Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([NH:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:16])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OCCCc1cccnc1)[C@@H]1CCCN1
Reactant: O=C=NC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCCc1cccnc1)[C@@H]1CCCN1C(=O)NC1CCCCC1
Reaction time: 1 h
Yield: 37.1 %

Procedure:
A mixture of cyclohexylisocyanate (100 mg; 0.9 mmol), 3-(3-pyridyl)-1-propyl (2S)-pyrrolidine-2-carboxylate (200 mg; 0.9 mmol) and triethylamine (90 mg; 0.9 mmol) in 20 mL of methylene chloride was stirred for 1 hour and then partitioned between water and a 1:1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50w ethyl acetate/hexane) to obtain 120 mg (36%) of the compound of Example 4 (Compound 4, Table I). 1H NMR (CDCl3, 300 MHz):δ 1.10-1.27 (m, 6H); 1.69-1.75 (m, 4H); 1.94-2.03 (m, 4H); 2.67-2.73 (t, 2H); 3.31-3.44 (m, 3H); 4.12-4.16 (m, 2H); 4.39-4.42 (m, 1H); 7.25-7.34 (m, 1H); 7.25-7.55 (dd, 1H); 8.45 (s, 2H). Analysis calculated for C20H29N3O3—0.6 H2O: C, 64.88; H, 8.22; N, 11.35. Found: C, 64.60; H, 8.18; N, 11.21.
Reaction SMILES: C([S:4][CH2:5][C@H:6]1[N:11]([CH2:12][CH:13](Cl)[C:14]2[C:15]([CH3:24])=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[O:18][CH2:17]3)[CH2:10][CH2:9][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:7]1)(=O)C.C[O-].[Na+].CO>C1COCC1>[CH3:24][C:15]1[C:14]([C@@H:13]2[S:4][CH2:5][C@@H:6]3[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:9][CH2:10][N:11]3[CH2:12]2)=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][O:18][C:19]2=[O:23]
Reactant: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(Cl)c1ccc2c(c1C)COC2=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c([C@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CS2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (3S)-tert-butyl 3-(acetylthiomethyl)-4-(2-chloro-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazine-1-carboxylate (596 mg, 1.234 mmol) in anhydrous THF (20 mL) was treated dropwise with sodium methoxide, 25% solution in methanol (0.846 mL, 3.70 mmol). The reaction mixture was stirred for 2 hours under nitrogen at room temperature. LCMS showed formation of the desired product. Solvent was removed under reduced pressure. Residue was redissolved in dichloromethane and washed with brine. Organic layer was dried over MgSO4, filtered and concentrated. Residue was purified on Biotage SP 1, eluting with 20-80% ethyl acetate/hexanes, 16 CV (CV stands for column volume): 1H NMR (500 MHz, CDCl3) δ 8.64 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 5.29 (s, 2H), 3.81-4.20 (m, 3H), 3.38 (dd, J=2.3, 12.6 Hz), 3.00-3.22 (m, 2H), 2.57-2.82 (m, 2H), 2.24-2.56 (m, 7H), 1.51 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N.[CH3:8][C:9]1[C:21]([CH3:22])=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([C:23](O)=[O:24])[C:18]=3[NH:19]2)=[CH:11][CH:10]=1>>[CH3:8][C:9]1[C:21]([CH3:22])=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([C:23]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:24])[C:18]=3[NH:19]2)=[CH:11][CH:10]=1
Reactant: Cc1ccc2c([nH]c3c(C(=O)O)cccc32)c1C
Reactant: C1COCCN1
Agent: N
Product: Cc1ccc2c([nH]c3c(C(=O)N4CCOCC4)cccc32)c1C
Yield: 75 %

Procedure:
Under the conditions of Example 31, but with the difference that excess morpholine is added to the reaction mixture in place of the ammonia, 7,8-dimethylcarbazole-1-carboxylic acid is converted into the carboxylic acid morpholide. After recrystallization from dioxane - water, 7,8-dimethylcarbazole-1-carboxylic acid morpholide is obtained in a 75% yield, m.p. 183° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:6][CH:5]=[C:4]([CH3:15])[N:3]=1.[CH2:16]([NH2:18])[CH3:17]>>[CH2:16]([NH:18][C:2]1[C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:6][CH:5]=[C:4]([CH3:15])[N:3]=1)[CH3:17]
Reactant: Cc1ccc(C(=O)c2cccs2)c(Cl)n1
Reactant: CCN
Product: CCNc1nc(C)ccc1C(=O)c1cccs1

Procedure:
In a sealed tube were heated and stirred 2-chloro-6-methyl-3-(thiophene-2-carbonyl)pyridine and a 70% ethylamine aqueous solution. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 2-ethylamino-6-methyl-3-(thiophene-2-carbonyl)pyridine. NMR1: 7.97 (1H, d, J=8.1 Hz), 7.62 (1H, dd, J=5.0, 1.1 Hz), 1.28 (3H, t, J=7.3 Hz).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].F[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc(O)c1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1cccc(Oc2ccc(C=O)cc2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
The crude product from Example 61B in anhydrous DMF (40 mL) was treated with K2CO3 (15.5 g, 112 mmoles) and 4-fluorobenzaldehyde (4.82 mL, 44.9 mmoles). The reaction mixture was stirred overnight at 100° C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The mixture was washed with H2O (2×), brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 8% ethyl acetate:hexanes) to provide the title compound (5.75 g, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=O)[NH:8][C:5]2=[N:6][CH:7]=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[N:6][CH:7]=1)[NH:8][CH:9]=[CH:10]2
Reactant: O=C1Cc2cc(Br)cnc2N1
Solvent: C1CCOC1
Product: Brc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
Under an argon atmosphere and in an anhydrous medium, 37.6 ml (37.6 mmol) of a 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran are added at 0° C. and dropwise to a suspension of 2 g (9.4 mmol) of the compound obtained in Step B in 50 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred for 35 minutes at room temperature and then evaporated to dryness. The residue is taken up in an aqueous 6M hydrochloric acid solution and heated until the solid has completely dissolved. After cooling, the solution is rendered alkaline with an aqueous 6M sodium hydroxide solution and extracted with ethyl acetate. After drying over magnesium sulphate and evaporation, an equimolar mixture of 5-bromo-7-azaindoline and 5-bromo-7-azaindole is obtained. The preceding residue, which is dissolved in 20 ml of acetic acid, is added at room temperature to a suspension of 4.10 g (15.3 mmol) manganese(III) acetate dihydrate in 20 ml of acetic acid. After 45 minutes' stirring at 75° C. the solution is evaporated to dryness and coevaporated with toluene. The residue, which is taken up in water, is rendered alkaline with an aqueous saturated sodium hydrogen carbonate solution. After extraction with ethyl acetate the organic phases are dried over magnesium sulphate and evaporated. The resulting residue is purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate) to yield the title compound in the form of a yellow solid.
Reaction SMILES: FC(F)C1C([C:8](Cl)=[O:9])=CN(C)N=1.Cl.[Cl:14][C:15]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[C:16]=1[O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1.C(N(CC)CC)C>ClCCl>[Cl:14][C:15]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[C:16]=1[O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH:8]=[O:9]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: Clc1cc(Cl)c(OC[C@@H]2CCCN2)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CN1CCC[C@H]1COc1c(Cl)cc(Cl)cc1Cl
Reaction time: 3 h

Procedure:
At a temperature of 0° C., a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.243 g; 1.24 mmol) in dichloromethane (5 ml) was added dropwise to a stirred solution of (S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidine hydrochloride (0.35 g; 1.24 mmol), which was prepared as described in example P12, and triethylamine (0.35 ml; 2.48 mmol) in dichloromethane (10 ml). The ice bath was removed and reaction mixture was allowed stirring for 3 hours. The reaction mixture was washed with 1M NaOH (10 ml), 2M HCl (10 ml) and saturated NaCl (50 ml) and then dried over Na2SO4. After removal of the solvent, the residue (0.45 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 2:8). 0.27 g (50% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-[(S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidin-1-yl]-methanone was obtained in form of an oil which solified after standing.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:25][CH3:26])[C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:11]=2)=[N:6][CH:7]=1.[C:27]1([SH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:26][O:25][C:4]1[C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:11]=2)=[N:6][CH:7]=[C:2]([S:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:3]=1
Reactant: COc1cc(Br)cnc1NC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1
Reactant: Sc1ccccc1
Product: COc1cc(Sc2ccccc2)cnc1NC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1

Procedure:
The entitled compound was produced according to the method of Reference Example 8 (step 1) but using the compound obtained in Example 109 (step 1) and benzenethiol as the starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.CS(O)(=O)=O.[N-:18]=[N+]=[N-].[Na+].[OH-].[Na+]>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:12])[NH:18][CH2:7][CH2:8][O:9][C:10]=2[CH:11]=1
Reactant: O=C1CCOc2cc(Br)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C1NCCOc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 101.9 %

Procedure:
A solution of 7-bromochroman-4-one (340 mg, 1.5 mmol) and methanesulfonic acid (3 mL, 23.0 mmol) in DCM was cooled to 0° C. and treated with NaN3 (146 mg, 2.25 mmol) portionwise, while maintaining the internal temperature below 5° C. The reaction was then stirred at 0° C. for 4 h. At completion, the reaction was slowly neutralized with 8 N aq. NaOH, then diluted with DCM (20 mL) and water (20 mL). The layers were separated and the organics were dried over MgSO4, filtered and evaporated to afford 8-bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (370 mg, 100% yield). MS (EI) m/z=242.1 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[CH2:4][S:5][C:6]#[N:7].[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([O:1][CH2:2][C:3]([CH3:9])([CH3:8])[CH2:4][S:5][C:6]#[N:7])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(CO)CSC#N
Solvent: c1ccncc1
Product: CC(=O)OCC(C)(C)CSC#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 58.7 g of 3-hydroxy-2,2-dimethyl-1-propylthiocyanate, 400 ml of acetic anhydride and 400 ml of pyridine was stirred for 16 hours at room temperature. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 500 ml of diethyl ether. The solution was washed in turn with 1N-hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. After removing the solvent, the residue was purified by distillation under reduced pressure, thereby affording 53.2 g of 3-acetoxy-2,2-dimethyl-1-propylthiocyanate.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[O:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=[C:7]1[N:1]1[CH2:6][CH2:5][N:4]([C:26]([C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:20]3[N:19]=[C:18]([C:17]([F:32])([F:16])[F:33])[O:22][N:21]=3)[CH:24]=2)=[O:27])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: c1ccc2oc(N3CCNCC3)nc2c1
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(c2nc3ccccc3o2)CC1
Yield: 12 %

Procedure:
This compound was synthesized from 2-(piperazin-1-yl)benzo[d]oxazole and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (20 mg, yield 12%). 1H NMR (400 MHz, CDCl3) δ 8.26-8.22 (m, 2H), 7.69-7.63 (m, 2H), 7.40-7.39 (m, 1H), 7.31-7.29 (m, 1H), 7.23-7.19 (td, J=7.7 Hz, 1.1 Hz, 1H), 7.10-7.06 (m, 1H), 3.96-3.63 (m, 8H). MS (ESI) m/z: Calculated for C21H16F3N5O3: 443.12. found: 444.2 (M+H)+
Reaction SMILES: S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[C:16]([O:35][CH2:36][C@H:37](O)[CH3:38])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:50][O:51][C@@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1>C(Cl)Cl>[CH3:50][O:51][C@@H:52]1[CH2:56][CH2:55][N:54]([C@@H:37]([CH3:38])[CH2:36][O:35][C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:53]1
Reactant: C[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CO[C@@H]1CCNC1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CO[C@@H]1CCN([C@@H](C)COC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: -20 °C
Yield: 65.8 %

Procedure:
Triflic anhydride (1M in DCM, 1.67 mL, 1.67 mmol) was added to a solution of (R)-1-(trityloxy)propan-2-ol (505 mg, 1.59 mmol) and diisopropylethylamine (0.55 mL, 3.16 mmol) in DCM (10 mL) at −78° C. The reaction was allowed to warm to −20° C. over 1 h. Diisopropylethylamine (0.32 mL, 1.84 mmol) and (R)-3-methoxypyrrolidine hydrochloride (255 mg, 1.85 mmol) were added to the reaction and the mixture was allowed to warm to room temperature over 3 h. The reaction mixture was washed with 2×10 mL saturated aqueous NaHCO3, washed with 10 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to yield (R)-3-methoxy-1-((S)-1-(trityloxy)propan-2-yl)pyrrolidine (420 mg). 1H NMR (DMSO-d6): δ 7.40-7.20 (m, 15H), 3.76 (m, 1H), 3.26 (m, 1H), 3.11 (s, 3H), 3.09 (m, 1H), 2.82 (m, 1H), 2.64 (m, 1H), 2.48 (m, 1H), 2.38 (m, 2H), 1.84 (m, 1H), 1.55 (m, 1H), 1.05 (d, 3H).
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[CH:39][C:40]([C:43]#[C:44][C:45]3[CH:46]=[CH:47][C:48]([O:54][CH2:55][CH2:56][N:57]4[CH2:61][CH2:60][CH2:59][CH2:58]4)=[C:49]([CH:53]=3)[C:50]([OH:52])=O)=[N:41][CH:42]=2)=[CH:33][CH:32]=1.CN>CN(C=O)C>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[CH:38]=[CH:39][C:40]([C:43]#[C:44][C:45]3[CH:46]=[CH:47][C:48]([O:54][CH2:55][CH2:56][N:57]4[CH2:58][CH2:59][CH2:60][CH2:61]4)=[C:49]([CH:53]=3)[C:50]([NH:2][CH3:1])=[O:52])=[N:41][CH:42]=2)=[CH:35][CH:36]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 mg (0.25 mmol) TBTU and 69 μL triethylamine are added to a solution of 112 mg (0.25 mmol) 5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzoic acid (Example 22) in 5 mL DMF and the reaction mixture is stirred for 2 h at RT. Then 31 mg (1.0 mmol) methylamine are added and stirring is continued for a further 2 h at RT. The mixture is evaporated down i. vac., the residue is combined with dilute Na2CO3 solution, extracted exhaustively with DCM and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, DCM to DCM/MeOH/NH3 7:3:0.3).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].Cl.[CH3:6][O:7][C:8](=[O:21])[C:9]1[C:10](=[C:15]([CH2:19][NH2:20])[CH:16]=[CH:17][CH:18]=1)[C:11]([O:13][CH3:14])=[O:12]>O>[CH3:6][O:7][C:8](=[O:21])[C:9]1[C:10](=[C:15]([CH2:19][NH:20][C:2]([NH2:3])=[O:1])[CH:16]=[CH:17][CH:18]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: N#C[O-]
Reactant: COC(=O)c1cccc(CN)c1C(=O)OC
Agent: Cl
Agent: [K+]
Solvent: O
Product: COC(=O)c1cccc(CNC(N)=O)c1C(=O)OC
Reaction time: 2 h
Yield: 68.3 %

Procedure:
Potassium cyanate (1.9 g, 22.93 mmol) was added portionwise over 2 hours to a stirred solution of 3-aminomethyl-phthalic acid dimethyl ester hydrochloride (2.0 g, 7.7 mmol) in water (60 mL). After stirred for another 2 hours, the mixture was acidified to pH 4. The mixture was filtered to give 3-ureidomethyl-phthalic acid dimethyl ester (1.4 g, 70%): 1H NMR (DMSO-d6) δ 3.82 (s, 6H), 4.19 d, J=6.0 Hz, 2H), 5.63 (s, 2H), 6.38 (t, J=5.8 Hz, 1H), 7.54-7.62 (m, 2H), 7.78-7.81 (dd, J=2.2 and 6.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([I:12])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.I[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([I:12])[C:5]([O:11][CH2:15][CH3:16])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)c(C)c(I)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1c(C(C)=O)cc(Cl)c(C)c1I
Temperature: 60 °C
Yield: 91.7 %

Procedure:
1-(5-Chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone (18.9 g, 60.9 mmol) (from Example 1, Step 1) was dissolved in N,N-dimethylformamide (60.8 mL). Iodoethane (7.3 mL, 91 mmol) was added followed by potassium carbonate (17 g, 120 mmol). The reaction was heated at 60° C. for 1 hour. The mixture was cooled to room temperature, diluted with ether. The organic layers were combined, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0-10% EtOAc in hexanes) to give the desired product (18.9 g, 91.7%). LCMS calculated for C11H13ClIO2 (M+H)+: m/z=339.0; Found: 339.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[F:9][C:10]([Si](C)(C)C)([F:12])[F:11].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:9][C:10]([F:12])([F:11])[CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[OH:8]
Reactant: O=Cc1ccccn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccccn1)C(F)(F)F
Yield: 126.7 %

Procedure:
According to Reference Example 8-12, by use of 2-pyridinecarboxaldehyde (500 μL, 5.26 mmol), (trifluoromethyl)trimethylsilane (932 μL, 6.31 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 526 μL, 0.526 mmol) and tetrahydrofuran (10 mL), the mixture was stirred and reacted at room temperature for 10 minutes. Then, purification by silica gel column chromatography (chloroform/methanol=9/1) was performed to give 2-(2,2,2-trifluoro-1-hydroxyethyl)pyridine (Compound CN) (1.18 g, yield: quantitative).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:9][C:8]=1[Cl:17])C.[Br:19]Br>CO.Cl>[Cl:17][C:8]1[CH:9]=[C:10]([C:13](=[O:16])[CH:14]([Br:19])[CH3:15])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([O:3][CH3:1])=[O:18]
Reactant: CCOC(=O)COc1ccc(C(=O)CC)cc1Cl
Reactant: BrBr
Agent: Cl
Solvent: CO
Product: COC(=O)COc1ccc(C(=O)C(C)Br)cc1Cl

Procedure:
Ethyl-2-(2-chloro-4-propionylphenoxy)acetate(4 g) was dissolved in methanol (40-50 ml). HCl (2 drops, conc) was added, followed by the dropwise addition over 5-10 minutes of bromine (2.62 g, 0.016 mole). After the bromine addition was complete the mixture was heated on a steam bath for 15-30 minutes allowing much of the solvent to evaporate. The residue was washed with cold water and the remaining solid recrystallized several times from hexane to give methyl 2-[2-chloro-4-(2-bromopropionyl)phenoxy]acetate (4.6 g, 90%, mp 63°-65° C.
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:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Clc1ccccc1N1CCNCC1
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3Cl)CC2)c(OC)nc1C
Yield: 82 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([CH3:15])[C:8]([C:12](O)=[O:13])=[CH:9][CH:10]=2)[S:5](=[O:17])(=[O:16])[CH2:4][CH2:3]1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([CH3:15])[C:8]([C:12]([Cl:21])=[O:13])=[CH:9][CH:10]=2)[S:5](=[O:17])(=[O:16])[CH2:4][CH2:3]1
Reactant: Cc1c(C(=O)O)ccc2c1S(=O)(=O)CCC2(C)C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Cl)ccc2c1S(=O)(=O)CCC2(C)C

Procedure:
20.0 g (0.075 mol) of 4,4,8-trimethyl-1,1-dioxothiochroman-7-carboxylic acid were dissolved in 200 ml of toluene and three drops of dimethylformamide and 10.7 g (0.09 mol) of thionyl chloride were added. After three hours of heating under reflux, the solvent was removed and the colorless oil that remained (yield 21.3 g) was directly used further.
Reaction SMILES: C(O)(=O)CC.[NH4+:6].[OH-].[CH3:8][C:9]1[C:14](NC(=O)CC)=[C:13]([CH3:20])[N:12]=[C:11]([NH:21][C:22](=O)[CH2:23][CH3:24])[CH:10]=1>>[CH3:20][C:13]1[N:12]=[C:11]2[N:21]=[C:22]([CH2:23][CH3:24])[NH:6][C:10]2=[C:9]([CH3:8])[CH:14]=1
Reactant: [NH4+]
Reactant: CCC(=O)Nc1cc(C)c(NC(=O)CC)c(C)n1
Agent: [OH-]
Solvent: CCC(=O)O
Product: CCc1nc2nc(C)cc(C)c2[nH]1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a mixture of 8.44 g of a 55:45 mixture of 2-amino-3-nitro-4,6-dimethylpyridine and 2-amino-5-nitro-4,6-dimethylpyridine in MeOH (1.2 L) was added 10% Pd/C (2.4 g). The reaction vessel was evacuated then purged with H2 at 1 atm. and stirred vigorously for 18 h. Filtration through a celite pad, and concentration gave 6.65 g of a mixture of 2,3-diamino-4,6-dimethylpyridine and 2,5-diamino-4,6-dimethylpyridine as a dark solid. To 5.40 g (39.4 mmol) of this mixture was added propionic acid (8.80 mL, 118 mmol) followed by polyphosphoric acid (100 mL). This stirred mixture was heated to 90° C. for 3 h then to 100° C. for 1 hour. The inside walls of the flask were scraped with a spatula to assist dissolution of the solids. After the reaction was complete, the warm mixture was poured onto 300 g of ice and the mixture was made basic with NH4OH. The mixture was extracted (4×50 mL CH2Cl2), dried (K2CO3) and concentrated to give a mixture of the title compound and 4,6-dimethyl-2,5-bis(propionamido)pyridine. Purification (SiO2, 5% MeOH/EtOAc) gave 1.66 g of the title compound as the slower eluting component.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O1CCOCC1>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1CCN(C(=O)c2cncc(Br)c2)CC1
Reaction time: 72 h

Procedure:
5-Bromonicotinic acid (0.020 g, 0.10 mmol), 1-methylpiperazine (0.015 g, 0.15 mmol), HATU (0.046 g, 0.12 mmol), DIPEA (0.052 g, 0.40 mmol), and dioxane (2 mL) were added to a 20 mL vial. The vial was sealed and placed on a heater/shaker for 3 days at 40° C. The reaction mixture, containing the title compound, was used without purification.