Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]#[N:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]([O:20][CH3:21])=[O:19].C(O)(=O)C(O)=O>CCOCC>[CH3:11][N:12]1[C:16]([C:1]([C:9]#[N:10])([OH:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: N#CC(=O)c1ccccc1
Reactant: COC(=O)Cc1cccn1C
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Product: COC(=O)Cc1ccc(C(O)(C#N)c2ccccc2)n1C
Reaction time: 144 h
Yield: 12 %

Procedure:
Benzoyl cyanide, 0.67 g (0.005 mole) and methyl 1-methylpyrrole-2-acetate, 0.76 g (0.005 mole) were stirred together in ether (2 ml) containing oxalic acid (0.04 g). The reaction was run in the dark at room temperature. After six days, the reaction mixture was placed in the freezer overnight, filtered, and washed with cold ether to yield 0.17 g (12 percent) of methyl 1-methyl-5-(cyanohydroxyphenylmethyl)pyrrole-2-acetate, mp 137°-8°. The solid state IR spectrum was identical to authentic material.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4]([Cl:11])[N:3]=1.[OH-].[K+].COCCOCCN(CCOCCOC)CCOCCOC.[CH2:36]([O:43][C@H:44]1[C@H:48]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@@H:47]([CH2:57][O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[O:46][CH:45]1Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CC#N>[NH2:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:45]3[O:46][C@H:47]([CH2:57][O:58][CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)[C@@H:48]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C@@H:44]3[O:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:6]=2[N:7]=1
Reactant: BrC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: Nc1nc(Cl)c2ccnc-2[nH]1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 2-amino-4-chloro-1H-pyrrolo[2,3-d]pyrimidine [Liebigs Ann. Chem. 1: 137 (1983)] (3.03 g, 18 mmol) in anhydrous MeCN (240 mL), powdered KOH (85%; 4.2 g, 60 mmol) and tris[2-(2-methoxyethoxy)-ethyl]amine (0.66 mL, 2.1 mmol) were added and the mixture was stirred at room temperature for 10 min. Then a solution of 2,3,5-tri-O-benzyl-D-arabinofuranosyl bromide [prepared from corresponding 1-O-p-nitrobenzoate (11.43 g, 20.1 mmol) according to Seela et al., J. Org. Chem. (1982), 47, 226] in MeCN (10 mL) was added and stirring continued for another 40 min. Solid was filtered off, washed with MeCN (2×25 mL) and combined filtrate evaporated. The residue was purified on a silica gel column with a solvent system of hexanes/EtOAc:7/1, 6/1 and 5/1. Two main zones were separated. From the more rapidly migrating zone was isolated the α anomer (0.74 g) and from the slower migrating zone the desired β anomer (4.01 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]>>[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([NH:33][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH2:14][CH2:15][CH3:16])=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:21])[CH:30]=[CH:31][CH:32]=1)(=[O:25])=[O:26]
Reactant: CCCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Reactant: CS(=O)(=O)c1cccc(N)c1
Product: CCCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)Nc3cccc(S(C)(=O)=O)c3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-propyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.27) and 3-methanesulfonyl-phenylamine according to general procedure II. Pale-yellow solid. MS (ISP) 469.5 [(M+H)+]; mp 214-217° C.
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14]CC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH:2]([CH3:4])[CH3:3].[CH3:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH:52][C@H:53](C(O)=O)[CH2:54][CH2:55][CH2:56][CH2:57][NH:58]C(OC(C)(C)C)=O)(=[O:51])=[O:50])=[CH:45][CH:44]=1>>[CH3:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH:52][C@H:53]([C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([N:5]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH2:1][CH:2]([CH3:3])[CH3:4])[C:29]([OH:31])=[O:30])=[O:14])[CH2:54][CH2:55][CH2:56][CH2:57][NH2:58])(=[O:51])=[O:50])=[CH:45][CH:44]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N[C@@H](CCCCN)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine as described in general procedure Bb using Nα-(4-methylbenzenesulfonyl)-Nε-tert-butoxycarbonyl-L-lysine (360 mg, 1.2 mmol) prepared in step A of this example. The final product was purified by preparative HPLC to yield 10 mg (12%) of the desired material.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][C@H:6]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)[C:7]([O:9][CH3:10])=[O:8].Cl.[CH3:26][C:27]1[CH:36]=[C:35]([CH2:37][O:38][C:39]2[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1.FC1C=CC(CN2CCN(C(CNS(C3C=CC(OCC4C5C(=CC=CC=5)N=C(C)C=4)=CC=3)(=O)=O)C([O-])=O)CC2)=CC=1>>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:14]2[CH2:13][CH2:12][N:11]([C@@H:6]([CH2:5][NH:4][S:45]([C:42]3[CH:43]=[CH:44][C:39]([O:38][CH2:37][C:35]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=[C:27]([CH3:26])[CH:36]=4)=[CH:40][CH:41]=3)(=[O:46])=[O:47])[C:7]([O:9][CH3:10])=[O:8])[CH2:16][CH2:15]2)=[CH:23][CH:22]=1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Reactant: COC(=O)[C@H](CN)N1CCN(Cc2ccc(F)cc2)CC1
Agent: Cc1cc(COc2ccc(S(=O)(=O)NCC(C(=O)[O-])N3CCN(Cc4ccc(F)cc4)CC3)cc2)c2ccccc2n1
Agent: Cl
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1)N1CCN(Cc2ccc(F)cc2)CC1

Procedure:
In a manner analogous to example 3.6, using 1.5 g (3.7 mmol) of methyl (S)-3-amino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propanoate trihydro chloride and 1.6 g (4.1 mmol) of 4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride hydrochloride (prepared as described in 17.2), 1.0 g (46%) of methyl (S)-2-[4-(4-fluorobenzyl)piperazin-1-yl-3-(4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate is obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([CH:24]1[C:28]2[S:29][CH:30]=[CH:31][C:27]=2[C:26](=O)[O:25]1)[CH3:23].Cl>C1COCC1>[CH2:22]([CH:24]1[C:28]2[S:29][CH:30]=[CH:31][C:27]=2[C:26](=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[O:25]1)[CH3:23]
Reactant: CCC1OC(=O)c2ccsc21
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2ccsc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32.5 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (440 mg, 2.9 mmol.) in THF (3 mL) is cooled to 0° C. under an Argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (5.8 mL of a 1 M solution in THF, 5.8 mmol) dropwise. The resulting solution is stirred at 0° C. for 10 min and warmed to room temperature. A solution of 6-ethyl-6H-thieno[2,3-c]furan-4-one, (328 mg, 1.94 mmol) in THF (4 mL) and added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (100 mL.). The resulting mixture is heated to 90° C. for 45 min and stirred at room temperature for 36 h. The precipitate which formed is collected by filtration and dried. The solid obtained is purified by chromatography (30% EtOAc/hexane). The product containing fractions are concentrated to give the title compound as a yellow solid (190 mg, 33%).
Reaction SMILES: [C-]#[N:2].[K+].[C:4]([C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[NH:14][C:15](=O)C(Cl)Cl)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.C(O)C.C>[NH2:2][C:15]1[C:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)([OH:11])[C:12]2[C:13](=[CH:20][CH:21]=[C:22]([Cl:24])[CH:23]=2)[N:14]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(Cl)Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC1=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Reaction time: 8 h
Yield: 86.4 %

Procedure:
Potassium cyanide (18 g) in water (150 ml) was added to a suspension of 2'-benzoyl-2,2,4'-trichloro-acetanilide (30 g) in ethanol (400 ml). The reaction was stirred overnight and after treatment with charcoal diluted with water, 2-Amino-5-chloro-3-phenyl-3H-indol-3-ol (19.57 g) was obtained as off white crystals m.p. 205°-208°C after recrystallization from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[C:3]=1[CH2:11][CH3:12].[N:13]#[C:14]Br.O.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Cl:1][C:2]1[C:3]([CH2:11][CH3:12])=[C:4]([CH3:10])[C:5]2[N:6]([C:14]([NH2:13])=[N:9][N:8]=2)[N:7]=1
Reactant: N#CBr
Reactant: CCc1c(Cl)nnc(NN)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCc1c(Cl)nn2c(N)nnc2c1C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
(6-Chloro-5-ethyl-4-methylpyridazin-3-yl)hydrazine (W3.007; 340 mg) was dissolved in ethanol/water (10/2 ml) at RT while stirring. Thereafter, cyanogen bromide (386 mg, dissolved in 5 ml of ethanol and 1 ml of water) was cautiously added dropwise. After stirring at RT for 5 h, the mixture was left to stand overnight and then the solvent was drawn off, and the residue was admixed with water. Once the residue had been alkalized with saturated potassium carbonate solution, it was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after filtering off the desiccant, dried under reduced pressure. 385 mg of the title compound were obtained. LC-MS rt: 0.62 min [M+H]+: 212.1 (met. b)
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:30][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[CH:26][CH:25]=[C:24]5Br)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:39]([NH2:43])(=[O:42])[CH:40]=[CH2:41].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:30][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[CH:26][CH:25]=[C:24]5/[CH:41]=[CH:40]/[C:39]([NH2:43])=[O:42])=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)=[O:38])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cccc(Br)c5nn4cc3-c3ccccc3)cc2)CCC1
Reactant: C=CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cccc(/C=C/C(N)=O)c5nn4cc3-c3ccccc3)cc2)CCC1
Yield: 143 %

Procedure:
200 mg (0.351 mmol) {1-[4-(7-Bromo-3-phenylpyrimido[1,2-b]indazol-2-yl)phenyl]-cyclobutyl}carbamic acid tert-butyl ester (intermediate example Int-2-1), 49.9 mg (0.7 mmol) acrylamide, 18.2 mg (0.06 mmol) tri-2-tolylphosphane and 7.9 mg (0.035 mmol) palladium(II) acetate were treated in 2.47 mL degassed acetonitrile as described in example 13 (step 1). After the work-up 281 mg (>100%) of the crude product were obtained and used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O>>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: OB(O)c1ccco1
Reactant: COc1cc(Br)cc(OC)c1O
Product: COc1cc(-c2ccco2)cc(OC)c1O
Yield: 79 %

Procedure:
4-Bromo-2,6-dimethoxyphenol (Lee, H.; et al. Tetrahedron Letters, 2004, 45, 1019) was coupled with 2-furylboronic acid according to the procedure used in the synthesis of Example 21. Purification by chromatography (20-40% EtOAc-hexanes) gave 4-(furan-2-yl)-2,6-dimethoxyphenol as a light orange solid (1.95 g, 79% yield).
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][NH:14][C:15]([C:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][C:18]=1[CH2:26][CH2:27][CH2:28][CH3:29])=[O:16])=[CH:7]2.Br[CH2:31][C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:11]([O:12][CH2:31][C:32]#[N:33])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][NH:14][C:15]([C:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][C:18]=1[CH2:26][CH2:27][CH2:28][CH3:29])=[O:16])=[CH:7]2
Reactant: N#CCBr
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide (300 mg, 0.66 mmol), prepared in the previous step, bromoacetonitrile (56 μL, 0.80 mmol) and potassium carbonate (460 mg, 3.32 mmol) in 15 mL of DMF was stirred under nitrogen at room temperature for 18 h (overnight). The reaction was diluted with ethyl acetate, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 2-butyl-benzofuran-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (324 mg, 99%) as an off-white solid, mp154-157° C.
Reaction SMILES: [OH-].[Na+].[N:3]1([CH:8]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O-:17])=[O:16])[CH:7]=[CH:6][N:5]=[CH:4]1>CO.O>[N:3]1([CH:8]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CCCCCCCCCCC(CCCCCCC(=O)[O-])n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCC(CCCCCCC(=O)O)n1ccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 125.7 %

Procedure:
Sodium hydroxide (0.67 g, 1.68 mmol) was added to a stirred solution of 8-(1H-imidazol-1-yl)octadecanoate (0.305 g, 0.84 mmol) in a mixture of methanol (9 ml) and water (3 ml) at 0° C., warmed to room temperature and stirring continued another 3 h. Methanol was removed from the mixture by evaporation. The pH was adjusted to 4 with 1N HCl, and the mixture extracted with dichloromethane (3×15 ml). The combined organic layers were washed with brine solution, dried on anhydrous MgSO4, and concentrated. Crude product was purified on silica gel column (5% methanol in dichloromethane) to obtain a gummy liquid (370 mg, 83%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=2)[NH2:9])[CH:3]=[N:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](O)=[O:26])=[C:16]([C:29]([O:31]C)=[O:30])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](=[O:26])[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([C:4]3[CH:5]=[N:1][NH:2][CH:3]=3)[CH:7]=2)=[C:16]([CH:15]=1)[C:29]([OH:31])=[O:30]
Reactant: Nc1cccc(-c2cn[nH]c2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2cn[nH]c2)c1

Procedure:
Using the same method as in Example 1-(ii), 3-(1H-pyrazol-4-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-oxo-2-([3-(1H-pyrazol-4-yl)phenyl]amino)ethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 72%).
Reaction SMILES: C(Cl)Cl.C=O.[Br:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:15])=[CH2:14])[CH:10]=[CH:9][C:8]=1[F:16].[C:17](=O)([O-])[OH:18].[Na+]>C(OCC)(=O)C>[Br:6][C:7]1[CH:12]=[C:11]([C:13](=[CH2:15])[CH2:14][CH2:17][OH:18])[CH:10]=[CH:9][C:8]=1[F:16]
Reactant: O=C([O-])O
Reactant: C=C(C)c1ccc(F)c(Br)c1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=C(CCO)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
A molecular sieve 4A (3.14 g) and a boron trifluoride-diethyl ether complex (2.16 mL, 17.5 mmol) were added to methylene chloride (31 mL), and the mixture was stirred at room temperature for 1 hour. Subsequently, paraformaldehyde (0.46 g, 14.6 mmol) and the compound (3.14 g, 14.6 mmol) obtained in Example 91a were added at −5° C., and the mixture was stirred at the same temperature for 18 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1→3:1, v/v) to give the title compound (1.24 g; yield, 35%) as a colorless oily substance.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][CH2:8][Li])[CH2:4][CH3:5])[CH3:2].[Cl-].[CH3:11][Ga+:12][CH3:13]>CCCCC>[CH2:1]([N:3]([CH2:6][CH2:7][CH2:8][Ga:12]([CH3:13])[CH3:11])[CH2:4][CH3:5])[CH3:2]
Reactant: C[Ga+]C
Reactant: [Li]CCCN(CC)CC
Agent: [Cl-]
Solvent: CCCCC
Product: CCN(CC)CCC[Ga](C)C
Reaction time: 24 h

Procedure:
3.6 g (30 mmol) of diethylaminopropyllithium dissolved in 100 ml of pentane are added to a solution of 4 g (30 mmol) of dimethylgallium chloride in 50 ml of pentane at -78°. The solution is allowed to come to room temperature and is stirred for a further 24 hours. The working up is carried out analogously to Example 1. Instead of the distillation, a sublimination is carried out. Diethylaminopropyl(dimethyl)gallium with an M.p. of 43°-45° is obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][OH:14].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:14][CH2:13][C:9]1[N:8]([CH2:7][C:6]2[CH:15]=[C:16]([Cl:18])[CH:17]=[C:4]([Cl:3])[CH:5]=2)[CH:12]=[CH:11][N:10]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: OCc1nccn1Cc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cc(Cl)cc(Cn2ccnc2COCc2ccccc2)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
To NaH in DMF, was added [1-(3,5-dichloro-benzyl)-1H-imidazol-2-yl]-methanol (see Example 1) in DMF. The reaction mixture was stirred at 40° C. for 30 min and benzyl bromide was dropwise added. The reaction mixture was stirred at 40° C. for another 3 h. The mixture was diluted with EtOAc and washed with water, 1N HCl and saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using CH2Cl2:MeOH 98:2 as an eluent to afford the title compound (7 mg, 5%); MS m/z 347 [C18H16Cl2N2O+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:12]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[C:12]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:7][C:6]2[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=2)=[CH:26][CH:25]=1)#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCC#Cc1ccc(C=O)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: CCCCCCCCCCC#Cc1ccc(CNc2ccc(C(F)(F)F)cc2)cc1
Yield: 42 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-(trifluoromethyl)aniline and 4-dodec-1-ynylbenzaldehyde gave the title compound as a pale yellow oil (42%). 1H NMR (CDCl3, 300 MHz) δ 7.40-7.23 (m, 8H), 4.35 (s, 2H), 2.40 (m, 2H), 1.62-1.27 (m, 16H), 0.88 (t, 3H, J=6.8 Hz). HPLC (Condition A), Rt: 7.0 min (HPLC purity: 99.4%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][CH:14]=2)=[C:9]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[CH:8]=1)[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>ClCCl>[CH3:27][O:26][CH2:25][CH2:24][CH2:23][O:22][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:28])[CH:12]=[CH:11][C:10]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:64]2[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]2)=[O:21])=[CH:15][CH:14]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(C(=O)O)cc2)c(OCCCOC)c1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(-c2ccc(C(=O)N3CCN(C)CC3)cc2)c(OCCCOC)c1
Reaction time: 18 h
Yield: 76.8 %

Procedure:
In a round bottom flask, under an atmosphere of argon, 4′-(3-ethoxy-3-oxopropyl)-2′-(3-methoxypropoxy)biphenyl-4-carboxylic acid (0.48 g, 1.2 mmol) was dissolved in dichloromethane (20 mL). EDCl (0.29 g, 1.5 mmol), HOBT (0.20 g, 1.5 mmol) and diisopropylethylamine (1.08 mL, 6.2 mmol) were added at room temperature. After consumption of all the acid, N-methylpiperazine (0.11 mL, 1.0 mmol) was added and the mixture, was stirred for 18 hrs. The organic layer was washed twice with water. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/ethanol, 90/10) to yield 0.36 g (62%) of the desired product as a yellow oil.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.Br[C:29]1[C:30]([O:49][CH3:50])=[C:31]([C:36]([CH2:39][S:40]([N:43]2[CH2:47][CH2:46][CH:45]([OH:48])[CH2:44]2)(=[O:42])=[O:41])=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33]>>[O:25]1[CH:26]=[CH:27][C:23]([C:29]2[C:30]([O:49][CH3:50])=[C:31]([C:36]([CH2:39][S:40]([N:43]3[CH2:47][CH2:46][CH:45]([OH:48])[CH2:44]3)(=[O:42])=[O:41])=[CH:37][CH:38]=2)[C:32]([O:34][CH3:35])=[O:33])=[CH:24]1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: COC(=O)c1c(CS(=O)(=O)N2CCC(O)C2)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)N2CCC(O)C2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-6-(3-hydroxypyrrolidin-1-ylsulphonylmethyl)-2-methoxybenzoate (Intermediate 166).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1.[CH3:11][NH:12][C:13]([C:15]1[C:16](=[O:32])[C:17]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[C:18]([CH3:21])[NH:19][CH:20]=1)=[O:14]>>[CH3:11][NH:12][C:13]([C:15]1[C:16](=[O:32])[C:17]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[C:18]([CH3:21])[N:19]([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=2)[CH:20]=1)=[O:14]
Reactant: N#Cc1ccc(CBr)nc1
Reactant: CNC(=O)c1c[nH]c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O
Product: CNC(=O)c1cn(Cc2ccc(C#N)cn2)c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O

Procedure:
Example 44 is prepared as described for example 2.1, substituting benzyl bromide with 6-bromomethyl-nicotinonitrile and substituting preparation 5 with preparation 36a. ESI mass spectrum: [M+H]+=428; Retention time HPLC: 0.99 min (Z018_S04).