Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([CH2:18][C:19]#[CH:20])[CH:15]=[C:14]([O:21][CH3:22])[C:13]=1[O:23][CH3:24]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:20]#[C:19][CH2:18][C:16]2[CH:15]=[C:14]([O:21][CH3:22])[C:13]([O:23][CH3:24])=[C:12]([O:11][CH3:10])[CH:17]=2)=[CH:4][N:3]=1
Reactant: C#CCc1cc(OC)c(OC)c(OC)c1
Reactant: Nc1ncc(I)c(N)n1
Product: COc1cc(CC#Cc2cnc(N)nc2N)cc(OC)c1OC
Yield: 79.9 %

Procedure:
2,4-Diamino-5-iodopyrimidine (236 mg) was allowed to react with 1,2,3-Trimethoxy-5-(prop-2-ynyl)benzene (412 mg) as per the general procedure to afford 2,4-Diamino-5-(3-(3,4,5-trimethoxyphenyl)prop-1-ynyl)pyrimidine as a white powder (251 mg, 80%): Rf=0.23 (9:1, CHCl3:MeOH); mp=decomposed above 190° C.; 1H NMR (DMSO-d6) δ 7.84 (s, 1H), 6.71 (s, 2H), 6.26 (s, 2H), 3.80 (s, 2H), 3.77 (s, 6H), 3.63 (s, 3H); 13C NMR (DMSO-d6) δ 163.8, 162.2, 158.7 152.8, 136.0, 132.8, 105.2, 93.1, 90.1 76.5, 60.1, 55.8, 25.6; Anal. (C16H18N4O3) C, H, N.
Reaction SMILES: [CH:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([O:19]C)=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].O.[OH-].[Li+]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([OH:19])=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)=[CH:21][CH:22]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(C(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1ccc(CC2CCc3[nH]c(C(=O)O)cc32)cc1

Procedure:
The title compound was synthesized from methyl 4-(4-isopropylbenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate and lithium hydroxide monohydrate according to General Procedure 7. Silica gel was added, the solvent stripped off and the silica gel-imbedded material was purified by flash chromatography (0-80% EtOAc/Heptane) to give 4-(4-isopropylbenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid (33) as a light yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:20]([CH2:21][CH2:22][O:23][CH2:24][C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[C:19]3[CH:30]=[CH:31][CH:32]=[CH:33][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[O:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[CH2:24][O:23][CH2:22][CH2:21][N:20]1[C:19]2[CH:30]=[CH:31][CH:32]=[CH:33][C:18]=2[N:17]=[C:16]1[C:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2CCOCc2ccco2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1nc2ccccc2n1CCOCc1ccco1)C1CCNCC1
Reaction time: 0.5 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(2-fur-2-ylmethoxy-ethyl)-1 H-benzoimidazole-2-carbonyl)-piperidine (0.43 g, 0.94 mmol) and dioxane (3 mL). Add a solution of hydrochloric acid in dioxane (4.0 mL, 4 M, 16 mmol). After 30 minutes, partition the residue between ethyl acetate and saturated aqueous sodium bicarbonate solution. Separate the organic layer and extract with saturated aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: C(OC([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)=[CH:9][NH:8][CH:7]=1)=O)C.[OH-].[Na+].[Na+].[Cl-]>C(O)CO>[I:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[CH:6]=[CH:7][NH:8][CH:9]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc(I)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Product: Ic1ccc(-c2cc[nH]c2)cc1
Temperature: 160 °C
Reaction time: 2.5 h
Yield: 378.7 %

Procedure:
Following earlier procedures (Balasubramanian, T.; Lindsey, J. S. Tetrahedron 1999, 55, 6771-6784), a mixture of 3-ethoxycarbonyl-4-(4-iodophenyl)pyrrole (7.20 g, 21.1 mmol) and ethylene glycol (55 mL) in a 100-mL Claisen flask was flushed with argon for 10 min and powdered NaOH (2.2 g, 55 mmol) was then added. The flask was placed in an oil bath at 120° C. and the oil bath temperature was raised to 160° C. After 2.5 h, the flask was cooled to room temperature and treated with 10% aq NaCl (100 mL). The aqueous layer was extracted with CH2Cl2, the organic layers were collected, washed with 10% aq NaCl, dried (Na2SO4), concentrated, and recrystallized in ethanol affording light brown crystals (5.18 g, 91%). mp 164-165° C.; 1H NMR δ 6.51 (m, 1H), 6.83 (m, 1H), 7.08 (s, 1H), 7.27 (d, J=8.7 Hz, 2H), 7.63 (d, J=8.7 Hz, 2H); 13C NMR δ 89.9,106.3, 114.7, 119.1, 123.8, 127.0, 135.2, 137.5; EI-MS obsd 268.9702, calcd 268.9702. Anal. Calcd for C10H8IN: C, 44.6; H, 3.0; N, 5.2. Found: C, 44.7; H, 3.0; N, 5.1. The synthesis starting from 4-iodobenzaldehyde (35 g), monoethyl malonate, and TosMIC has been performed with linear scale up of the established procedures, affording 21.5 g of 4.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:10]=2)[N:5]([CH3:21])[C:4](=[O:22])[C:3]=1[C:23]([NH:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[O:24].Cl[C:35]1[N:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1>>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([C:35]3[N:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=3)[CH:10]=2)[N:5]([CH3:21])[C:4](=[O:22])[C:3]=1[C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24]
Reactant: Cc1ccnc(Cl)n1
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Product: Cc1ccnc(-c2cnc3c(c2)c(O)c(C(=O)NCC(=O)O)c(=O)n3C)n1

Procedure:
The title compound was prepared from tert-butyl 2-(4-hydroxy-1-methyl-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamido)acetate (Example 26 (h)) and 2-chloro-4-methylpyrimidine analogously to the procedures described for the preparation of Example 26 (i) and Example 26 (k), or Example 21 (b). MS (ESI, pos. ion) m/z: 370 (M+1). 1NMR (400 MHz, DMSO-d6) δ ppm: 10.41 (s, 1 H), 9.65 (s, 1 H), 9.24 (s, 1 H), 8.80 (d, J=4.9 Hz, 1 H), 7.41 (d, J=4.9 Hz, 1 H), 4.13 (d, J=5.3 Hz, 2 H), 3.74 (s, 3 H), 2.59 (s, 3 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH:2]=1.[CH3:17][C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:17][C:18]1[N:19]=[C:20]([NH:23][C:14](=[O:16])[C:10]2[CH:9]=[C:8]([O:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:13]=[CH:12][N:11]=2)[S:21][CH:22]=1
Reactant: O=C(O)c1cc(Oc2cccnc2)ccn1
Reactant: Cc1csc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1csc(NC(=O)c2cc(Oc3cccnc3)ccn2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
Compound 2 (3.0 g, 14 mmol, 1.0 eq), 4-methylthiazol-2-amine (1.66 g, 14.5 mmol, 1.05 eq), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (5.54 g, 14.5 mmol, 1.05 eq), and DIEA (2.6 mL, 15 mmol, 1.1 eq) were dissolved in DMF (69 mL) and stirred overnight at rt. The reaction was diluted with EtOAc and washed with H2O (2×). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by preparative HPLC afforded 1.5 g (35%) of the title compound as an off-white powder: 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J=5.5 Hz, 1H), 8.59-8.57 (m, 2H), 7.79 (d, J=8.4 Hz, 1H), 7.60-7.56 (m, 2H), 7.31 (dd, J=5.5, 2.4 Hz, 1H), 6.89 (s, 1H), 2.29 (s, 3H); ES-MS [M+1]+: 313.1.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[I-].[Na+]>C(#N)C.C(OCC)(=O)C>[CH2:35]([NH:42][CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COS(C)(=O)=O)cc1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)methyl methanesulfonate (225 mg, 0.552 mmol) obtained in Example 126a), potassium carbonate (76.3 mg, 0.552 mmol, 1.0 eq.) and benzylamine (0.123 ml, 1.10 mmol, 2.0 eq.) were suspended in acetonitrile (7.5 ml), sodium iodide (16.6 mg, 0.110 mmol, 0.2 eq.) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (30 ml), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated. Diethyl ether was added and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (208 mg, 0.497 mmol, 90.0%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)=[CH:32][CH:31]=1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: Oc1ccc(F)cc1
Product: O=S(=O)(Nc1nccnc1-c1ccc(COc2ccc(F)cc2)cc1)c1ccccc1C(F)(F)F
Yield: 67 %

Procedure:
Following the general method as outlined in Example 1 (Method A), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 4-fluorophenol, the title compound was isolated as a yellow solid in 67% yield (95% purity by HPLC).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:7]=1.N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:19](=[O:21])[CH3:20])[CH:5]=[N:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Brc1cncc(C2CCCN2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCCC1c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 132 %

Procedure:
To a solution of 3-bromo-5-(2-pyrrolidinyl)pyridine (200 mg, 0.881 mmol) and pyridine (0.2 mL, 1.96 mmol) in DCM (1 mL) in a 8-mL vial is added acetic anhydride (0.093 mL, 0.969 mmol) dropwise. The mixture is stirred at room temperature for 2.5 h. The mixture is concentrated. The resulting crude product is purified by normal phase chromatography using 0-4.5% MeOH in DCM as the gradient to afford 1-[2-(5-bromo-pyridin-3-yl)-pyrrolidin-1-yl]-ethanone (313 mg, 83% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][NH:6][CH3:7].[C:9](Cl)(=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[C:9]([N:6]([CH3:7])[CH2:5][CH2:4][CH2:3][N:2]([CH3:8])[CH3:1])(=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CNCCCN(C)C
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)N(C)CCCN(C)C
Reaction time: 8 h

Procedure:
To a solution of N,N,N'-trimethyl-1,3-propanediamine (25 g, 0.22 mmole) in methylene chloride (500 mL) was added palmitoyl chloride (57 g, 0.20 mmole) dropwise over 4 hours. After the addition was complete the solvent was removed under reduced pressure. The residue was refluxed in diethyl ether (600 mL) overnight. A portion of the precipitate was collected by filtration and stirred in saturated aqueous sodium bicarbonate (500 mL) overnight. The reaction mixture was extracted three times with chloroform (500 mL portions). The organic layer was dried over magnesium sulfate and the salts removed by filtration. The solvent was removed under reduced pressure. The residue was Kugelrohr distilled to give the title compound as a clear yellow oil. 1H NMR (300 MHz, CDCl3): δrotamers 0.861 (3H, t, J=6.4 Hz), 1.234 (24H, bs) 1.61 to 1.74 (4H, m), 2.196 (6H, s), 2.10 to 2.33 (4H, m) 2.894 and 2.969 (3H, s), 2.767 and 3.139 (2H, t, J=7.3 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([CH3:17])[CH:13]=[C:12]([NH:18][CH2:19][C:20]4([C:23]([F:26])([F:25])[F:24])[CH2:22][O:21]4)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:27]([NH2:29])[CH3:28]>ClCCl>[CH2:27]([NH:29][CH2:22][C:20]([CH2:19][NH:18][C:12]1[CH:13]=[C:14]([CH3:17])[CH:15]=[C:16]2[C:11]=1[CH:10]=[N:9][N:8]2[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)([OH:21])[C:23]([F:25])([F:24])[F:26])[CH3:28]
Reactant: Cc1cc(NCC2(C(F)(F)F)CO2)c2cnn(-c3ccc(F)cc3)c2c1
Reactant: CCN
Solvent: ClCCl
Product: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A solution of 1-(4-fluorophenyl)-6-methyl-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-indazol-4-amine (1.52 g, 4.16 mmol) in dichloromethane (30 ml) was added to ethylamine (2M in tetrahydrofuran) (70 ml, 140 mmol). The reaction was stirred at room temperature overnight and then evaporated in vacuo. The crude product was purified on a 70 g silica Bond Elut cartridge using a 0-100% ethyl acetate in dichloromethane gradient over 60 mins to give the title compound (1.463 g).
Reaction SMILES: [O-2:1].[Zn+2:2].C(=O)([O-])[O-:4].[Li+:7].[Li+:8].[O-2].[V+5:10].[O-2].[O-2].[O-2].[O-2].[V+5]>>[O-2:4].[Zn+2:2].[O:1]([Li:8])[Li:7].[O-2:4].[V+5:10].[O-2:4].[O-2:4].[O-2:4].[O-2:4].[V+5:10]
Reactant: O=C([O-])[O-]
Reactant: [Li+]
Agent: [V+5]
Agent: [O-2]
Agent: [Zn+2]
Product: [Li]O[Li]

Procedure:
The humidity-sensitive element in accordance with the present invention is produced in the following manner. First, fine powders of chromic oxide (Cr2O3), zinc oxide (Cr2O3), cupric oxide (CuO), lithium carbonate (Li2CO3) and vanadium oxide (V2O5) are used as starting materials. The starting materials were weighed so as to give Cr2O3, ZnO, CuO, Li2O, V2O5 mol ratios of 45%, 45%, 4%, 3% and 3%, respectively. The materials are then wet-mixed for 24 hours in a ball mill. After wet-mixing, the mixture is dried for 12 hours at 120° C. and then calcined at 800° C. The calcined material is pulverized for 24 hours in a ball mill and is dried again for 12 hours at 120° C. to form a powder. Next, 2 wt.% of polyvinyl alcohol is added to the powder as a binder. The mixture is then granulated in a granulating machine. The granulated material is then formed under 500 kg/cm2 of pressure into a disc with a diameter of approximately 8 mm and a thickness of approximately 2 mm to form the body of the element. The disc is then sintered for 2 hours at a temperature of 1300° C. A ruthenium oxide paste is then screen-printed in a lattice-shaped configuration on each surface of the body to form the electrodes. The body is then heated to approximately 700° C. Thus a humidity-sensitive element is formed in accordance with the present invention.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[Cl:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[CH:18]1[CH2:22][CH2:21][O:20][CH2:19]1)[CH2:9][NH:8][CH2:16]2
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3CCOC3)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc2c(cc1C1CCOC1)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 5-chloro-6-(tetrahydro-furan-3-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown oil. MS (m/e): 226.2 ([{37Cl}M+H]+, 33%), 224.2 ([{35Cl}M+H]+, 100%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]([CH3:43])[CH2:31][CH2:32][CH2:33][N:34]([C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH3:35]>>[CH3:43][N:30]([CH3:29])[CH2:31][CH2:32][CH2:33][N:34]([C:36]1[CH:37]=[CH:38][C:39]([NH:40]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:41][CH:42]=1)[CH3:35]
Reactant: CN(C)CCCN(C)c1ccc(N)cc1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)CCCN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(N-(3-dimethylamino-propyl)-N-methyl-amino)-aniline Rf value: 0.5 (aluminium oxide, ethyl acetate) C30H34N4O3
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:4]=2[N:5]=[CH:6][N:7]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[C:3]2[C:2]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:7][CH:6]=[N:5][C:4]=2[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(Cl)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(-c3ccccc3)c12
Temperature: 120 °C

Procedure:
To a nitrogen gas purged mixture of 4-chloro-5-(2-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (50 mg, 0.13 mmol) and phenyl boronic acid (23.5 mg, 0.192 mmol) in 2 M potassium carbonate (0.192 mL, 0.385 mmol) and tetrahydrofuran (1.0 mL) was added PdCl2(dppf)-CH2Cl2 (10 mg, 0.013 mmol). The reaction was sealed and heated to 120° C. for 20 minutes. Upon cooling, the reaction mixture was diluted with EtOAc and washed with saturated sodium bicarbonate and brine. The organic layer was then dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica chromatography eluting with 1-20% ethyl acetate/hexanes to afford 5-(2-methoxyphenyl)-4-phenyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine. LRMS (ESI) calcd for C25H30N3O2Si [M+H]+: 432, found 432.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:15]2[S:14][C:13]([N:16]3[CH2:21][N:20]([CH3:22])[CH2:19][N:18]([CH2:23][CH3:24])[C:17]3=[O:25])=[N:12][C:11]=2[CH:10]=[C:9]([C:26]2[CH:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][C:35]([CH2:43][CH3:44])([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33]3)=[N:30][CH:31]=2)[CH:8]=1.CN([CH:48]=[O:49])C>C1COCC1>[CH2:43]([C:35]1([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:36][CH2:37][N:32]([C:29]2[N:28]=[CH:27][C:26]([C:9]3[CH:8]=[C:7]([CH:48]=[O:49])[C:15]4[S:14][C:13]([N:16]5[CH2:21][N:20]([CH3:22])[CH2:19][N:18]([CH2:23][CH3:24])[C:17]5=[O:25])=[N:12][C:11]=4[CH:10]=3)=[CH:31][N:30]=2)[CH2:33][CH2:34]1)[CH3:44]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(Br)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(C=O)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
1.4M BuLi (600 μL, 0.84 mmol) was added to ethyl 1-[5-[7-bromo-2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-ethyl-piperidine-4-carboxylate (250 mg, 0.41 mmol) in THF (10 mL) at −90° C. and the reaction stirred for 10 mins before DMF (300 μL) was added and the mixture stirred for a further 20 mins. The reaction was quenched with sat. NH4Cl (aq) then allowed to warm to rt before extraction with EtOAc (3×). Combined EtOAc extracts were dried and the solvent evaporated to yield the crude product which was purified by flash chromatography on 12 g SiO2 using EtOAc/Cyclohexane gradient 0-0% 3CV, 0-100% 20CV, 100-100% 5CV to yield the desired product (105 mg, 46%). 1H NMR (CDCl3) δ 10.22 (s, 1H), 8.63 (s, 2H), 8.06 (d, J=1.7 Hz, 1H), 7.83 (d, J=1.7 Hz, 1H), 5.21 (s, 2H), 4.56 (dt, J=13.8, 3.5 Hz, 2H), 4.33 (s, 2H), 4.23 (q, J=7.1 Hz, 2H), 3.51 (q, J=7.2 Hz, 2H), 3.23-3.13 (m, 2H), 2.67 (s, 3H), 2.25 (bd, J=13.4 Hz, 2H), 1.61 (q, J=7.6 Hz, 2H), 1.45 (ddd, J=13.5, 11.9, 4.2 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H), 0.86 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:10](O)[C:11]#[CH:12]>>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH2:12][C:11]#[CH:10])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(O)cc1C
Reactant: C#CCO
Product: C#CCOc1ccc(C)c(C)c1

Procedure:
The title compound was synthesized using 3,4-dimethylphenol and propargyl alcohol by conducting a reaction similar to that mentioned in Reference example 35.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.C(N(CC)CC)C.[CH2:24]([N:26]([CH2:39][CH3:40])[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=1[O:37][CH3:38])[CH3:25].O>O1CCCC1>[Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][N:26]([CH2:39][CH3:40])[CH2:24][CH3:25])=[C:31]([O:37][CH3:38])[CH:32]=1)=[O:8]
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)CCOc1ccc(N)cc1OC
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1OC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
171 mg (0.82 mmol) of CDl was added to a solution of 185 mg (0.73 mmol) of (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (cf intermediate product Z2b) in 5 mL tetrahydrofuran and the reaction mixture was stirred for 30 minutes at 50° C. Then 0.1 mL (0.73 mmol) of triethylamine and 200 mg (0.73 mmol) of 4-(2-diethylamino-ethoxy)-3-methoxy-phenylamine (see intermediate product Z6b) were added and the solution was stirred for 16 hours at RT. The reaction solution was added to water and stirred for 45 minutes at RT. After filtration the residue was dried in the circulating air dryer.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[F:16][C:17]1[CH:23]=[C:22]([S:24][CH3:25])[CH:21]=[CH:20][C:18]=1[NH2:19]>>[F:16][C:17]1[CH:23]=[C:22]([S:24][CH3:25])[CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: CSc1ccc(N)c(F)c1
Reactant: CCOC(=O)c1nn(C)c(=O)c(C)c1Cl
Product: CCOC(=O)c1nn(C)c(=O)c(C)c1Nc1ccc(SC)cc1F
Yield: 81 %

Procedure:
The title compound was prepared in 81% yield by the procedure described in Example 166 (step H) using ethyl 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylat (500 mg, 2.17 mmol) and 2-fluoro-4-methylthioaniline (375 mg, 2.38 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Br:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Br:12][CH2:13][CH2:14][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: BrCCBr
Reactant: Oc1cccc2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCOc1cccc2ncccc12
Temperature: 85 °C
Reaction time: 24 h
Yield: 100.1 %

Procedure:
A mixture of 5-hydroxyquinoline (0.3 g, 2.1 mmol), 1,2-dibromoethane (3.9 g, 21 mmol) and potassium carbonate (1.5 g, 11 mmol) in methyl ethyl ketone (15 mL) was allowed to stir at 85° C. for 24 h. The mixture was evaporated in vacuo and the residue was partitioned between ether (200 mL) and water (200 mL). The organic layer was dried over sodium sulfate and evaporated in vacuo to give the title compound (0.53 g).