Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[S:18])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CO.[NH3:21]>O>[C:6]1([CH:5]([CH2:4][C:3]([NH2:21])=[S:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N
Reactant: COC(=S)CC(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CO
Product: NC(=S)CC(c1ccccc1)c1ccccc1
Temperature: 35 °C
Reaction time: 16 h

Procedure:
A reactor equipped with an impeller stirrer and a gas introduction tube was charged with methyldiphenylmethylthioacetate (100 g; 1 equivalent) and methanol (300 mL; 3 volumes) at room temperature. The mixture was heated to 35° C. Ammonia (7 equivalents) was introduced within 3 hours, and the mixture contacted at 35° C. for 16 hours before adding 3 equivalents of ammonia. When the reaction was completed, the mixture was cooled to 25° C. and water (90 ml; 0.9 volume) added. The mixture was filtered and dried under vacuum.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:29]=[C:30]([S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1)N>>[CH3:38][N:37]([CH3:39])[S:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([N:26]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=1)(=[O:35])=[O:36]
Reactant: CN(C)S(=O)(=O)c1cccc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: CN(C)S(=O)(=O)c1cccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 3-hydrazino-N,N-dimethyl-benzenesulfonamide according to the method described for example 91.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](O)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[CH3:34][O:35][CH2:36][CH:37]([NH2:39])[CH3:38].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:24])[NH:39][CH:37]([CH3:38])[CH2:36][O:35][CH3:34])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Reactant: COCC(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)NC(C)COC
Yield: 79.8 %

Procedure:
The same operation as in Example (247a) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained in Example (50a) (250 mg, 0.50 mmol), 1-methoxy-2-propylamine (0.11 mL, 1.00 mmol), WSC hydrochloride (288 mg, 1.50 mmol) and 1-hydroxybenzotriazole (68 mg, 0.50 mmol), to obtain 228 mg of the title compound as a white solid (80%).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:22]1[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23]1>CS(C)=O>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([N:22]3[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23]3)=[N:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(O)C1CCNC1
Reactant: Clc1nccnc1Oc1ccc(Nc2ccccn2)cc1
Solvent: CS(C)=O
Product: CC(C)(O)C1CCN(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)C1
Temperature: 80 °C

Procedure:
A mixture of N-(4-(3-chloropyrazin-2-yloxy)phenyl)pyridin-2-amine (0.150 g, 0.502 mmol) and 2-(pyrrolidin-3-yl)propan-2-ol (0.187 g, 1.447 mmol) in 3 mL of DMSO was sealed in a microwave tube and heated at 80° C. overnight. The reaction was cooled to RT, filtered and purified by purified by reverse-phase HPLC (Gilson; Gemini-NX 10m C18 110A AXIA, 100×50 mm column) eluting with 0.1% TFA-H2O:0.1% TFA CH3CN (9:1→1:9). The fractions containing the desired product were combined and basified with satd NaHCO3 and extracted with DCM (3×). The combined organic layers were dried over Na2SO4 filtered and concentrated to dryness to give the title compound as a light-yellow crystalline solid. MS (ESI, pos. ion) m/z: 392 (M+1). IC50 (uM) 0.02882.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[C:5](/[CH3:18])=[CH:6]/[C@@H:7]1[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@@H:12]2[C@@H:8]1[C@@H:9]([OH:17])[CH2:10][CH2:11]2)[CH3:2].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:19])/[C:5](/[CH3:18])=[CH:6]/[C@@H:7]1[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@@H:12]2[C@@H:8]1[C:9](=[O:17])[CH2:10][CH2:11]2)[CH3:2]
Reactant: CCOC(=O)/C(C)=C/[C@@H]1CC[C@@H](C)[C@H]2CC[C@H](O)[C@@H]21
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)/C(C)=C/[C@@H]1CC[C@@H](C)[C@H]2CCC(=O)[C@@H]21

Procedure:
Compound (11a) is dissolved in an appropriate solvent, preferably in dimethylsulfoxide, and treated with a solution of IBX, preferably in dimethylsulfoxide. After stirring for up to several hours, water is added and the white precipitate is removed by filtration. The precipitate is washed, preferably with dimethylsulfoxide/water and a small amount of AcOEt. The filtrate is extracted, preferably with dichloromethane for several times, the combined organic phases are dried (using e.g. Na2SO4) and concentrated, preferably in vacuo. Chromatography purification (using e.g. a polar solvent gradient) is employed to yield compound (12a). The reaction of compound (11a) (A) and IBX (B) is preferably carried out with equivalents, on a molar basis, of A:B in the ratio of about 1:2.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:34])[NH:11][N:12]1[CH2:18][CH:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[C:16]2[CH:30]=[CH:31][CH:32]=[CH:33][C:15]=2[CH2:14][CH2:13]1)[CH3:8].S(OC)(OC)(=O)=O.O>O1CCCC1>[CH2:7]([O:9][C:10](=[O:34])[N:11]([CH3:1])[N:12]1[CH2:18][CH:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=2)[C:16]2[CH:30]=[CH:31][CH:32]=[CH:33][C:15]=2[CH2:14][CH2:13]1)[CH3:8]
Reactant: CCOC(=O)NN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)N(C)N1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
Potassium-t-butoxide (3 g) was added as a powder to an ice-cooled solution of N-[2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)3-benzazepin-3-yl]carbamic acid ethyl ester (8 g) in 100 ml tetrahydrofuran. After thirty minutes, a solution of dimethyl sulfate (3.1 g) in 25 ml tetrahydrofuran was slowly added. After one hour, the reaction mixture was stirred with water and extracted with ethyl acetate. The dried (anhydrous magnesium sulfate) organic layer was filtered and concentrated. The residue was triturated with ether to yield 6 g solid, mp 204°-205°. A 2 gram sample was recrystallized from acetonitrile to yield 1.6 g white crystals, mp 218°-219°.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30])[CH:13]=2)[C:8]=1[Cl:32])C.[OH-].[K+].Cl>C1COCC1.O>[Cl:32][C:8]1[C:9]2[C:14](=[CH:13][C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][CH2:5][C:4]([OH:33])=[O:3]
Reactant: CCCCC(=O)c1c(-c2ccc3c(Cl)c(OCC(=O)OCC)ccc3c2)sc2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(=O)c1c(-c2ccc3c(Cl)c(OCC(=O)O)ccc3c2)sc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.9 %

Procedure:
A mixture of [1-chloro-6-(3-pentanoyl-benzo[b]thiophen-2-yl)-naphthalen-2-yloxy]-acetic acid ethyl ester (0.0701 g, 0.146 mmol) and potassium hydroxide (0.032 g, 0.57 mmoles) in THF (4 mL) and water (4 mL) was stirred for 1.5 hours at ambient temperature. It was then poured in excess water and acidified with 2N hydrochloric acid. This was then extracted with ethyl acetate and washed with water and brine. The organic phase was dried with anhydrous magnesium sulfate, filtered, solvent evaporated dried in vacuo at 60° C. for 14 hours to yield [1-chloro-6-(3-pentanoyl-benzo[b]thiophen-2-yl)-naphthalen-2-yloxy]-acetic acid as a yellow semi-solid (0.0462 g, 69.9%); Mass spectrum (+ES, [M+H]+) m/z 453; 1H NMR (500 MHz, DMSO-d6): δ12.9–13.5 (br, 1H), 8.26 (d, 1H, J=8.85 Hz), 8.16 (d, 1H, J=1.83 Hz), 8.09–8.10 (m, 2H), 7.97–7.99 (m, 1H), 7.77 (dd, 1H, J=8.70 and 1.83 Hz), 7.47–7.56 (m, 3H), 5.03 (s, 2H), 2.43 (t, 2H, J=7.25 Hz), 1.42–1.48 (m, 2H), 0.98–1.06 (m, 2H), 0.59 ppm (t, 3H, J=7.40 Hz). Elemental Analysis for C25H21ClO4S+0.2 moles H2O: Calcd: C, 65.77; H, 4.72; N, 0.00; Found: C, 65.74; H, 4.99; N, 0.00.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]=O.[Na]>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1/[CH:10]=[CH:3]\[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1cc2ccccc2[nH]1
Agent: [Cl-]
Agent: [Na]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: C(=C\c1cc2ccccc2[nH]1)\c1ccccc1
Reaction time: 1.5 h

Procedure:
2.0 g (13.7 mmole) 2-indolealdehyde and 5.3 g (13.7 mmole) benzyltriphenylphosphonium chloride are heated to a boil in 30 ml dry ethanol. A freshly prepared solution of 0.32 g (13.9 mmole) sodium in 15 ml ethanol is added dropwise thereto within about 1.5 hours. Subsequently, it is boiled under reflux for one hour, after cooling the solvent is distilled off, and the residue is partitioned between dichloromethane and water. The organic phase is dried over sodium sulphate, evaporated, and the residue chromatographed o silica gel with cyclohexane/toluene 7:3. The fraction with the Rf of 0.4 is isolated. One obtains (Z)-1-(2-indolyl)-2-phenylethylene in the form of a pale yellow oil which, in the case of drying in a vacuum, crystallizes. The fraction with the Rf of 0.2 is evaporated, the residue stirred with cyclohexane, and the crystals formed are filtered off. One obtains (E)-1-(2-indolyl)-2-phenylethylene in the form of almost colorless crystals of the mp 205°-206° C. The preparation of the 2-indolealdehyde takes place according to the statements in the literature (Arch Pharm 310, 975, 1977) from 2-indolecarboxylic acid esters.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([F:20])[CH:19]=1>>[N+:10]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:21][C:16]1[CH:15]=[C:14]([F:13])[CH:19]=[C:18]([F:20])[CH:17]=1)[C:6]#[N:7])([O-:12])=[O:11]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Oc1cc(F)cc(F)c1
Product: N#Cc1ccc(Oc2cc(F)cc(F)c2)c([N+](=O)[O-])c1

Procedure:
In a similar manner, 4-chloro-3-nitrobenzonitrile (4.6 g, 25 mmol) and 3,5-difluorophenol were combined to produce 6.9 g of 3-nitro-4-(3,5-difluorophenoxy)benzonitrile (26.2), mp 132–136° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](C3CCN(C(OC(C)(C)C)=O)CC3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[ClH:26].C(O[CH2:31][CH3:32])(=O)C>>[ClH:26].[ClH:26].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:9]3[CH2:32][CH2:31][CH2:4][CH2:5][CH2:8]3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)cc3)cs2)CC1
Agent: Cl
Product: Fc1ccc(-c2csc(N3CCCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
To a solution of tert-butyl 4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (2.49 g, 6.85 mmol) in ethyl acetate (100 ml) was added a 4N solution (100 ml) of hydrogen chloride in ethyl acetate, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure to give 1.88 g (82.0%) of the desired product as a solid.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])/[CH:9]=[C:10](\[CH3:14])/[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1>C(O)C.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.[Ru](I)I.[Ru](I)I>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: C/C(=C\[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: I[Ru]I
Solvent: CCO
Solvent: Cc1ccc(C(C)C)cc1
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 40 °C
Reaction time: 6 h

Procedure:
To a suspension of (E)-(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid [2(ii-a)] (200 g, 524.3 mmol) in degassed ethanol (900 ml) at 40° C. a solution of diiodo(p-cymene)ruthenium(II) dimer (0.052 g, 0.0524 mmol) and (αR,αR)-2,2′-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphine]ferrocene (=Mandyphos SL-M004-1) (0.116 g, 0.110 mmol) is added in degassed ethanol (100 ml). The solution is degassed using vacuum and a pressure of 20 bar hydrogen applied. The mixture is stirred at 40° C. for 6 h. Vessel is then purged with nitrogen. Ethanol (700 ml) is removed by distillation. Isopropyl acetate (600 ml) is added. Solvent (600 ml) is removed by distillation. Isopropyl acetate (600 ml) is added. Solvent (600 ml) is removed by distillation. Isopropyl acetate (300 ml) is added and the solution is heated to reflux. Heptane fraction (1200 ml) is added and the mixture is cooled to room temperature. The solid is collected by filtration and washed with heptane fraction-isopropyl acetate 2:1 mixture (360 ml). The solid is dried overnight at 50° C. under 1-50 mbar vacuum to afford the title compound as a white/off-white solid [Ratio 2(i-a): 2(i-b) 99:1, as determined by HPLC analysis]. Mpt 146-147° C.; δH (500 MHz; DMSO) 1.07 (3H, d, J 7.0, 1-CH3), 1.34 (9H, s, (CH3)3), 1.38 (1H, m, 3-HA), 1.77 (1H, m, 3-HB), 2.43 (1H, m, 2-H), 2.70 (2H, d, J 7.0, 5-H), 3.69 (1H, m, 4-H), 6.74 (1H, d, J 9.0, NH), 7.27 (2H, d, J 8.0, Ar-ortho-H(Ph)), 7.36 (1H, t, J 7.0, Ar-(Ph)-para-H), 7.46 (2H, t, J 7.5, Ar-(Ph)-meta-H), 7.57 (2H, d, J 8.0, Ar-meta-H(Ph), 7.64 (2H, d, J 7.5, Ar-(Ph)-ortho-H), 12.01 (1H, s, CO2H); δC (500 MHz, DMSO) 18.1 (1-CH3), 28.3 [(CH3)3], 35.9 (2-C), 37.9 (3-C), 40.7 (5-C), 50.0 (4-C), 77.4 [(C(CH3)3], 126.3, 126.5, 127.2, 128.9, 129.8 (Ar—CH), 137.7 (Ar-ipso-C(Ph)), 138.3 (Ar-para-C(Ph)), 140.1 (Ar-(Ph)-ipso-C), 155.2 (NCO), 177.2 (CO2H); m/z (+ESI) 406 ([MNa]+, 6%), 384 ([MH]+, 31), 328 (100), 284 (19); Found: [MH]+, 384.21691. C23H30NO4 requires MH 384.21693.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:15][C:16]1[CH:17]=[C:18]([C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH:19]=[C:20]([Cl:22])[CH:21]=1.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12](=[O:14])[CH2:13][C:23]([C:18]3[CH:19]=[C:20]([Cl:22])[CH:21]=[C:16]([Cl:15])[CH:17]=3)([OH:28])[C:24]([F:27])([F:26])[F:25])=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1ccc(-n2ccnc2)cc1
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2ccnc2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
0.50 g (2.69 mmol) of 1-(4-(1H-imidazol-1-yl)phenyl)ethanone, 0.65 g (2.69 mmol) of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.31 g of toluene and 0.15 g (0.81 mmol) of tributylamine were fed and the mixture was stirred for 8 hours at 60° C. After leaving the reaction mixture for one night at room temperature, the solid was filtered under reduced pressure to obtain 0.94 g of 1-(4-(1H-imidazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one as a white solid (yield 85.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][C:11]([C:12]#[N:13])([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(CC#N)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(OC)c(OC)c1
Temperature: 10 °C

Procedure:
Combined 3,4-dimethoxy-phenyl-acetonitrile (20.0 g, 113 mmol) and THF (100 mL). Cooled in a dry-ice/acetone bath. Added dropwise, sodium bis(trimethylsilyl)amide (226 mL, 1.0M in THF, 226 mmol, 2 eq.). After the addition was complete, allowed to warm to 10 ° C. Cooled in a dry-ice/acetone bath. Added dropwise, ethyl bromoacetate (37.7 g, 226 mmol). After the addition was complete, the reaction mixture was allowed to warm to ambient temperature and maintained overnight. Filtered the reaction mixture and concentrated in vacuo to obtain a residue. The residue was partitioned between diethyl ether (600 mL) and water (200 mL). The organic layer was extracted with water (200 mL), saturated NH4Cl (2×100 mL), dried over MgSO4, filtered, and concentrated in vacuo to obtain a residue. Chromatographed on silica gel eluting with ethyl acetate/hexane (1:2) to obtain the title compound: Rf =0.42 (silica gel, 1:2 ethyl acetate/hexane).
Reaction SMILES: [ClH:1].[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][C:20]1=[O:26].C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[ClH:1].[C:2]1([C:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][C:20]3=[O:26])[CH2:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=C1CCCC(=O)N1CCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCCC(=O)N1CCCCN1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Phenyl-1,2,3,6-tetrahydropyridine, hydrochloride (10g) is converted to its free base and mixed with 11.0g of N-(4-bromobutyl)glutarimide and 18g of sodium carbonate in 200 ml of toluene. The mixture is refluxed for 5 hours, cooled to 25° C, and 50 ml of water is added. After stirring for 15 minutes, the layers are separated and the organic layer is filtered through fritted glass and extracted with 10% hydrochloric acid. The acid layer is made alkaline (pH 10) with sodium hydroxide producing an insoluble gum that crystallizes on standing. The supernatant is decanted and the residue is recrystallized by dissolving in methanol and slowly diluting with an equal volume of water. An oil is produced that crystallizes on standing.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8](C(Cl)(Cl)Cl)[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:28]([OH:33])[CH:29]([OH:32])[CH2:30][OH:31]>CN(C)C=O>[NH2:20][C:16]1[N:15]=[C:14]([N:7]2[C:6]3[CH:21]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:33][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[CH:19]=[CH:18][N:17]=1
Reactant: OCC(O)CO
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nccc(-n2c(OCC(O)CO)nc3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.2 %

Procedure:
A mixture of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (500 mg, 1.23 mmol), cesium carbonate (3.2 g, 9.82 mmol) and propane-1,2,3-triol (565 mg, 6.14 mmol) in N,N-dimethylformamide (3 mL) was stirred for 12 h at room temperature. The reaction mixture was filtered through a frit filter to remove any solid material and the filtrate was purified by Flash-Preparative HPLC to give 90 mg (19%) of 3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]propane-1,2-diol as a yellow solid. 1H NMR (400 MHz, DMSO) delta 8.46 (s, 1H), 8.37 (d, J=5.2 Hz, 1H), 7.44-7.38 (m, 2H), 7.13-7.09 (m, 3H), 5.18 (d, J=5.2 Hz, 1H), 4.80 (d, J=6.0 Hz, 1H), 4.68-4.64 (m, 1H), 4.52-4.48 (m, 1H), 3.93 (d, J=4.8 Hz, 1H), 3.52-3.46 (m, 2H); LC-MS: m/z=+380 (M+H)+.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+]>O>[N+:15]([C:12]1[CH:13]=[CH:14][C:7]([O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([CH:11]=1)[C:9]#[N:10])([O-:17])=[O:16]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a dimethylformamide solution (30 ml) containing 2-chloro-5-nitrobenzonitrile (10 g) and phenol (5.7 g) was added sodium hydride (60% content, 2.63 g) under ice-cooling, and the mixture was stirred for 1 h. The reaction mixture was added to water and extracted with toluene. The organic layer was washed saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether to give 5-nitro-2-phenoxybenzonitrile (10.8 g), melting point: 126° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=2)[CH2:25][NH:26]C(=O)OC(C)(C)C)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]([CH3:48])[C:45](=[O:47])[CH3:46])=[CH:40][CH:39]=1.C[Si](Cl)(C)C>C(O)CCC>[NH2:26][CH2:25][C:24]1[CH:23]=[C:22]([NH:21][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([NH:37][C:38]3[CH:39]=[CH:40][C:41]([N:44]([CH3:48])[C:45](=[O:47])[CH3:46])=[CH:42][CH:43]=3)[N:3]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: CC(=O)N(C)c1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(CNC(=O)OC(C)(C)C)c4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N(C)c1ccc(Nc2nc(Nc3cccc(CN)c3)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n2)cc1
Yield: 8.4 %

Procedure:
A solution of tert-butyl 3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzylcarbamate (306 mg, 0.580 mmol), N-(4-aminophenyl)-N-methylacetamide (190 mg, 1.16 mmol) and trimethylsilyl chloride (0.100 mL, 0.791 mmol) in nBuOH (5 mL) was stirred at 116° C. for 20 h. The mixture was then purified by HPLC to give N-(4-(4-(3-(aminomethyl)phenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide (27 mg).