Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([CH2:12][Br:13])=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:14][C:15]([NH2:17])=[S:16]>C(O)C>[BrH:13].[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:14]=[C:15]([NH2:17])[S:16][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NOC)C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Br
Product: CCOC(=O)C(=NOC)c1csc(N)n1

Procedure:
A solution of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (17.4 g.) and thiourea (5.4 g.) in ethanol (100 ml.) was refluxed for 4 hours. The reaction mixture was allowed to stand and cooled in refrigerator to precipitate crystals. The crystals were collected by filtration, washed with ethanol and dried to give ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate hydrobromide (anti isomer) (9.5 g.). The filtrate and the washings were put together and concentrated under reduced pressure. Water (100 ml.) was added to the residue and the mixture was washed with ether. The aqueous layer was alkalized with a 28% aqueous solution of ammonia and extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give crystalline substance of ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (5.2 g.).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=O)[C:16]1[C:17]([O:22][CH3:23])=[CH:18][CH:19]=[CH:20][CH:21]=1>CN1CCCC1=O>[C:1]1([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=[C:15]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:1]1([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=[C:15]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: COc1ccccc1C(=O)Cl
Solvent: CN1CCCC1=O
Product: COc1ccccc1-c1nc2ccccc2n1-c1ccccc1
Product: Oc1ccccc1-c1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-phenyl-1,2-phenylenediamine (25 g, 0.136 mol) was dissolved in 100 ml N-methyl-2-pyrrolidinone (NMP) and o-anisoyl chloride (23.2 g, 0.136 mol) was then added to the solution at room temperature under nitrogen. The reaction mixture was stirred for 30 minutes at room temperature and then the temperature was increased to 220° C. for three hours during which time a white solid precipitated out of solution. After cooling, 150 ml of water was added to the reaction mixture and product was extracted with 300 ml of dichloromethane. The organic layer was washed with water and then dried with sodium sulfate. After removal of the solvents, the desired product o-(N-phenyl-2-benzimidazolyl) anisole was obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:10]([O-:13])([OH:12])=[O:11].[N:14]#[C:15][NH2:16]>CCO>[N+:10]([O-:13])([OH:12])=[O:11].[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:15]([NH2:16])=[NH:14]
Reactant: Nc1ccc(F)cc1F
Reactant: N#CN
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N=C(N)Nc1ccc(F)cc1F
Yield: 40 %

Procedure:
To a mixture of 2,4-difluoroaniline (25 mmol, 3.2 g) in EtOH (10 mL) in an ice bath was added nitric acid (69% aq soln.; 1.8 mL) dropwise. After completion of the addition cyanamide (50% aq. soln.; 4 mL) was added. The reaction mixture was refluxed under N2 for 22 h. The solvent was evaporated. The solid residue was washed with EtOH and was dried under high vacuum to afford the title compound as a purple solid (2.32 g, 40%).
Reaction SMILES: O.NN.[NH2:4][C:5]1[C:6]([C:23]2[O:27][C:26]([NH:28][C:29](=[O:42])[CH2:30][N:31]3C(=O)C4C(=CC=CC=4)C3=O)=[N:25][N:24]=2)=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:9][N:10]=1.C(Cl)Cl>CO>[NH2:31][CH2:30][C:29]([NH:28][C:26]1[O:27][C:23]([C:6]2[C:5]([NH2:4])=[N:10][CH:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:18])=[O:19])=[CH:15][CH:16]=3)[N:7]=2)=[N:24][N:25]=1)=[O:42]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(NC(=O)CN4C(=O)c5ccccc5C4=O)o3)n2)cc1
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(NC(=O)CN)o3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.9 %

Procedure:
Hydrazine hydrate (8.065 mg, 7.838 μL, 0.1611 mmol) was added to a stirred suspension of N-(5-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)-2-(1,3-dioxoisoindolin-2-yl)acetamide (147 mg, 0.1611 mmol) in MeOH (5 mL)/CH2Cl2 (5 mL) and the reaction mixture was allowed to stir at ambient temperature for 2 hours. A further portion of hydrazine hydrate (16.13 mg, 15.68 μL, 0.3222 mmol) was added and the reaction stirred for a further 16 hours. The solvent was removed in vacuo and residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3 CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as a yellow solid (10 mg, 11%); 1H NMR (400.0 MHz, DMSO) d 1.18 (d, 6H), 3.50-3.53 (m, 1H), 4.11 (s, 1.4H), 4.33 (s, 0.6H), 7.81 (s, 2H), 7.91 (d, 2H), 8.53 (d, 2H), 9.07 (s, 1H), 10.99 (s, 0.7H) and 11.16 (s, 0.3H) ppm; MS (ES+) 418.2
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]O)[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[CH:24]=1
Reactant: OCc1cccnc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1N(Cc2cccnc2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a mixture of 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.30 g, 1.00 mmol), 3-pyridinemethanol (0.15 mL, 1.50 mmol) and triphenylphosphine (0.36 g, 1.36 mmol) in tetrahydrofuran (7 mL) under nitrogen was slowly added a solution of diethyl azodicarboxylate (0.29 g, 1.67 mmol) in tetrahydrofuran (3 mL). The resulting mixture was stirred at ambient temperature for 21 h. The solvents were removed under reduced pressure, and the residue was taken up into 2 M sodium carbonate (50 mL) and extracted with dichloromethane (2×30 mL). The combined organic solution was dried with sodium sulfate, filtered and concentrated under reduced pressure. The filterate was purified by flash column chromatography with dichloromethane/isopropanol (49:1, increased to 29:1) to give a mixture of the desired product and triphenylphosphine oxide. This material was acidified with 1 M hydrochloric acid (30 mL) and extracted with diethyl ether (3×30 mL). The aqueous solution was made basic with 5 M sodium hydroxide and extracted with dichloromethane (3×30 mL). Once dried with sodium sulfate, the organic solution was concentrated under reduced pressure to afford 1-(pyridin-3-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.22 g, 57%) as a colorless solid: mp 142-143° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.93-8.47 (m, 2H), 7.79 (d, J=7.8 Hz, 1H), 7.45-7.36 (m, 1H), 7.23 (ddd, J=7.8, 7.8, 0.9 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.19 (s, 1H), 5.09 (d, J=15.8 Hz, 1H), 4.924 (d, J=9.0 Hz, 1H), 4.919 (d, J=15.8 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.22-4.17 (m, 2H), 4.14-4.09 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.8, 155.4, 148.0, 147.5, 144.9, 141.5, 138.5, 137.0, 132.2, 129.1, 124.3, 124.0, 120.8, 111.5, 109.0, 99.6, 80.2, 64.6, 64.0, 58.1, 41.7; MS (ES+) m/z 386.7 (M+1).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][N:16]4[CH:23]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:24]N1C(=O)CCC1=O.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C>[NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][N:16]4[C:23]=3[Cl:24])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccn2cc(CCc3ccc4nc(N)oc4c3)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccn2c(Cl)c(CCc3ccc4nc(N)oc4c3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
A mixture of 2-amino-6-[2-(7-methoxyimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (1.0 g) and N-chlorosuccinimide (0.43 g) in dioxane (15 ml) was stirred for 2 hours at ambient temperature. To the reaction mixture was added a mixture of ethyl acetate and water, and the mixture was adjusted to pH 1 with 6N hydrochloric acid. The separated aqueous layer was adjusted to pH 8 with 20% potassium carbonate aqueous solution and the mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was purified by silica gel column chromatography eluting with a solution of chloroform and methanol (19:1, V/V). The fractions containing object compound were concentrated to give 2-amino-6-[2-(3-chloro-7-methoxyimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.41 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)(=[O:3])[CH3:2].C(O[C:16]([C:18]1[N:19]=[C:20](Br)[S:21][CH:22]=1)=[O:17])C.[NH:24]1[C@H:33]2[C@@H:28]([CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:27][CH2:26][CH2:25]1>>[CH2:33]1[C@H:28]2[C@@H:27]([CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][N:24]1[C:16]([C:18]1[N:19]=[C:20]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:1](=[O:3])[CH3:2])[S:21][CH:22]=1)=[O:17]
Reactant: C1CC[C@H]2NCCC[C@@H]2C1
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: CC(=O)c1ccccc1B(O)O
Product: CC(=O)c1ccccc1-c1nc(C(=O)N2CC[C@@H]3CCCC[C@H]3C2)cs1

Procedure:
1-{2-[4-((trans)-Octahydro-isoquinoline-2-carbonyl)-thiazol-2-yl]-phenyl}-ethanone was synthesized in a similar manner, by the reaction of 2-acetyl-phenyl-boronic acid (Aldrich) with 2-bromo-thiazole-4-carboxylic acid ethyl ester (Combi-Blocks, Inc., San Diego, Calif.) in a Suzuki reaction, followed by hydrolysis and coupling with trans-decahydroquinoline.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][OH:7])=[N+:2]=[N-:3].[H-].[Na+].[CH2:10]([O:13][C:14]1[N:19]=[C:18](OCC=C)[N:17]=[C:16]([O:24][CH2:25][CH:26]=[CH2:27])[N:15]=1)[CH:11]=[CH2:12]>C1COCC1>[N:1]([CH2:4][CH2:5][CH2:6][O:7][C:18]1[N:19]=[C:14]([O:13][CH2:10][CH:11]=[CH2:12])[N:15]=[C:16]([O:24][CH2:25][CH:26]=[CH2:27])[N:17]=1)=[N+:2]=[N-:3]
Reactant: C=CCOc1nc(OCC=C)nc(OCC=C)n1
Reactant: [N-]=[N+]=NCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOc1nc(OCC=C)nc(OCCCN=[N+]=[N-])n1
Temperature: -78 °C
Yield: 33.9 %

Procedure:
To 3-azido-1-propanol (8.7 g, 85.7 mmol) in THF (200 mL) was added sodium hydride (5.6 g, 128.6 mmol) at −78° C. The reaction mixture was stirred at −78° C. for about minutes and then allowed to equilibrate at room temperature and stirred for an additional 3 hours. The reaction mixture was recooled to −78° C. and added to a solution of 2,4,6-triallyloxy-1,3,5-triazine (21.4 g, 85.7mmole) in THF (200 mL). The reaction mixture was stirred at room temperature for about 16 hours. The reaction mixture was evaporated to a brown residue. The residue was purified by flash column chromatography over silica gel using EtOAc/hexane as the eluent. The pure fractions were pooled together and evaporated to dryness to give 8.5 g (36%) of the title compound. TLC (Rf: 0.5; 20% EtOAc/Hexane, I2). 1H NMR (CDCl3) δ2.1 (m, 2H, CH2), 3.5 (t, 2H, CH2), 4.5 (t, 2H CH2), 4.9 (m, 4H, CH2), 4.3 (m. 4H, CH2), 6.0 (m, 2H, CH).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH2:23][CH:24]3[CH2:26][O:25]3)[C:14]3[C:19]([C:20]=2[CH:21]=1)=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=3>CO>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH2:23][CH:24]([OH:25])[CH2:26][S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:14]3[C:19]([C:20]=2[CH:21]=1)=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=3
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Reactant: Sc1ccccc1
Solvent: CO
Product: OC(CSc1ccccc1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Benzenethiol (30 Tl, 0.29 mmol) was added to a solution of 3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (101.6 mg, 0.27 mmol) in 5.0 ml MeOH at r.t. The reaction mixture was heated to 80° C. and stirred overnight at the same temperature. The reaction was monitored by 1 c/ms for the consumption of SM. The reaction was cooled, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4, filtered and condensed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:8][CH2:7]1.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.[CH2:33](N(CC)CC)C>ClCCl>[Cl:23][C:24]1([CH3:33])[CH:32]=[CH:31][C:27]([C:28]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4]3[CH:19]=[CH:20][C:21]([Cl:22])=[C:2]([Cl:1])[CH:3]=3)[CH2:11][CH2:10]2)=[O:29])=[CH:26][CH2:25]1
Reactant: Nc1ccccc1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Product: CC1(Cl)C=CC(C(=O)Nc2ccccc2N2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)=CC1

Procedure:
2-[4-(3,4-dichlorobenzyl)-piperazin-1-yl]-phenylamine (45 mg) was dissolved in a solution of triethylamine in dichloromethane (3 mL, 0.29 M in triethylamine). This solution was added to a test tube containing 4-chlorobenzoyl chloride (60 mg). After standing at ambient temperature for several days, the reaction was directly passed through a small pad of silica and eluted with 10% ethyl acetate in hexanes, then with 50% ethyl acetate in hexanes. Solvent removal left 49.6 mg of the product, which was subsequently repurified by silica gel chromatography to afford 11.4 mg product: MS m/z 473 (M)+.
Reaction SMILES: [H-].[Na+].C(S)C.C[O:7][C:8]1[CH:9]=[C:10]([C:14]23[CH:22]4[CH2:23][CH:19]([CH:20]=[CH:21]4)[CH:18]2[CH2:17][N:16]([CH3:24])[CH2:15]3)[CH:11]=[CH:12][CH:13]=1>CN(C)C=O>[CH3:24][N:16]1[CH2:15][C:14]2([C:10]3[CH:9]=[C:8]([OH:7])[CH:13]=[CH:12][CH:11]=3)[CH:18]([CH:19]3[CH2:23][CH:22]2[CH:21]=[CH:20]3)[CH2:17]1
Reactant: COc1cccc(C23CN(C)CC2C2C=CC3C2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: CN1CC2C3C=CC(C3)C2(c2cccc(O)c2)C1

Procedure:
A 733 mg portion of sodium hydride was suspended in 25 ml of dry dimethylformamide and 1.2 ml of ethane thiol in 10 ml of dry dimethylformamide was added dropwise at ice bath temperature. A 1.92 g portion of 2,3,3a,4,7,-7a-hexahydro-3a-(3-methoxyphenyl)-2-methyl-4,7-methano-1H-isoindole was added and the solution was heated at reflux for 6 hours, then cooled and evaporated in vacuo. The residue was taken up in water, extracted with ether, then hexane and neutralized with acetic acid giving a solid which was dissolved in hot methanol and precipitated with ether, then filtered. The filtrate was partially evaporated, then precipitated with ether and hexane. Evaporation of the ether extract gave a foam which was triturated with hexane, giving 240 mg of the desired product as a brown solid, mp 129°-136° C.
Reaction SMILES: F[C:2]1[C:7]([NH:8][C:9]([C:11]2[CH:12]=[C:13]3[CH:19]=[CH:18][N:17]([CH3:20])[C:14]3=[N:15][CH:16]=2)=O)=[CH:6][CH:5]=[C:4]([F:21])[N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[F:21][C:4]1[N:3]=[C:2]2[S:31][C:9]([C:11]3[CH:12]=[C:13]4[CH:19]=[CH:18][N:17]([CH3:20])[C:14]4=[N:15][CH:16]=3)=[N:8][C:7]2=[CH:6][CH:5]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1ccc2cc(C(=O)Nc3ccc(F)nc3F)cnc21
Solvent: Cc1ccccc1
Product: Cn1ccc2cc(-c3nc4ccc(F)nc4s3)cnc21
Temperature: 130 °C
Yield: 167.1 %

Procedure:
To a suspension of 1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (2,6-difluoro-pyridin-3-yl)-amide (300 mg, 1.04 mmol) in toluene in a sealable vial was added Lawesson's Reagent (210 mg, 0.52 mmol). The vial was capped and heated to 130° C. for 12 h, cooled to room temp, and loaded directly onto a silica gel column and purified by flash column chromatography (0 to 100% EtOAc in hexanes) to afford 5-fluoro-2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-thiazolo[5,4-b]pyridine (247 mg, 83% yield). ES MS (M+H+)=285; 1H NMR δ (ppm)(DMSO-d6): 8.99 (1H, d, J=2.23 Hz), 8.64 (1H, s), 8.66-8.53 (1H, m), 7.67 (1H, d, J=3.50 Hz), 7.38 (1H, dd, J=8.74, 1.80 Hz), 6.65 (1H, d, J=3.49 Hz), 3.87 (3H, s).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][CH2:4][O:5][C:6]([CH2:8][C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=O)=[O:7].Cl[CH2:18][C:19](=O)[CH3:20].O>C(Cl)Cl>[CH3:1][N:2]1[CH:18]=[C:19]([CH3:20])[C:8]([C:6]([O:5][CH2:4][CH3:3])=[O:7])=[C:9]1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: CC(=O)CCl
Reactant: CN
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1C
Temperature: 90 °C
Yield: 23 %

Procedure:
In a comparative example anhydrous gaseous methylamine was bubbled through a mixture of diethyl acetone dicarboxylate and chloroacetone in methylene chloride for about five minutes while the temperature rose from 25 to about 40° C. After reaction for one-half hour, water was added and the reaction mixture was heated to 90° C. for about one-half hour. Extraction with chloroform gave a dark oil containing 23 percent yield of desired ethyl 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:18])[CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:16][OH:17].B(F)(F)F.[CH3:23]COCC>C(OC)(OC)OC>[O:1]1[CH:23]=[N:18][C:3]([CH2:4][CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:16][OH:17])=[N:2]1
Reactant: N=C(CCCn1c(CO)nc2ccccc21)NO
Reactant: CCOCC
Agent: FB(F)F
Solvent: COC(OC)OC
Product: OCc1nc2ccccc2n1CCCc1ncon1
Temperature: 100 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A suspension of N-hydroxy-4-(2-hydroxymethyl-benzoimidazol-1-yl)-butyramidine, 203, (500 mg, 2.01 mmol) in trimethyl orthoformate (5 mL) in the presence of BF3.OEt2 (50 μL) in a sealed tube was placed in a microwave oven (Smith Creator, Personal Chemistry) and heated at 100° C. for 15 min while stirring, resulting in the dissolution of all the material. The reaction was repeated 5 times. The 6 batches were combined and concentrated in vacuo. The residue was treated with 1M HCl (15 mL) and THF (15 mL) and left overnight. Concentration followed by trituration from dichloromethane and recrystallization from isopropyl alcohol and methanol afforded [1-(3-[1,2,4]oxadiazol-3-yl-propyl)-1H-benzoimidazol-2-yl]-methanol (2.28 g, 73%) as a white solid:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:30]=3[F:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(F)c(C=O)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1ccc(F)c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-fluoro-5-methoxy benzaldehyde. MS (ESI) m/z 517.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH2:10]1[C:12]2([CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:18](Cl)=[O:19])[CH2:11]1.CCN(C(C)C)C(C)C.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:18]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:12]32[CH2:10][CH2:11]3)=[O:19])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: O=C(Cl)N1CCCCC12CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(NNc1ccc(F)cn1)N1CCCCC12CC2
Yield: 74 %

Procedure:
A red solution of (5-fluoro-pyridin-2-yl)-hydrazine (477 mg, 3.75 mmol), Intermediate 148a (3.00 mmol) and DIPEA (0.78 mL, 4.5 mmol) in DCM (20 mL) was stirred at reflux for 40 h. To the cooled solution was added water (20 mL) and the mixture shaken. The aqueous was extracted with DCM (2×10 mL), then the combined organics passed through a hydrophobic frit and concentrated in vacuo. Flash chromatography (silica 40 g, 1-5% [2M NH3 in MeOH] in DCM) gave the title compound as a yellow solid (587 mg, 74%). LCMS (Method 3): Rt 2.66 min, m/z 265 [MH+].
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.[H-].[Na+].[CH2:48](I)[CH3:49].O>CN(C)C=O.C(OCC)(=O)C>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:42])([F:41])[F:43])[CH:39]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:48][CH3:49])[C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1)OCc1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)OCc1ccccc1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reaction time: 0.5 h

Procedure:
Benzyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-carbamate (1.5 g) is dissolved in N,N-dimethylformamide (15 ml), and thereto is sodium hydride (60%) (127 mg) under ice-cooling, and the mixture is stirred for 30 minutes and thereto is added ethyl iodide (255 μl), and the mixture is stirred at room temperature overnight. Thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→17:3) to give benzyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamate (1.30 g). MS (m/z): 735/737 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:22]([NH2:24])[CH3:23]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][NH:24][CH2:22][CH3:23])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CCN
Product: CCNCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and Ethylamine were converted to yield {3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-ethyl-amine as white solid, MS: 391 (MH+, 1Br).