Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].[NH:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.O.C(=O)(O)[O-].[Na+].[C:14]([O:17]C(=O)C)(=O)[CH3:15]>O1CCCC1>[Br:1][C:6]1[C:5]([NH:7][C:14](=[O:17])[CH3:15])=[CH:4][NH:3][N:2]=1
Reactant: Nc1cn[nH]c1
Reactant: CC(=O)OC(C)=O
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1c[nH]nc1Br
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
A 250-mL 3-neck round bottom flask was charged with 1H-pyrazol-4-amine.hydrobromide (4.00 g, 24.7 mmol) and water (23 mL). To the mixture, sodium bicarbonate (8.30 g, 99.0 mmol) was added slowly over 10 minutes, followed by tetrahydrofuran (23 mL). The mixture was cooled to 5° C. and acetic anhydride (2.60 g, 25.4 mmol) was added over 30 minutes while maintaining the internal temperature at <10° C. The reaction mixture was stirred at −5° C. for 20 minutes, at which point 1H NMR and UPLC analyses indicated that the starting material was consumed and the desired product as well as bis-acetylated byproduct was formed. The reaction was extracted with ethyl acetate (×3) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude mixture was triturated with methyl tert-butylether to remove the bisacetylated product to afford ˜1.24 g of a white solid. 1H NMR analysis showed it was 1:1.1 desired to undesired bisacetylated product. The solid was purified by flash column chromatography using 50-100% ethyl acetate/hexanes as eluent to afford the desired product as a white solid (380 mg, 7.5%) and the bisacetylated product as a white solid (˜800 mg): 1H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 9.36 (s, 1H), 7.92 (s, 1H), 2.03 (s, 3H); 13C NMR (101 MHz, DMSO) δ 167.94, 123.93, 119.19, 119.11, 22.63; ESIMS m/z 204 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[N:13]#[C:14][NH2:15].[CH:16](OCC)(OCC)OCC>>[C:14]([NH:15][CH:16]=[N:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1)#[N:13]
Reactant: CCOC(OCC)OCC
Reactant: N#CN
Reactant: Nc1ccc(-c2ncc[nH]2)cc1
Product: N#CNC=Nc1ccc(-c2ncc[nH]2)cc1
Temperature: 150 °C
Yield: 62.2 %

Procedure:
A mixture of 2-(4-amino-phenyl)-1-H-imidazole (3.1 g), cyanamide (0.8 g) and triethyl orthoformate (3.6 g) was heated at 150° C. for a few minutes. The product which crystallized out was filtered off, washed with ethanol and dried to give 2.5 g of the title compound, M.p. 228°-229° C.
Reaction SMILES: [C:1](=[O:17])([O:14][CH2:15]Cl)[O:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[I-:18].[Na+].O>C(#N)C>[C:1](=[O:17])([O:14][CH2:15][I:18])[O:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(OCCl)OCCCOCc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(OCI)OCCCOCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
[3-(Benzyloxy)propyl] chloromethyl carbonate (2.0 g) was dissolved in acetonitrile (3 ml), and sodium iodide (4.6 g) was added. The mixture was stirred under a nitrogen atmosphere at 60° C. for 2 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml). The ethyl acetate layer was washed with an aqueous 5% sodium thiosulfate solution (50 ml×2), water (50 ml×2), and a saturated sodium chloride aqueous solution (50 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain [3-(benzyloxy)propyl] iodomethyl carbonate (2.5 g) as a pale yellow liquid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][C@@H:23]4[CH3:35])=[C:19]([OH:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)([O-])O.[Na+]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][C@@H:23]4[CH3:35])=[C:19]([OH:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1c(O)ccc2c1O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CNCCN1Cc1c(O)ccc2c1O/C(=C\c1n[nH]c3ccccc13)C2=O
Reaction time: 8 h
Yield: 17.5 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)-3-(S)-methylpiperazine-1-carboxylate (0.329 g, 0.672 mmol) in methylene chloride (8 mL) was added with trifluoroacetic acid (8 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated, then the residue was added with methanol (20 mL) and a 5% solution of hydrogen chloride in methanol (5 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and then the residue was suspended in acetonitrile and thereby washed to obtain orange solid. This solid was dissolved in saturated aqueous sodium hydrogencarbonate, and the solution was extracted three times with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate to obtain the objective (Z)-2-[(1H-indazol-3-yl)methylene]-6-hydroxy-7-{[2-(S)-methylpiperazin-1-yl]methyl}benzofuran-3(2H)-one (0.0460 g, 17%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:26]4[N:30]=[C:29]([C:31]5[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH3:40])=[C:33]([Cl:41])[CH:32]=5)[O:28][N:27]=4)[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.C(OC1C=C(C2ON=C(C3C=CC=C4C=3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)N=2)C=CC=1OCC)C>>[NH2:7][C:8]([CH2:16][N:17]1[C:25]2[C:20](=[C:21]([C:26]3[N:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH3:40])=[C:33]([Cl:41])[CH:32]=4)[O:28][N:27]=3)[CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CCCOc1ccc(-c2nc(-c3cccc4c3ccn4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1Cl
Agent: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Product: CCCOc1ccc(-c2nc(-c3cccc4c3CCN4CC(N)(CO)CO)no2)cc1Cl
Yield: 54 %

Procedure:
When the product of Step F was substituted for tert-butyl 5-((4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 34, Step E, the identical process afforded the title compound in 54% yield, as a fluffy white solid. 1H-NMR (DMSO-d6) 0.99 (tr, 3H, J=7.4 Hz); 1.74-1.81 (m, 2H); 3.03 (s, 2H); 3.27-3.32 (m, 6H); 3.53 (rt, 2H, J=8.03 Hz); 4.73 (m, 2H); 6.78 (d, 1H, J=7.8 Hz); 7.14 (tr, 1H, J=7.78 Hz); 7.25 (d, 1H, J=7.12 Hz); 7.36 (d, 1H, J=8.72 Hz); 8.0 (d, 1H, J=8.31 Hz); 8.11 (d, 1H, J=3.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[N:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH:15][C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)[N:3]=1
Reactant: Cc1cccc(C)n1
Reactant: O=Cc1ccncc1
Solvent: CC(=O)OC(C)=O
Product: Cc1cccc(C=Cc2ccncc2)n1

Procedure:
A solution of 2,6-dimethyl pyridine (5.8 ml, and 50 mMol), and pyridine-4-carbaldehyde (4.9 ml, and 52 mMol) in acetic anhydride (9.5 ml) is heated under reflux for 16 hours. The acetic anhydride is then evaporated in vacuo and the residue purified on column chromatography (silica gel 900 g). The column is first eluted with toluene/acetone 4:1 (5 L), then with toluene/acetone 3:1 (5 L) and finally with toluene/acetone 2:1 (15 L). The fractions containing the desired compound are combined, evaporated in vacuo. The solid residue is recrystallized from methylene chloride/diisopropyl ether and 0.956 g of white crystals are isolated. (melting point: 72-73° C.).
Reaction SMILES: [C:1]1([P:7]2(=[O:26])[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][C:10](=O)[CH:9]=[C:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27](#[N:31])[CH2:28][C:29]#[N:30]>C(O)C.N1CCCCC1>[C:29]([C:28]([C:27]#[N:31])=[C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[P:7](=[O:26])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:9]1)#[N:30]
Reactant: O=C1C=C(c2ccccc2)P(=O)(c2ccccc2)C(c2ccccc2)=C1
Reactant: N#CCC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(C#N)=C1C=C(c2ccccc2)P(=O)(c2ccccc2)C(c2ccccc2)=C1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
To a mixture of 0.25 g of 1,2,6-triphenylphospha-2,5-cyclohexadien-4-one P-oxide and 0.060 g of malononitrile in 100 ml of ethanol was added 1 drop of piperidine. The red mixture was heated on a steam bath for about one hour, then allowed to cool to room temperature overnight. The product crystallized as dark greenish brown metallic needles. It was collected and dried to give 0.247 g of 4-dicyanomethylene-1,2,6-triphenylphospha-2,5-cyclohexadiene P-oxide, whose structure was confirmed by 1HNMR and FDMS analyses.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12]([NH:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:14])=[O:13])[CH:8]=2)[O:3]1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[Br:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50]Br)=[CH:46][CH:45]=1>CC#N>[Br:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][N:15]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[O:3][C:2]([CH3:24])([CH3:1])[CH2:11][CH2:10]3)(=[O:14])=[O:13])=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Reactant: BrCc1ccc(Br)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(Cc1ccc(Br)cc1)S(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 90 °C
Yield: 85.6 %

Procedure:
To a solution of tert-butyl 2-(2,2-dimethylchroman-6-sulfonamido)acetate (500 mg, 1.407 mmol) in MeCN (15 mL) was added resin-supported BEMP (786 mg, 1.547 mmol) and 1-bromo-4-(bromomethyl)benzene (602 mg, 2.409 mmol). The mixture was heated in a microwave synthesizer at 90° C. for 3 hours. The reaction mixture was filtered, rinsed alternatively by dichloromethane and methanol. The filtrate was concentrated to give a reddish orange residue, which was purified by silica chromatography to obtain a white powder (632 mg, 86% yield). 1H NMR (500 MHz, CDCl3) δ 7.59-7.55 (m, 2H), 7.43 (d, J=8.3 Hz, 2H), 7.14 (d, J=8.3 Hz, 2H), 6.84 (d, J=9.1 Hz, 1H), 4.45 (s, 2H), 3.78 (s, 2H), 2.79 (t, J=6.7 Hz, 2H), 1.83 (t, J=6.7 Hz, 2H), 1.35 (s, 6H), 1.33 (s, 9H). LRMS [ESI, MH+] m/z calcd for C24H31BrNO5S 524.11, found 524.1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]([O:16][C:17](=[O:26])[NH:18][CH:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:26])[NH:18][CH:19]1[CH2:20][CH2:21][CH:22]([NH:25][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:2]=2[OH:1])[CH2:23][CH2:24]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2ccc(O)cc2O)CC1
Yield: 26.1 %

Procedure:
2,4-Dihydroxy benzoic acid (1.6 g, 10.38 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (2.22 g, 10.38 mmol) and other reagents as described in Example 9(e) were used to afford 0.95 g of the required product. 1H NMR (DMSO-d6): δ 1.20 (4H, m), 1.4 (9H, m), 2.1 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 6.2 (2H, d), 6.74 (1H, s), 7.7 (1H, s), 8.26 (1H, s), 10.0 (1H, brs), 13.0 (1H, brs).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:21][CH2:20][NH:19][CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:21][CH2:20][N:19]([C:23]4[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cccnc1Cl
Reactant: CC(C)(C)c1ccc(Nc2ncnc3c2CCNC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(Nc2ncnc3c2CCN(c2ncccc2Cl)C3)cc1
Product: Cl
Temperature: 200 °C
Yield: 13.3 %

Procedure:
A mixture of N-(4-tert-butylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine 0.173 g, 0.61 mmol), 2,3-dichloropyridine (0.91 g, 0.61 mmol) and potassium carbonate (0.234 g, 1.84 mmol) in DMF was heated in a sealed tube in a microwave oven (Emrys Optimizer model, Personal Chemistry) at 200° C. for 2 h. The mixture was cooled to r.t. and diluted with water (30 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to leave an oil. The product was purified by silica gel chromatography (ethyl acetate/hexane gradient) to obtain 0.035 g of the title compound as a light yellow oil. The oil was dissolved in 1 mL ethyl acetate and treated with 1.0 M HCl in diethyl ether (0.09 mL). The resulting solid was collected by filtration, washed with diethyl ether and dried to give 0.030 g light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[F:31][C:32]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:33]=1[CH2:34][NH2:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:35][CH2:34][C:33]1[CH:36]=[C:37]([F:40])[CH:38]=[CH:39][C:32]=1[F:31])=[O:29]
Reactant: NCc1cc(F)ccc1F
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2cc(F)ccc2F)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2,5-difluorobenzylamine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][C:24]#[N:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.S(C)C.CO>C1COCC1>[NH2:25][CH2:24][CH2:23][O:22][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC#N)c2cccc(Cl)c2)C1
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Temperature: 25 °C

Procedure:
(R)-tert-Butyl 3-((R)-(3-chlorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate (23 g, 0.04 mol) was dissolved in anhydrous THF (300 mL), and the solution was heated to reflux under nitrogen. A solution of BH3.Me2S (12 mL, 0.12 mol) in THF was added dropwise, and stirring was continued at reflux overnight. The resulting solution was cooled to rt and MeOH was added dropwise to quench the reaction. After evaporation of the solution, the crude (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate was obtained which was used for the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][C:10]([NH2:12])=[O:11])=[C:4]([F:13])[CH:3]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][CH:9]([C:5]1[C:4]([F:13])=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[F:8])[C:10]([NH2:12])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: NC(=O)Cc1c(F)cc(Br)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: NC(=O)C(Br)c1c(F)cc(Br)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
A solution of 2-(4-bromo-2,6-difluorophenyl)acetamide (0.4 g, 1.6 mmol) in carbon tetrachloride (5 mL) was degassed with nitrogen for 5 min. To this was added N-bromosuccinimide (0.28 g, 1.6 mmol) and then azobisisobutyronitrile (0.039 g, 0.24 mmol) while stirring. The reaction mixture was stirred at 80° C. overnight and then cooled to room temperature. The reaction mixture was concentrated to dryness in vacuo, and the residue was purified by flash chromatography (0-100% ethyl acetate/hexanes) to afford the title product (60 mg, 11%). MS(ES)+ m/e 328 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of commercially available 4-chloro-3-(trifluoromethyl)aniline (15.0 g, 76.7 mmol) in anhydrous THF (200 mL) cooled to 0-5° C. was added triethylamine (11.7 mL, 84.4 mmol) followed by pivaloyl chloride (10.4 mL, 84.4 mmol) over 30 min. The ice bath was removed and the mixture stirred at rt for 1 h. The mixture was diluted with ether and filtered. The filtrate was washed with water (2×) and brine, dried over MgSO4, filtered and concentrated. The residue was triturated with hexanes and the solid was filtered and dried in vacuo to afford compound 841A (20.4 g, 95%). MS (ES): m/z=280 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=C[CH:5]=[C:6]2NC(=O)OC(=O)[C:7]=12.[C:14]1([NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].O.[C:23]([OH:26])(=O)[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:21][C:23](=[O:26])[C:24]=2[CH:3]=1
Reactant: CC(=O)O
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Reactant: Nc1ccccc1N
Solvent: O
Product: O=C1Nc2ccccc2Nc2ccc(Cl)cc21
Temperature: 100 °C

Procedure:
6-Chloro isatoic anhydride (0.1 mol) and 1,2-phenylenediamine (0.1 mol) were dissolved in acetic acid (90%) and the mixture heated at 100° C. for 2.5 hrs. The mixture was poured into water and extracted with ethyl acetate, neutralized, dried and 2-chloro-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-11-one was isolated (94%) after removal of solvent under reduced pressure.
Reaction SMILES: [Na+].[CH2:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1S([O-])(=O)=O)[CH2:3][CH2:4]CCCCCCCCC.[C:24]([OH:28])(=[O:27])[CH:25]=[CH2:26]>O>[CH2:3]=[CH:2][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:24]([O:28][CH2:14][CH2:2][CH2:3][CH3:4])(=[O:27])[CH:25]=[CH2:26]
Reactant: C=CC(=O)O
Reactant: CCCCCCCCCCCCc1ccccc1S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: C=CC(=O)OCCCC
Product: C=Cc1ccccc1
Temperature: 135 °C
Reaction time: 0.08 h

Procedure:
An aqueous solution was prepared that contained dodecylbenzenesulfonic acid sodium salt (“SDBS”) (6 g), Na2S2O7 (1.42 g, 0.0059 mol), HOTEMPO (1.85 g, 0.0107 mol), acrylic acid (9 ml) and de-ionized water (1.2 L). To this was added 300 mL of the pre-polymer (prepared according to Example 1) and stirred for about 5 minutes. The mixture was then piston homogenized for one pass at about 700 BAR. The mini-emulsion was transferred to the 2 L PARR reactor and then deoxygenated by 10 pressurization/depressurization cycles with argon. The mini-emulsion was then heated to 135° C. After 1 hour at temperature, 8 ml of ascorbic acid (0.189 g/ml) was continuously added at a rate of 0.033 ml per minute over a 4-hour period. After a total of 6 hours at temperature the reaction was cooled to yield a poly(styrene/butyl acrylate) latex of Mn=13,000, Tg of ˜50C with a PD of 1.46 and particle size of ˜190 nm.
Reaction SMILES: C([O:8][C:9](=[O:17])[CH2:10][C@@H:11]([OH:16])[CH2:12][C:13]([NH2:15])=[O:14])C1C=CC=CC=1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C)C=O.ClCCl.CCCCCCC>[Si:23]([O:16][C@H:11]([CH2:10][C:9]([OH:8])=[O:17])[CH2:12][C:13]([NH2:15])=[O:14])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: NC(=O)C[C@H](O)CC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: CC(C)(C)[Si](C)(C)O[C@@H](CC(N)=O)CC(=O)O
Temperature: 5 °C

Procedure:
(S)-Benzyl-3-hydroxyglutaramate (100 g) was dissolved in dimethyl formamide. To this Imidazole (35 g) was added and the solution was cooled to 5° C. To this a solution of tert-butyldimethylsilylchloride (68.5 g) dissolved in dimethyl formamide (250 ml) was added under cooling. The mixture was warmed to 20-25° C. and stirred. The reaction mixture was cooled and quenched with water. To the reaction mixture ethyl acetate and water was added and stirred. The layers were separated and the organic phase was washed thrice with water. To the organic phase Palladium on charcoal (5%, 1 g) was added and stirred under hydrogen atmosphere (˜2.8 Kg). Palladium was removed by filtration. The filtrate was mixed with water and adjusted pH to ˜9.0 by using Aq ammonia solution. The reaction mass was stirred and layers were separated. The aqueous phase was washed with dichloromethane and dichloromethane was added to aqueous phase. The reaction mass was cooled to 5° C. and pH was adjusted to 4.0 with Aq phosphoric acid. The reaction mass was stirred and layers were separated. The organic phase was washed with water and dried over sodium sulphate. The organic layer was evaporated under vacuum to yield residue. Residue was dissolved in dichloromethane and to this solution heptane was added, stirred, filtered and dried to yield (S)-3-(tert-butyl dimethylsilyloxy)glutaric acid monoamide.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Cl:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:21]([CH2:23]Cl)=[N:22][C:18]=2[CH:17]=1>>[Cl:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:29])=[O:30])[C:21]([CH2:23][N:8]3[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:7]3)=[N:22][C:18]=2[CH:17]=1
Reactant: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Reactant: CCS(=O)(=O)c1c[nH]c2ccccc12
Product: CCS(=O)(=O)c1cn(Cc2nc3cc(Cl)ccc3n2CCCS(C)(=O)=O)c2ccccc12

Procedure:
Example 1-5 was prepared in analogy to Example 1-2 by using 3-ethanesulfonyl-1H-indole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole instead of 3-(methylsulfonyl)-1H-indole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1.[CH3:22][O:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:25]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:22][O:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)[CH:27]=1)=[O:25]
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(-c2ccnc3c(C(F)(F)F)cccc23)c2ccccc12
Temperature: 100 °C
Reaction time: 20 h
Yield: 84.6 %

Procedure:
1.04 g (7.5 mmol) of potassium carbonate and 0.695 g (3 mmol) of 4-chloro-8-(trifluoromethyl)quinoline are added to 0.525 g (3 mmol) of 3-methoxycarbonyl-1H-indole in 10 cm3 of dimethylformamide under an argon atmosphere. After stirring at a temperature in the region of 100° C. for 20 hours, the reaction mixture is cooled and diluted with 100 cm3 of ethyl acetate and 100 cm3 of water. The organic phase is separated off by settling and washed with twice 100 cm3 of water and 100 cm3 of saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa), resulting in an orange-coloured oil. This oil is triturated in 20 cm3 of isopropyl ether and the resulting precipitate is filtered off, giving 0.94 g of 3-methoxycarbonyl-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a yellow powder. Mass spectrum (EI): m/e 370 (M+•), m/e 339.