Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.OS(O)(=O)=O.Cl.[OH-].[Na+].[CH3:19][N:20]1[CH2:26][CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1>O1CCOCC1>[CH3:19][N:20]1[CH2:26][CH2:25][C:24]2[C:6]3[CH:7]=[C:2]([CH3:10])[CH:3]=[CH:4][C:5]=3[NH:8][C:23]=2[CH2:22][CH2:21]1
Reactant: Cc1ccc(NN)cc1
Reactant: CN1CCCC(=O)CC1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 1. p-Tolyl hydrazine hydrochloride (15 g, 94.55 mmol) was taken into 7% H2SO4 in 1,4-dioxane (650 mL), 1-methylazepan-4-one.HCl (15.4 g, 94.55 mmol) was added and stirred at RT for 10 min. The reaction mixture was stirred at 80° C. for 14 h. After completion of the reaction, reaction mass was slowly basified with 50% NaOH solution, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness and purified by column chromatography (silica gel 100-200 mesh; eluent: 10% methanol-DCM) to afford 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (5 g).
Reaction SMILES: [O:1]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](=O)([O-])[O-].[Li+].[Li+].CI.C(OCC)C>CN(C)C=O>[O:1]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([CH:14]=[CH:15][C:16]([O:18][CH3:21])=[O:17])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C=CC(=O)c1ccc(Oc2ccccc2)cc1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CI
Product: COC(=O)C=CC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
5.36 g of 3-(4-phenoxybenzoyl)acrylic acid were dissolved in 30 ml of dimethylformamide, then 1.48 g of lithium carbonate and 5.68 g of methyl iodide were added. The mixture was stirred at room temperature for 3 hours and then allowed to stand overnight. Diethyl ether was added to the reaction mixture, which was then washed, in turn, with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over magnesium sulfate. The diethyl ether was removed by evaporation under reduced pressure, and the residue was recrystallized from a mixture of benzene and hexane to give 5.24 g of methyl 3-(4-phenoxybenzoyl)acrylate.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:19]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:20][C:21](O)=[O:22].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:21](=[O:22])[CH2:20][C:19]([O:25][CH2:26][CH3:27])=[O:24])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CC(=O)O
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Temperature: 25 °C
Yield: 69 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (400 mg), ethyl hydrogen malonate (225 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (326 mg), 1-hydroxy-1H-benzotriazole monohydrate (260 mg), triethylamine (0.697 mL), and N,N-dimethylformamide (5 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 90:10-70:30 hexane/ethyl acetate) to provide the title compound (312 mg, 69%) as a colorless oil.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([CH3:14])[CH3:13].[OH-].[Na+].O>C(O)C>[CH:12]([C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[CH:10]/[C:9](=[O:11])/[CH:8]=[CH:7]/[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:17][CH:16]=1)([CH3:14])[CH3:13]
Reactant: CC(=O)/C=C/c1ccccc1
Reactant: CC(C)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc(/C=C/C(=O)/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.7 %

Procedure:
A mixture of 81.0 grams (0.555 mol) trans-4-phenyl-3-buten-2-one, 81.7 grams (0,552 mol) 4isopropylbenzaldehyde, 12 mL of 10% sodium hydroxide, 150 mL water and 220 mL ethanol was stirred at ambient temperature for 15 hours. The crystalline product was collected by vacuum filtration to give 90.0 grams (59% of theoretical yield) of E,E-1-(p-isopropylphenyl)-5-phenyl-1,4-pentadien-3-one as a yellow solid. Melting point=76.0°-78.0° C. IR (KBr) 2960, 1655, 1595, 1345, 1195, 980, 820, 760, 695 cm-1 ; FDMS, m+ /z 276 (C20H20 0). 1H NMR (CDCl13) d 7.74 (d, 2H, J=-16 Hz), 7.59 (m, 2H), 7.55 (d, 2H, J=8 Hz), 7.39 (m, 3H), 7.26 (d, 2H, J=8 Hz), 7.09 (d, 1H, J=16 Hz), 7.045 (d, 1H, J=16 Hz), 2.93 (septet, 1,H, J=7 Hz), 1.26 (d, 6H, J=7 Hz). Anal. Calcd. for C20H20 0: C, 86.92; H, 7.29. Found: C, 86.87, 7.32.
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].[C:24]([O:28][C:29]([N:31]([CH3:40])[C@@H:32]([C@@H:36]([CH3:39])[CH2:37][CH3:38])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:33](=[O:34])[C@@H:32]([N:31]([C:29]([O:28][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:30])[CH3:40])[C@@H:36]([CH3:39])[CH2:37][CH3:38])([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]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Product: CC[C@H](C)[C@@H](C(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC)N(C)C(=O)OC(C)(C)C

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 (2S,3S)-2-(tert-butoxycarbonyl-methyl-amino)-3-methyl-pentanoic acid to yield (3aR,4S,7aR)-4-[(2S,3S)-2-(tert-butoxycarbonyl-methyl-amino)-3-methyl-pentanoyloxy]-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. This NBoc-protected product was then stirred in hydrochloric acid dioxane solution (4M, 10 equiv.) at room temperature for 6 hrs. Subsequently the solvent was removed the residue dissolved in dichloromethane and washed with saturated sodium hydrogencarbonate solution. The organic layer was tried with sodium sulfate, filtrated and evaporated. The crude product was subjected to silica gel flash chromatography (ISCO CombiFlash; dichloromethane/methanol; 100/0 to 95/5) to yield (3aR,4S,7aR)-4-((2S,3S)-3-methyl-2-methylamino-pentanoyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT=5.213 min; HPLC Method I
Reaction SMILES: Br.[NH2:2][C:3]1[N:4]=[C:5]([Br:8])[S:6][CH:7]=1.N1C=CC=CC=1.[C:15]([O-])(=[O:17])[CH3:16].[Na+]>C(OC(=O)C)(=O)C>[C:15]([NH:2][C:3]1[N:4]=[C:5]([Br:8])[S:6][CH:7]=1)(=[O:17])[CH3:16]
Reactant: Nc1csc(Br)n1
Reactant: CC(=O)[O-]
Agent: Br
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1csc(Br)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-Amino-2-bromothiazole hydrobromide (52 g, 0.2 m) was suspended in acetic anhydride (200 ml) then treated dropwise with pyridine (100 ml), maintaining the temperature at 0° C. by means of an ice bath. After the addition was complete, the reaction mixture was stirred for 2 h. at room temperature then poured onto 20% aqueous sodium acetate (2 l.). The solution was cooled, filtered and the precipitate washed with water (2×200 ml.). The product was air dried and recrystallised from acetone to give the title compound (35 g, 80%) m.p. 165° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[SH:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]>C(#N)C>[Br:1][C:2]1[C:3]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: OCCCCS
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OCCCCSc1nc(Cl)ncc1Br

Procedure:
A solution of 2.27 g (10.0 mmol) of 5-bromo-2,4-dichloro-pyrimidine in 30 ml of acetonitrile is mixed while being stirred at −20° C. with 1.39 ml (10 mmol) of triethylamine. Then, a solution of 1.06 g (10 mmol) of 4-mercapto-1-butanol in 1 ml of acetonitrile is added in drops. The reaction mixture is heated overnight to room temperature while being stirred. The batch is filtered, and the filtrate is evaporated to the dry state. The residue that is obtained is purified by chromatography (Flashmaster II, hexane/ethyl acetate 1:1). 2.89 g (9.7 mmol, 97% of theory) of the product 4-(5-bromo-2-chloro-pyrimidin-4-ylsulfanyl)-butan-1-ol is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(OCC)(=O)C.[CH3:41][N:42](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:17]1([NH:16][C:15]2[N:10]3[N:9]=[C:8]([C:4]4[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=4)[C:41]#[N:42])[C:22]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:24]=4)=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Brc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 25 °C
Yield: 42 %

Procedure:
To a solution of 2-(3-bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (500 mg, 0.97 mmol) in N,N-dimethylformamide (25 mL) was added zinc cyanide (68 mg, 0.58 mmol), tris(dibenzylidineacetone)bipalladium(0) (888 mg, 0.97 mmol) and 1,1′-bis(diphenylphosphino) ferrocene (1.29 g, 2.3 mmol). The resultant mixture was heated at 120° C. for 20 hours. After cooling to room temperature, ethyl acetate was added to the reaction mixture. The organic phase was washed with water, brine and dried over magnesium sulfate. Filtration and concentration, followed by purification with flash chromatography (40:60 ethyl acetate:hexanes) gave 3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}benzonitrile (0.19 g, yield 42%) as a yellow foam. 1H NMR (CDCl3): δ 8.07 (m, 2H), 7.89 (d, 1H), 7.70 (d, 1H), 7.62 (d, 1H), 7.52 (t, 1H), 7.33 (t, 1H), 6.33 (d, 1H), 6.06 (d, 1H), 6.00 (d, 1H), 5.16 (d, 1H), 4.25 (m, 1H), 4.02 (m, 1H), 2.15 (m, 2H), 2.03 (m, 2H), 1.85–1.51 (m, 12H). MS m/z 464 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=2[NH2:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[K+].[C:18]([C:20]1[N:21]=[C:22]([C:33]([O-])=[O:34])[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=1)#[N:19].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]([CH3:14])[CH3:15])[CH:10]=[CH:9][C:8]=2[NH:16][C:33]([C:22]2[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=[C:20]([C:18]#[N:19])[N:21]=2)=[O:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(C)c1ccc(N)c(C2=CCCCC2)c1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
To a mixture of 2-cyclohex-1-enyl-4-isopropyl-phenylamine (as prepared in the previous step, 30.0 mg, 0.139 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 43.0 mg, 0.141 mmol) and PyBroP (65.0 mg, 0.139 mmol) in 1.5 mL of DMF was added DIEA (73 μL, 0.417 mmol). The resulting mixture was stirred at RT for 16 h under Ar. Treated with 30 mL of EtOAc, the mixture was washed with H2O (2×10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (DCM) gave 55.4 mg (86%) of the title compound as a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C26H36N4O2Si, 465.3 (M+H), found 464.9.
Reaction SMILES: C([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][C@@H:10]([OH:15])[CH2:9]1)(OC(C)(C)C)=O.[F:16][C:17]1[C:18](I)=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])/[C:20]/2=[CH:27]\[C:28]1[NH:29][CH:30]=[CH:31][C:32]=1[O:33][CH3:34].O>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.FC(F)(F)C(O)=O.C(Cl)Cl.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.[Cu]I>[F:16][C:17]1[C:18]([C:14]#[C:13][C@@H:12]2[CH2:11][C@@H:10]([OH:15])[CH2:9][NH:8]2)=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])/[C:20]/2=[CH:27]\[C:28]1[NH:29][CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: C#C[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H]3C[C@@H](O)CN3)c21
Reaction time: 2 h

Procedure:
Using Method C above, (3R,5S)-N-Boc-3-Hydroxy-5-ethynyl-pyrrolidine (98 mg, 0.47 mmol) (Example 99C above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.16 mmol) (Starting Material 6) using (Ph3P)4Pd (18 mg, 0.02 mmol) and a catalylic amount of CuI in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 6 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 0-100% EtOAc in hexanes gradient. The intermediate that resulted from this operation was directly dissolved in 5 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.2 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (Z)-1,3-Dihydro-5-fluoro-4-[(2S,4R)-(4-hydroxy-pyrrolidin-2-yl)-ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with 0-20% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 12 mg, 31%).
Reaction SMILES: [C:1]1([C:7]2OC(=O)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([C:19]([O:21][CH3:22])=[O:20])#[C:14][C:15]([O:17][CH3:18])=[O:16].C(=O)=O>ClC1C=CC=CC=1>[C:1]1([C:7]2[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([C:19]([O:21][CH3:22])=[O:20])[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: O=c1oc(-c2ccccc2)ns1
Agent: O=C=O
Solvent: Clc1ccccc1
Product: COC(=O)c1snc(-c2ccccc2)c1C(=O)OC
Yield: 61.6 %

Procedure:
A solution of 412.2 g (2.3 mol) of 5-phenyl-1,3,4-oxathiazol-2-one, 662.7 g (4.66 mol) of dimethyl acetylenedicarboxylate, and 1 l. of chlorobenzene was heated at 135° for 6.5 hours, at which time CO2 evolution became very slow. Infrared and gas chromatography assays also indicated that the reaction was complete. The reaction mixture was concentrated under vacuum to 0.2 mm and 90°. The 680 g of pot residue was crystallized from about 700 ml of methanol to give 393 g of solid dimethyl 3-phenyl-4,5-isothiazoledicarboxylate, m.p. 70°-71.5°. An additional 69.9 g of solid, m.p. 70°-72°, was obtained from the filtrate. The total of 462.9 g amounted to a 72.7% yield.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)O)=[CH:2]1.S(Cl)([Cl:20])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:20][CH:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1
Reactant: OC(c1csc2ccccc12)C1CCCCC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: ClC(c1csc2ccccc12)C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of 1-benzothiophen-3-yl(cyclohexyl)methanol (2.32 g) synthesized above in toluene (25 mL) was added dropwise thionyl chloride (824 μL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (2.42 g, 97%) as an orange oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].C(N(CC)CC)C.[Cl:31][C:32]1[CH:33]=[C:34]([N:39]=[C:40]=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]>C1COCC1>[Cl:31][C:32]1[CH:33]=[C:34]([NH:39][C:40]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:7]3=[O:23])=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]
Reactant: Cc1ccc(N=C=O)cc1Cl
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)NCc2ccc3nc(C)n(C4CCC(=O)NC4=O)c(=O)c3c2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.46 g, 1.4 mmol) and triethylamine (0.27 mL, 1.9 mmol) in THF (10 mL) at 5˜10° C., was added 3-chloro-4-methyl-phenyl isocyanate (0.24 mL, 1.8 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (˜1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-(3-chloro-4-methyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-urea as an off-white solid (450 mg, 70% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.38 min (98.4%); mp, 186-188° C.; 1HNMR (DMSO-d6) δ 2.15-2.23 (m, 4H, CHH and CH3Ar), 2.56-2.86 (m, 6H, CHCH2, CH3), 4.40 (d, J=6 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 6.81 (t, J=5 Hz, 1H, CH2NH), 7.11-7.95 (m, 6H, Ar), 8.75 (s, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 18.71, 20.93, 23.39, 30.61, 42.34, 56.53, 116.45, 117.66, 120.01, 123.67, 126.54, 127.39, 130.99, 132.96, 133.95, 139.05, 139.58, 145.76, 154.51, 155.08, 160.47, 169.47, 172.60. LCMS MH=468, 470; Anal Calcd For C23H22N5O4Cl+0.6H2O: C, 57.71; H, 4.88; N, 14.63; Cl, 7.41. Found: C, 57.63; H, 4.96; N, 14.50; Cl, 7.64.
Reaction SMILES: [C:1]([N:11]1[CH2:13][CH:12]1[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:15]([CH:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[OH:20])([CH3:18])([CH3:17])[CH3:16].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([NH:11][CH:12]([CH3:14])[CH2:13][O:20][CH:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]([CH3:18])([CH3:17])[CH3:16])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC1CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)C(O)C(C)(C)C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(COC(C(C)(C)C)C(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
N-Cbz-2-Methyl aziridine and di-t-butylmethanol are dissolved in CH2Cl2 at 0° C. under argon. Boron trifluoride etherate is added and the flask is stirred overnight. The contents are poured into saturated NaHCO3 and are extracted with ethyl acetate. The organic layer is drid over MgSO4 and evaporated to yield N-Cbz-2-amino 1-[di-(t-butyl)methoxy]propane.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([N:11]([CH3:13])[CH3:12])=[O:10].[C:17]([N:19]=[C:20]([N:23]([CH3:32])[N:24]=CC1C=CC=CC=1)SC)#[N:18].Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:18][C:17]1[N:19]=[C:20]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[C:9]([N:11]([CH3:12])[CH3:13])=[O:10])[N:23]([CH3:32])[N:24]=1
Reactant: CN(C)C(=O)c1cccc(NCCCN)c1
Reactant: CSC(=NC#N)N(C)N=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)C(=O)c1cccc(NCCCNc2nc(N)nn2C)c1
Yield: 42.7 %

Procedure:
3-[(3-Aminopropyl)amino]-N,N-dimethylbenzamide (0.8 g) and N-cyano-1-methyl-2-(phenylmethylene)hydrazine carboximidothioic acid, methyl ester (0.84 g) were heated together under reduced pressure of 14 mm Hg during 4 hr at 100°. The cooled reaction mixture was dissolved in acetone, treated with 1 N hydrochloric acid (2 ml) and heated at 60° for 0.5 hr. The mixture was cooled, basified with potassium carbonate and extracted with ethyl acetate. Evaporation of the organic extracts gave a viscous oil which was triturated with ether to give the title compound (0.49 g). TLC silica; methanol:ammonia (80:1) Rf 0.63. NMR (CDCl3) 2.9 m (1H); 3.2-3.7 m (3H); 5.28 t (1H); 6.12 s (2H); 6.7 s (3H); 7.0 s (6H); 6.4-7.4 m (5H); 8.23 t (2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[F-].[Cs+].Cl[C:14]1[CH:22]=[C:21]2[C:17]([C:18]([NH:31][C:32](=[O:36])[CH2:33][CH2:34][CH3:35])=[N:19][N:20]2[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:16][CH:15]=1>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([NH:31][C:32](=[O:36])[CH2:33][CH2:34][CH3:35])=[N:19][N:20]3[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:28])[CH3:29])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)ccc12
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(F)cc3)ccc12
Temperature: 102 °C
Yield: 49.9 %

Procedure:
840 mg of 4-fluorophenylboronic acid, 1.24 g of caesium fluoride, 13.5 mg of palladium acetate and finally 31 mg of 2-dicyclohexylphosphine-2-(N,N-dimethylamino)biphenyl are added to 1 g of N-[6-chloro-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 25, in 30 cm3 of dioxane. The mixture is then heated at about 102° C. for 22 hours and is then allowed to return to room temperature. The reaction medium is taken up in 75 cm3 of ethyl acetate, filtered on a sinter funnel packed with Celite and then concentrated to dryness under reduced pressure (2 kPa; 50° C.). The work-up and the purification are performed by analogy with Example 41. 580 mg of N-[6-(4-fluorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are thus obtained in the form of a yellow oil.