Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.Cl[C:19]([O:21][CH2:22][CH2:23][CH3:24])=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:20])[CH2:23][CH3:24]
Reactant: CCCOC(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CCCOC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 81.3 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 5.62 mg (0.0458 mMol) propyl chloroformate, 11.2 mg (81%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17](OCC)=[O:18])=[N:15][N:16]=2)[N:13]=1.[CH2:29]([CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CO>[CH2:29]([CH:36]1[CH2:41][CH2:40][N:39]([C:17]([C:14]2[N:12]3[N:13]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:9]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)=[CH:10][C:11]3=[N:16][N:15]=2)=[O:18])[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CO
Product: O=C(c1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.4 %

Procedure:
A solution of ethyl 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (21 mg, 0.05 mmol) and 4-benzylpiperidine (0.175 mL, 1.0 mmol) in methanol (0.5 mL) was heated in a microwave oven at 160° C. for 30 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, then the crude product was purified using reverse phase preparative HPLC (Conditions: Water SunFire Prep C18, OBD 19×100 m, 5 □m; Fluted with 0% to 100% B, 10 min gradient, 100% B hold for 5 min, (A 90% H2O, 10% MeOH, 0.1% of TEA and B 10% H2O, 90% MeOH, 0.1% of TFA); Flow rate at 20 mL/min, UV detection at 220 nm) to afford 18 mg (66%) of the title compound as a white powder. HPLC/MS (method A): retention time=4.12 min, (M+H)+=542.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11]O)=[NH:10])=[CH:4][CH:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].CCO.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH2:18]([O:17][C:13]([C:14]1[N:10]=[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[NH:11][CH:15]=1)=[O:16])[CH3:19]
Reactant: C#CC(=O)OCC
Reactant: N=C(Cc1ccc(Br)cc1)NO
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(Cc2ccc(Br)cc2)n1
Temperature: 190 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
2-(4-bromophenyl)-N-hydroxyacetamidine (5.0 g, 21.8 mmol) and ethyl propiolate (2.4 mL, 24.0 mmol) were dissolved in EtOH (100 mL, 2 mol). The mixture was heated to reflux for 7 hours, cooled and then concentrated. The residue was then dissolved in diphenyl ether (75 mL, 470 mmol), heated at 190° C. for 2 hours, cooled, combined with 400 mL of hexanes, and allowed to sit overnight. The solvent was decanted and the precipitant was dissolved in DCM and purified by column chromatography (0-10% MeOH in DCM) to yield 2-(4-bromobenzyl)-1H-imidazole-4-carboxylic acid ethyl ester (3.3 g).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([NH:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24]([N:26]=[C:27]=[S:28])=[O:25])[CH3:22]>CN(C=O)C.C(OCC)(=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:27]([NH:26][C:24]([O:23][CH2:21][CH3:22])=[O:25])=[S:28])[CH:12]=[CH:11][C:10]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1ccc(C(=O)OC)c(S(=O)(=O)NC(C)(C)C)c1
Reactant: CCOC(=O)N=C=S
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)NC(=S)CNc1ccc(C(=O)OC)c(S(=O)(=O)NC(C)(C)C)c1
Yield: 75 %

Procedure:
1.20 g (4.0 mmol) of N-tert-butyl-2-methoxycarbonyl-5-methylaminobenzenesulfonamide is dissolved in 5 ml of anhydrous DMF, and 0.60 g (4.3 mmol) of 95% strength ethoxycarbonyl isothiocyanate is added. After 3 h at room temperature the mixture is taken up in ethyl acetate and washed with 1N hydrochloric acid and water. The organic phase is dried over magnesium sulfate and the solvent is removed by distillation. The residue is taken up in a little ethyl acetate and precipitated with heptane at -25° C. The precipitate is filtered off with suction and dried to give 1.29 g (75% of theory) of colorless N-tert-butyl-5-[N-(ethoxycarbonylaminothiocarbonyl)methylamino]-2-methoxycarbonylbenzenesulfonamide. m.p.: 110° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:15]2[C:14]3[CH:13]=[C:12]([F:16])[CH:11]=[CH:10][C:9]=3[N:8]([CH2:17][CH3:18])[C:7]=2[C:6](=[O:19])[N:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=1.[C-:26]#[N:27].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[CH2:17]([N:8]1[C:9]2[CH:10]=[CH:11][C:12]([F:16])=[CH:13][C:14]=2[C:15]2[C:3]([CH2:2][C:26]#[N:27])=[N:4][N:5]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:6](=[O:19])[C:7]1=2)[CH3:18]
Reactant: CCn1c2ccc(F)cc2c2c(CBr)nn(-c3ccccc3)c(=O)c21
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCn1c2ccc(F)cc2c2c(CC#N)nn(-c3ccccc3)c(=O)c21
Yield: 93.3 %

Procedure:
A two-phase mixture of 7.2 g (18 mmol) of 1-(bromomethyl)-5-ethyl-8-fluoro-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one, of 3.53 g (72 mmol) of sodium cyanide and of 0.58 g (1.8 mmol) of tetrabutylammonium bromide in 300 ml of dichloromethane and 150 ml of water is stirred vigorously for 12 h. The organic phase is separated, washed several times with water, dried over magnesium sulphate and concentrated under reduced pressure. 5.8 g (16.8 mmol) of compound are isolated, which compound is used as is in the following stage.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>>[CH2:12]([NH:11][C:9](=[O:10])[C:8]([CH3:17])([C:5]1[CH:6]=[CH:7][C:2]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH3:27])=[CH:3][CH:4]=1)[CH3:16])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1ccc(C(C)(C)C(=O)NCC(C)C)cc1
Yield: 80 %

Procedure:
Prepared in a similar manner to Example 8 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and o-tolylboronic acid. Yield: 80%. 1H NMR (400 MHz, CDCl3): δ 0.8 (d, 6H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 2.3 (s, 3H), 3 (t, 2H), 5.2 (broad, 1H), 7.2-7.25 (m, 4H), 7.3 (d, 2H), 7.4 (d, 2H). MS (M+H, 310).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH2:24]([NH:26][C:27]([CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])=[O:28])[CH3:25]>>[CH2:24]([NH:26][C:27](=[O:28])[CH2:29][CH2:30][CH2:31][C:32]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:33])[CH3:25]
Reactant: CCNC(=O)CCCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CCNC(=O)CCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-ethylcarbamoyl-butyric acid to yield (3aR,4S,7aR)-methyl 4-(5-(ethylamino)-5-oxopentanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [2M+H]=910; RT=1.13 min; UPLC Method I
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[F:26])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:27]=1.BrC1C=CC2OCCN3C(CN4C=CN=C4C)=C(C(N)=O)N=C3C=2C=1.FC1C=CC=CC=1O.[CH3:61][C:62]([OH:66])([C:64]#[CH:65])[CH3:63]>>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][CH2:18][C:12]1[N:8]2[CH2:9][CH2:10][O:11][C:5]3[CH:4]=[CH:3][C:2]([C:65]#[C:64][C:62]([OH:66])([CH3:63])[CH3:61])=[CH:27][C:6]=3[C:7]2=[N:14][C:13]=1[C:15]([NH2:17])=[O:16]
Reactant: C#CC(C)(C)O
Reactant: NC(=O)c1nc2n(c1COc1ccccc1F)CCOc1ccc(Br)cc1-2
Agent: Cc1nccn1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: Oc1ccccc1F
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(COc3ccccc3F)n1CCO2
Yield: 6 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3((2-fluorophenoxy)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-((2-methyl-1H-imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing 2-methylimidazole with 2-fluorophenol) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as an off-white solid (7 mg, 6%).
Reaction SMILES: I[C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([Li])(C)(C)C.[C:22](=[O:24])=[O:23].[OH-].[Na+]>C1COCC1.CCOCC>[C:11]1([C:3]2[C:2]([C:22]([OH:24])=[O:23])=[C:7]3[CH2:8][CH2:9][O:10][C:6]3=[CH:5][CH:4]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Ic1c(-c2ccccc2)ccc2c1CCO2
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1c(-c2ccccc2)ccc2c1CCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A magnetically stirred solution of 2,3-dihydro-4-iodo-5-phenylbenzofuran (1.60 g, 4.97 mmol) in anhydrous THF (40 mL) under nitrogen at -78° C. was treated with tert-butyllithium (1.73 M in pentane, 6.10 mL, 10.6 mmol), keeping the temperature less than -65° C., throughout. The solution was stirred for 0.5 h and treated with anhydrous carbon dioxide over 1 h at such a rate as to keep the temperature below -60° C. during addition. The solution was stirred for 2 h, allowed to warm to room temperature, and treated with Et2O, ice (100 g), and 1 N NaOH (200 mL). The layers were separated and the organic portion was further extracted with fresh 1 N NaOH (2×200 mL). The combined organic extracts were acidified with concentrated HCl, extracted with CH2Cl2 (3×150 mL), and the extracts washed with brine (200 mL), dried (MgSO4), filtered, and concentrated in vacuo to give 0.795 g (67%) of the title compound: 1H NMR (300 MHz, CDCl3)δ 3.45 (t, J=8.5 Hz, 2H), 4.65 (t, J=8.5 Hz, 2H), 6.93 (d, J=8 Hz, 1H), 7.14 (d, J=8 Hz, 1H), 7.29-7.42 (m, 5H), 11.2 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.C([Sn](CCCC)(CCCC)[C:42]1[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=1)CCC.O.CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[C:5]2[C:10]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NCC4CCN(C(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NCC4CCN(C(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
A solution of tert-butyl 4-((2-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (336 mg, 0.520 mmol) in dioxane (4 mL) was degassed with Ar before being charged with 4-tributylstannylpyridine (452 mg, 1.23 mmol) and Pd(Ph3P)4 (110 mg, 0.095 mmol). The mixture was stirred at 100° C. for 4 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a flash column, eluted with EtOAc/hexane (0-100%) to give tert-butyl 4-((2-chloro-5-(pyridine-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (90 mg).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4](C(O)=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:30])=CC=1.C([N:42]([CH2:45]C)CC)C>CC(O)(C)C>[F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]2[NH:42][C:45](=[O:30])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:3]=12
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Solvent: CC(C)(C)O
Product: O=c1[nH]c2cc3snnc3c(F)c2n1-c1ccc(I)cc1F
Temperature: 25 °C
Yield: 83.9 %

Procedure:
To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid (120 mg, 0.30 mmol) in t-BuOH (10 mL) was added DPPA (48 mg, 0.45 mmol) followed by triethylamine (60 mg, 0.60 mmol). The mixture was heated under reflux for 3 h and allowed to slowly warm to room temperature. The solvent was removed in vacuo and the resultant crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 2:1, v/v). The corresponding product was obtained (100 mg, 83.9% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.14 (s, 1H), 8.01-7.99 (m, 1H), 7.89 (s, 1H), 7.83 (m, 1H), 7.59-7.55 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15](=[O:17])[CH3:16])[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.[OH-].[K+].C([O:24][C:25](=[O:36])/[CH:26]=[CH:27]/[C:28]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1)(C)(C)C>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:15](=[O:17])/[CH:16]=[CH:34]/[C:31]2[CH:30]=[CH:29][C:28](/[CH:27]=[CH:26]/[C:25]([OH:36])=[O:24])=[CH:33][CH:32]=2)[CH:5]=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cc1
Reactant: CC(=O)c1cc(Cl)cc(N2CCN(C)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCN(c2cc(Cl)cc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)c2)CC1
Temperature: -20 °C
Reaction time: 1 h
Yield: 8.2 %

Procedure:
A mixture of 1-[3-chloro-5-(4-methyl-piperazin-1-yl)-phenyl]-ethanone (prepared as described in Preparation 4, 300 mg, 1.19 mmol), KOH (133 mg, 2.38 mmol) and (E)-3-(4-formyl-phenyl)-acrylic acid tert-butyl ester (276 mg, 1.19 mmol) in EtOH (10 ml) and H2O (2 ml) was stirred at −20° C. for 1 h and then at room temperature for 12 h. The resulting mixture was partitioned between water and AcOEt and the organic phase was dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (eluent: AcOEt/MeOH 9:1). The collected fractions were evaporated in vacuo and the resulting powder was dissolved in DCM (5 ml) and TFA (1 ml). The solution was stirred at room temperature for 12 h and then the solvent was removed to give 40 mg (E)-3-(4-{(E)-3-[3-chloro-5-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid as its trifluoroacetate salt.
Reaction SMILES: Br[C:2]1[C:3]([C:7]([OH:9])=[O:8])=[CH:4][S:5][CH:6]=1.[C:10]([O:16][CH3:17])(=[O:15])[CH2:11]C(C)=O>>[C:7]([C:3]1[C:2]([CH2:11][C:10]([O:16][CH3:17])=[O:15])=[CH:6][S:5][CH:4]=1)([OH:9])=[O:8]
Reactant: COC(=O)CC(C)=O
Reactant: O=C(O)c1cscc1Br
Product: COC(=O)Cc1cscc1C(=O)O

Procedure:
Methyl (4-carboxy-3-thienyl)acetate was prepared from 4-bromothiophen-3-carboxylic acid and methyl acetoacetate by the method described by D E Ames and O Ribeiro, J.Chem.Soc., Perkin I, 1975, 1390, for the preparation of the corresponding ethyl ester. It is a solid which, after crystallisation from aqueous methanol, had mp 121°-122° C., 1H nmr: delta 3.72 (3H, s), 3.95 (2H, s), 7.18(1H, d J 3 Hz), 8.27 (1H, d J 3 Hz) ppm.
Reaction SMILES: [F:1][C:2]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:20][C:19]([CH2:21]O)=[CH:18][C:17]=3[CH2:23][CH3:24])[N:12]=2)=[CH:7][CH:6]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:55]1[CH2:58][CH:57]([C:59]([O:61][CH3:62])=[O:60])[CH2:56]1.C(N(CC)C(C)C)(C)C>>[F:1][C:2]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:20][C:19]([CH2:21][N:55]4[CH2:58][CH:57]([C:59]([O:61][CH3:62])=[O:60])[CH2:56]4)=[CH:18][C:17]=3[CH2:23][CH3:24])[N:12]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C1CNC1
Reactant: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3cccc(F)c3F)cc2)n1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3cccc(F)c3F)cc2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using (5-{5-[4-(2,3-difluorophenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-4-ethyl-2-thienyl)methanol (0.18 g, 0.43 mmol) that was obtained in Example 18 (18b), carbon tetrabromide (0.17 g, 0.52 mmol), triphenylphosphine (0.14 g, 0.52 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.10 g, 0.86 mmol), and N,N-diisopropylethylamine (0.15 mL, 1.1 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography using a mixed solvent of ethyl acetate and hexane (5:5) to afford the title compound (0.20 g) in a yield of 91% as a pale yellow oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.[CH3:19][Mg]Cl.S(=O)(=O)(O)O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2([CH3:19])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:12])[O:7]2)=[CH:17][CH:18]=1
Reactant: C[Mg]Cl
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(c2ccc(Cl)cc2)OC(=O)c2ccccc21
Temperature: 25 °C

Procedure:
Over a period of 30 minutes a solution of 130 g of 2-(4-chlorobenzoyl)benzoic acid in 300 ml of anhydrous tetrahydrofuran was added drop-wise under nitrogen to 900 ml of a stirred 3M solution of methylmagnesium chloride in anhydrous tetrahydrofuran. After the addition the reaction mixture was kept at reflux temperature for 1 hour. Afterwards it was cooled in an ice bath to room temperature and 1 L of an aqueous 2N sulfuric acid solution was added slowly, followed by 600 ml of toluene. The organic layer was separated and washed with brine, dried and evaporated in vacuo. Bulb to bulb destination (0.1 mm Hg/160° C.) afforded 60 g of 3-(4-chlorophenyl)-3-methyl-1(3H)-isobenzofuranone as a yellow oil. M.S. (C.I.) (M/Z): 260 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]([CH3:15])[C:7]=1[NH:8][C:9](=[O:14])[CH2:10][O:11][CH2:12][CH3:13].[CH3:17][N:18]=[C:19]=[O:20]>C1(CC#N)C=CC=CC=1.C(N(CC)CC)C>[CH3:17][NH:18][C:19](=[O:20])[O:16][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:14])[CH2:10][O:11][CH2:12][CH3:13])=[C:6]([CH3:15])[CH:5]=1
Reactant: CN=C=O
Reactant: CCOCC(=O)Nc1c(C)cc(O)cc1C
Solvent: CCN(CC)CC
Solvent: N#CCc1ccccc1
Product: CCOCC(=O)Nc1c(C)cc(OC(=O)NC)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3,5-Dimethyl-4-ethoxyacetamidophenol (1.1g., 0.0049 mole, m.p. 157°-59° C., prepared by reaction of ethoxyacetyl chloride with 3,5-dimethyl-4-aminophenol) was reacted with methyl isocyanate (0.3g., 0.0053 mole) using benzeneacetonitrile as solvent and triethylamine as a catalyst. The reaction mixture was stirred at ambient temperature for 31/2 hours, followed by warming at about 45° C. for 2 hours. Solvents were removed under reduced pressure, and the residual solid recrystallized from diethylether and benzene (m.p. 112.5°-115° C.).
Reaction SMILES: [Mg].II.[CH:4]1(Cl)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:11]([Si:15](OC)([O:18][CH3:19])[O:16][CH3:17])[CH:12]([CH3:14])[CH3:13].CO>COC(C)(C)C>[CH2:11]([Si:15]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([O:18][CH3:19])[O:16][CH3:17])[CH:12]([CH3:14])[CH3:13]
Reactant: CO[Si](CC(C)C)(OC)OC
Reactant: ClC1CCCCC1
Agent: II
Agent: [Mg]
Solvent: CO
Solvent: COC(C)(C)C
Product: CO[Si](CC(C)C)(OC)C1CCCCC1

Procedure:
Under an inert gas, 24.3 g magnesium chips (1.0 mol) were combined with about 10 ml methyl-tert-butylether, an iodine crystal and 3.6 g cyclohexylchloride (0.03 mol). To start the reaction, a solution of 152.0 g isobutyltrimethoxysilane (0.85 mol) and 115.0 g cyclohexylchloride (0.97 mol) in 130 ml methyl-tert-butylether was added dropwise, with stirring, to the first mixture at a rate to maintain a moderate reflux. At the end of this addition, the reaction was allowed to reflux for two more hours. After cooling the reaction mixture, 4.8 g methanol (0.15 mol) was added, stirred for a few minutes and then the precipitate was removed by filtration. The filter cake was washed with several portions of methyl-tert-butylether. The solvent was evaporated from the combined filtrates by water vacuum. The remaining residue consisted of 192.5 g (98.4% of the theoretical yield) isobutylcyclohexyldimethoxysilane which had a purity of 98% according to GC. Isobutyldicyclohexylmethoxysilane was not detected by GC.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([Br:15])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:19][O:20][CH2:21]Cl.Cl.C(OCC)C>CN(C=O)C>[Br:15][C:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=1[O:16][CH2:19][O:20][CH3:21]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Reactant: COCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCOc1c(Br)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 7.5 °C
Reaction time: 0.5 h

Procedure:
40.00 g (140.2 mmol) of 2,4-di-tert-butyl-6-bromophenol and 400 ml of DMF are introduced into a one liter three-necked flask. The solution obtained is cooled to 5-10° C., 4.70 g of sodium hydride are added and the mixture is stirred at 10° C. for 30 minutes. 11.7 ml (154.0 mmol) of chloromethyl methyl ether are then added dropwise and the reaction mixture is stirred for one hour at room temperature. The reaction mixture is poured into a 1N HCl/ethyl ether mixture and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. 46.00 g (100%) of the expected compound are collected in the form of an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.CN1CCCN(C)C1=O.[C:20]1([CH:26]2[CH2:28][O:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:28][CH:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[OH:27])[CH:8]=[CH:7]2
Reactant: c1ccc(C2CO2)cc1
Reactant: Brc1cccc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: OC(Cn1ccc2cccc(Br)c21)c1ccccc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a mixture of 7-bromoindole (3.3 g) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (33 mL) were added 2-phenyloxirane (2.5 mL) and cesium carbonate (11 g) at room temperature, followed by stirring at 80° C. for 12 hours. To the reaction mixture were added ethyl acetate and water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 2-(7-bromo-1H-indol-1-yl)-1-phenylethanol (5.1 g).