][CH:4]=1.S1C=CC=C1S(Cl)(=O)=O>N1C=CC=CC=1>[C:7]([NH2:9])(=[O:8])[C:6]1[CH:16]=[CH:17][CH:3]=[CH:4][CH:5]=1
Reactant: NCc1ccc(C(=O)Nc2cccnc2)cc1
Agent: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: NC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(aminomethyl)-N-(3-pyridinyl)benzamide (33) (256 mg, 1.1 mmol) and 2-thienylsulfonyl chloride (206 mg, 1.1 mmol) in dry pyridine (10 mL) was stirred at 20° C. for 16 h. The solvent was evaporated and the residue stirred in ice/water (20 mL) for 1 h. The precipitate was filtered, washed with water (5 mL) and dried. The crude solid was purified by column chromatography, eluting with EtOAc, to give benzamide I-4 (318 mg, 75%) as a white powder: mp (EtOAc) 185-188° C.; 1H NMR δ 10.38 (s, 1H, NHCO), 8.93 (d, J=2.2Hz, 1 H, H-2″), 8.46 (br s, 1 H, NHSO2), 8.31 (dd, J=4.7, 1.5Hz, 1 H, H-6″), 8.19 (ddd, J=8.2, 2.5, 1.5Hz, 1 H, H-4″), 7.90-7.95 (m, 3 H, H-2, H-6, H-5′), 7.61 (dd, J=3.7, 1.3 Hz, 1 H, H-3′), 7.43 (br d, J=8.3Hz, 2 H, H-3, H-5), 7.39 (ddd, J=8.2, 4.7, 0.5 Hz, 1 H, H-5″), 7.18 (dd, J=5.0, 3.7Hz, 1 H, H-4′), 4.17 (s, 2 H, CH2N); 13C NMR δ 165.4, 144.4, 141.9, 141.5, 141.4, 135.7, 133.0, 132.4, 131.5, 127.6 (2), 127.5, 127.3 (2), 127.2, 123.4, 45.8; MS m/z 374.6 (MH+, 100%). Anal. calcd for C17H15N3O3S2: C, 54.67; H, 4.05; N, 11.25. Found: C, 55.23; H, 4.11; N, 11.32%.