Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([OH:25])[C:13]1[N:17]2[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl.[NH2:27][NH:28][C:29]([NH2:31])=[O:30].C(N(CC)CC)C>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([OH:25])[C:13]1[N:17]2[N:18]=[C:19](/[C:22](=[N:27]/[NH:28][C:29]([NH2:31])=[O:30])/[CH3:23])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: NNC(N)=O
Reactant: CC(=O)c1ccc2ncc(C(O)c3cc4cccnc4cc3F)n2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C/C(=N\NC(N)=O)c1ccc2ncc(C(O)c3cc4cccnc4cc3F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
To a solution of 1-(3-((7-fluoroquinolin-6-yl)(hydroxy)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (100 mg, 0.27 mmol) in methanol (15 mL) was added semicarbazide hydrochloride (45 mg, 0.41 mmol). Triethyl amine was added dropwise to adjust the pH to 5-6. The reaction mixture was stirred at room temperature overnight. The precipitate was collected by filtration and dried over vacuum pump to afford 50 mg (yield: 47%) title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.68 (s, 1H), 8.89 (dd, 1H), 8.45 (d, 1H), 8.25 (m, 2H), 7.99 (d, 1H), 7.72 (d, 1H), 7.57 (s, 1H), 7.52 (q, 1H), 6.67 (b, 2H), 6.62 (s, 1H), 6.47 (b, 1H), 2.19 (s, 3H). LCMS (method A): [MH]+=394, tR=3.95 min.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11](=[O:45])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]2[O:33][CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)=[CH:16][CH:15]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>C[Si](C)(C)N[Si](C)(C)C.O1CCCC1>[CH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:43]=[CH:44][C:35]=1[CH2:34][O:33][CH:21]1[CH:20]([C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][C:11]3[O:45][C:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:9][N:10]=3)=[CH:19][CH:18]=2)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCC(=O)NNC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCc3nnc(-c4ccccc4)o3)cc2)C(OCc2ccc3ccccc3c2)C1
Yield: 68.2 %

Procedure:
A solution of 106 mg (0.174 mmol) of tert-butyl (3RS,4RS)-4-[4-[3-(N'-benzoyl-hydrazino)-3-oxo-propyl]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 1.5 ml of hexamethyidisilazane was treated with 39 μl (0.039 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran and heated to reflux for 20 hours. For the working-up, the reaction mixture was treated with 50 ml of a 1:1 mixture of methylene chloride and water, the organic phase was subsequently separated and the aqueous phase was back-extracted twice with 25 ml of methylene chloride each time. The combined organic phases were dried over sodium sulphate and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel with a 7:3 mixture of hexane and ethyl acetate as the eluent. There were obtained 70 mg (68% of theory) of tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)-ethyl]-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 590 (M+H)+.
Reaction SMILES: [CH2:1]=O.[C:3]([NH:11][C:12](=[O:20])[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2>C(O)(=O)C.O>[C:3]([NH:11][C:12]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:1][C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]=2[CH3:21])[CH2:18][CH2:19]1)=[O:20])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=O
Reactant: O=C(NC(=O)c1ccccc1)NC1CCNCC1
Reactant: Cc1cc2ccccc2[nH]1
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]c2ccccc2c1CN1CCC(NC(=O)NC(=O)c2ccccc2)CC1
Reaction time: 5 h

Procedure:
A solution of formaldehyde (1.6 cm3, 40% aqueous solution) was added to a stirred solution of 4-benzoylureidopiperidine (5 g, 0.02 mol) and 2-methylindole (2.6 g, 0.02 mol) in acetic acid (12 cm3). The solution was allowed to stand for 5 hours and diluted with water (100 cm3). The precipitated solid was removed by filtration and discarded. The filtrate was basified by addition of ammonia to precipitate the product which was collected by filtration. The product was triturated with ethanol, then recrystallised from a mixture of acetonitrile (120 cm3) and water (12 cm3) to give the title compound as the pure base (1.65 g, 21%) m.p. 209°-11° C.
Reaction SMILES: [OH:1][C@H:2]([C@@H:24]([NH:32][C:33](=[O:43])[C@H:34]([CH:40]([CH3:42])[CH3:41])[NH:35][C:36]([O:38][CH3:39])=[O:37])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][N:4]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[NH:5][C:6](=[O:16])[C@H:7]([CH:13]([CH3:15])[CH3:14])[NH:8][C:9]([O:11][CH3:12])=[O:10].[C:44](Cl)(=[O:60])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]>O1CCOCC1.N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:44]([O:1][C@H:2]([C@@H:24]([NH:32][C:33](=[O:43])[C@H:34]([CH:40]([CH3:42])[CH3:41])[NH:35][C:36]([O:38][CH3:39])=[O:37])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:3][N:4]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[NH:5][C:6](=[O:16])[C@H:7]([CH:13]([CH3:14])[CH3:15])[NH:8][C:9]([O:11][CH3:12])=[O:10])(=[O:60])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(CC1CCCCC1)NC(=O)[C@@H](NC(=O)OC)C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCC(=O)O[C@@H](CN(CC1CCCCC1)NC(=O)[C@@H](NC(=O)OC)C(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C

Procedure:
Analogously to Example 105, 200 mg (0.33 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(methoxy-carbonyl)-(L)-valyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[N-methoxycarbonyl-(L)-valyl]-hydrazine (Example 73a) in 2.6 ml of dioxane and 0.4 ml of pyridine are reacted with 0.15 ml (0.495 mmol) of palmitic acid chloride and 2 mg (0.017 mmol) of DMAP. To complete the reaction a further 0.3 ml of palmitic acid chloride and a small amount of DMAP are added and the mixture is stirred. Extraction and column chromatography (SiO2, ethyl acetate/hexane 3:2) yields the pure title compound: TLC Rf (H')=0.47; tRet (V)=25.2 min; FAB-MS (M+H)+ =844.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[C:20]([C:32]4[CH:33]=[C:34]([NH:38]C(=O)C5C(F)=CC=CC=5F)[CH:35]=[CH:36][CH:37]=4)=[N:21][N:22]4[CH:27]=[C:26](C(F)(F)F)[CH:25]=[CH:24][C:23]=34)[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1.ClCCO[C:54]1[CH:55]=C(NC2N=C(C3C(C4C=C(NC(=O)C(F)(F)F)C=CC=4)=NN4C=CC=CC=34)C=CN=2)C=C[CH:59]=1.CNCC=C>>[NH2:38][C:34]1[CH:33]=[C:32]([C:20]2[C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH2:55][CH:54]=[CH2:59])[CH:7]=4)[N:18]=3)=[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]3[N:21]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4cc(C(F)(F)F)ccc34)n2)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCl)c3)n2)c1)C(F)(F)F
Agent: C=CCNC
Product: C=CCN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1

Procedure:
The title compound can be prepared from N-(3-{3-[2-({3-[(2-chloroethyl)oxy]phenyl}amino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)-2,2,2-trifluoroacetamide (obtained according to the procedure described in Example 136, Step C) through a two step process consisting of treatment of N-(3-{3-[2-({3-[(2-chloroethyl)oxy]phenyl}amino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)-2,2,2-trifluoroacetamide with N-methyl-2-propen-1-amine to give 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[3-({2-[methyl(2-propen-1-yl)amino]ethyl}oxy)phenyl]-2-pyrimidinamine, which in turn can be treated with 2,6-difluorobenzoyl chloride in THF and TEA to give the product as a solid. ES-LCMS m/z 632 (M+H).
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3].ClB1OCCO1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][C:31](Cl)=[O:32].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.C(N(CC)CC)C>[CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH:13][C:31]([CH2:30][C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)=[O:32])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)Cc1cccs1
Agent: ClB1OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: -40 °C
Yield: 70.7 %

Procedure:
2.72 g 7-ACA were suspended in 60 ml methylene chloride, then adding 2.2 g triethylamine. After cooling to -40° C., 21 ml of a 1,1 molar solution of ethylene chloroboronate in methylene chloride was poured into the mixture. The mixture was heated to -10° C. and 1.9 g of 2-thienylacetic acid chloride were poured into the mixture. Stirring was maintained for 2 hours at 0° C. 40 ml water were poured therein and after unmixing, the organic phase was added with a solution of sodium bicarbonate to constant pH 7.5. The phases were separated and the aqueous phase was washed with 50 ml methylene chloride. The aqueous phase was treated with decolouring carbon and dicalite. The product was filtered and after addition of 65 ml acetone the filtrate was acidified to pH 2. The product was allowed to crystallize at +5° C. for 2 hours, then filtered, washing with water and acetone. After vacuum drying at 40° C. 2.8 g 7-(2-thienylacetamido) cephalosporanic acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:28])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH2:23][CH2:22]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C([O:32][C:33]([C:36](Cl)=[O:37])(C)C)(=O)C.C(N(CC)CC)C.[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[C:3](=[O:28])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:33](=[O:32])[CH2:36][OH:37])[CH2:23][CH2:22]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1ccc2c(c1)CCN2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CO)N1CCc2cc(Cn3ccc(OCc4ccc(F)cc4F)c(Cl)c3=O)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with compound of Example 88 (200 mg, 0.50 mmol), 1-chlorocarbonyl-1-methylethyl acetate (80 μL, 0.55 mmol), triethylamine (140 μL, 1.0 mmol) and tetrahydrofuran (4.0 mL). After stirring at 25° C. for 20 min the reaction was completed by LC-MS. NaOH (2.5M, 2.24 mmol, 1.5 mL) and MeOH (2.0 mL) was added and stirred for 20 min to give the title compound. The compound precipitated out of solution. The precipitated was filtered and washed with water and diethyl ether to obtain the title compound (136 mg, 55%) a white solid. 1H NMR (400 MHz, (DMSO) δ 7.98 (d, J=8.1, 1H), 7.9 (d, J=7.8 Hz, 1H), 7.6 (q, J=8.6 and 6.6 Hz, 1H), 7.3 (m, 1H), 7.1 (m, 2H), 6.56 (d, J=7.8 Hz, 1H), 5.25 (s, 2H), 5.0 (s, 2H), 4.3 (t, J=7.8 Hz, 2H), 3.0 (t, J=7.9 Hz, 2H), 1.3 (s, 6H) ppm. ES-HRMS m/z 489.1376 (M+H calcd for C25H24ClF2N2O4 requires 489.1387).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1.[Cl:14][C:15]1[CH:16]=[C:17]([C:22]2[O:23][CH2:24][CH2:25][N:26]=2)[CH:18]=[CH:19][C:20]=1[OH:21].Cl[CH2:28]C1C=C(C)ON=1>>[Cl:14][C:15]1[CH:16]=[C:17]([C:22]2[O:23][CH2:24][CH2:25][N:26]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:28][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1
Reactant: Cc1cc(CCl)no1
Reactant: Oc1ccc(C2=NCCO2)cc1Cl
Reactant: Cc1cc(CCCCCCBr)on1
Product: Cc1cc(CCCCCCCOc2ccc(C3=NCCO3)cc2Cl)on1

Procedure:
5-{6-[2-Chloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]hexyl}-3-methylisoxazole [IX; R=CH3, R1 =2-Cl, R2, R3, R4, R5 and R6 =H, Y=(CH2)6, oxazole at 4-position] was prepared from 5-(6-bromohexyl)-3-methylisoxazole (Example 14a) and 4,5-dihydro-2-(3-chloro-4-hydroxyphenyl)oxazole (Example 13b) according to the procedure of Example 9, part (b), and was obtained in the form of a colorless solid, m.p. 64.5°-65.5° C. when recrystallized from etherpentane.
Reaction SMILES: C([Cl:4])(=O)C.[CH3:5][O:6][CH2:7][CH2:8][C@H:9]1[CH2:14][N:13]([C:15]2[C:24]3[N:23]=[C:22]([C:25]([F:28])([F:27])[F:26])[S:21][C:20]=3[NH:19][C:18]3[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=3[N:16]=2)[CH2:12][CH2:11][N:10]1[CH2:33][CH2:34][OH:35]>C(O)C>[ClH:4].[ClH:4].[CH3:5][O:6][CH2:7][CH2:8][CH:9]1[CH2:14][N:13]([C:15]2[C:24]3[N:23]=[C:22]([C:25]([F:28])([F:27])[F:26])[S:21][C:20]=3[NH:19][C:18]3[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=3[N:16]=2)[CH2:12][CH2:11][N:10]1[CH2:33][CH2:34][OH:35]
Reactant: CC(=O)Cl
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1CCO
Solvent: CCO
Product: COCCC1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1CCO
Product: Cl
Yield: 79.7 %

Procedure:
Add a solution of acetyl chloride (0.194 mL, 2.47 mmol) in absolute ethanol to a solution of freebase (S)-2-[2-(2-methoxy-ethyl)-4-(2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene-10-yl)-piperazin-1-yl]-ethanol (0.213 g, 0.468 mmol) in absolute ethanol and stir. Isolate the precipitated solid by suction filtration, washing with diethyl ether, and dry the solid at ambient temperature under reduced pressure overnight to give the title compound (0.197 g, 79.8%): mass spectrum (APCI, m/e): 456 (M+1); exact mass spectrum (ES+, m/e, C20H24F3N5O2S.2HCl): calc. 456.1681 (M+1-2HCl), found 456.1668.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12](Cl)(=[O:14])=[O:13])[CH:3]=[N:2]1.[OH-].[NH4+:17]>O1CCCC1>[O:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12]([NH2:17])(=[O:14])=[O:13])[CH:3]=[N:2]1
Reactant: O=S(=O)(Cl)c1ccccc1-c1cnoc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1-c1cnoc1

Procedure:
By the procedure of Example 5, 15 g of 2-(isoxazol-4-yl)benzenesulfonyl chloride prepared in Example 12 was reacted with 30 ml of concentrated ammonium hydroxide in 150 ml of tetrahydrofuran to give, after recrystallization from 2-propanol, 11 g of the title compound; m.p. 165°-167° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[F:9][C:10]([F:24])([F:23])[C:11]([NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2)=[O:12].O>CN(C)C=O>[F:24][C:10]([F:9])([F:23])[C:11]([N:13]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2)[CH3:1])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1ccc2[nH]ncc2c1)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)C(F)(F)F)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
Potassium carbonate (415 mg, 3.00 mmol) and methyl iodide (0.20 ml, 3.21 mmol) were added to a solution of 2,2,2-trifluoro-N-(1H-indazol-5-yl)acetamide (688 mg, 3.00 mmol) in N,N-dimethylformamide (4 ml) at room temperature and stirred overnight at room temperature. Then, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=99/1) to obtain 2,2,2-trifluoro-N-(1H-indazol-5-yl)-N-methylacetamide (466 mg, 64%).
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].Br[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-:16].[K+].[K+]>CC(C)=O>[CH2:12]([O:16][C:10]1[CH:2]=[C:3]([CH:7]=[CH:8][CH:9]=1)[CH2:4][CH2:5][OH:6])[CH2:13][CH3:14]
Reactant: OCCc1ccccc1O
Reactant: CCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1cccc(CCO)c1
Yield: 86.9 %

Procedure:
A mixture of 2-hydroxyphenethyl alcohol (1.50 g), bromopropane (1.3 ml, 14.9 mmol), potassium carbonate (2.25 g) and acetone (50 ml) was heated at reflux for 3 days. After concentration under reduced pressure, the residue was mixed with water and was extracted with ethyl acetate. The organic layer was washed with a 1 N aqueous solution of sodium hydroxide and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. The resulting organic layer was concentrated under reduced pressure to obtain 3-propoxyphenethyl alcohol (1.70 g) as a light yellow, oily substance.
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].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][C:33](O)=[O:34]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:33](=[O:34])[CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH3:24])([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: COCCOCCOCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COCCOCCOCC(=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 [2-(2-methoxy-ethoxy)-ethoxy]-acetic acid to yield (3aR,4S,7aR)-4-{2-[2-(2-methoxy-ethoxy)-ethoxy]-acetoxy}-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 474; RT=7.747 min; HPLC Method I
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:13][C:12]([C:28]([C:34]([F:37])([F:36])[F:35])([C:30]([F:33])([F:32])[F:31])[OH:29])=[N:11]1.[CH3:38][N:39]([CH3:44])[S:40](Cl)(=[O:42])=[O:41]>>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:27][CH2:26][CH2:25][N:24]([S:40](=[O:42])(=[O:41])[N:39]([CH3:44])[CH3:38])[CH2:23][CH2:22]3)=[CH:19][CH:20]=2)[CH2:13][C:12]([C:28]([C:34]([F:35])([F:36])[F:37])([C:30]([F:31])([F:33])[F:32])[OH:29])=[N:11]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: OC(C1=NN(c2ccc(F)cc2F)C(c2ccc(N3CCCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Product: CN(C)S(=O)(=O)N1CCCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)CC1

Procedure:
The titled compound was prepared in accordance with the same procedures as in Example 410, except for using 1-(2,4-difluoro-phenyl)-5-[4-(homopiperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride prepared in Example 409; and using dimethylsulfamoyl chloride instead of methanesulfonyl chloride.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[C:14]#N.CC[O:23]CC>>[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[C:14](=[O:23])[CH2:7][C:6]1[CH:9]=[CH:10][C:3]([F:2])=[CH:4][CH:5]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOCC
Reactant: N#Cc1ccc(Cl)cc1Cl
Agent: [Mg]
Product: O=C(Cc1ccc(F)cc1)c1ccc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 6 h

Procedure:
To an oven-dried three-neck round bottom flask fitted with a condenser and addition funnel flushed with N2 was added magnesium (4.23 g; 174 mmol) and anhydrous ether (100 mL). A solution of 4-flourobenzyl bromide (8.69 mL; 69.7 mmol) in ether (50 mL) was added dropwise via the addition funnel at room temperature. After the addition, the reaction mixture was heated at 40° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and was cannulated into another dried flask charged with a solution of 2,4-dichlorobenzonitrile (10.0 g; 58.0 mmol) in ether (150 mL) under an N2 atmosphere. The resulting reaction mixture was stirred at 40° C. for 6 hours. The reaction was cooled to room temperature and quenched slowly with 2N aq. HCl, then partitioned between ethyl acetate and 2N aq. HCl. The organic portion was washed with 2N aq. HCl, water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was filtered through a silica gel plug (eluted with 20% ethyl acetate/hexane), and recrystallized from hexane to afford product: m/e=283 (M+1).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[CH3:25])[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[CH3:25])[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c(C)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.8 %

Procedure:
To a solution of N-tert-butyl-2-(2,4-dimethylphenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (82 mg, 175 mol) in dichloromethane (2.7 mL) was added trifluoroacetic acid (400 mg, 270 μL, 3.51 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.4 mL) and stirred at room temperature for 1 h. The mixture was concentrated and triturated with water. The solid was collected by filtration and washed with water and ether to give N-tert-butyl-2-(2,4-dimethylphenylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (7 mg, 20.7 mol, 12%) as a yellow solid. 1H NMR (400 MHz, CDCl3-d) δ ppm: 9.19 (s, 1H), 8.12 (d, J=3.0, 1 H), 7.95 (s, 1H), 7.86 (s, 1H), 7.50 (d, J=7.8, 1 H), 7.15 (s, 1H), 7.08 (d, J=8.2, 1 H), 6.33 (s, 1H), 2.38 (s, 3H), 2.34 (s, 1H), 1.49 (s, 9H); MS (EI/CI) m/z: 338.2 [M+H].
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.O=[C:16]([CH3:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19].[NH2:23][C:24]([CH3:35])=[CH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)=[O:27].C(O)(=O)C>CC(O)C>[CH3:22][C:16]1[NH:23][C:24]([CH3:35])=[C:25]([C:26](=[O:27])[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CC(N)=CC(=O)c1ccc(C)cc1
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: COC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)c2ccc(C)cc2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
848 mg (4.50 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 523 mg (4.50 mmol) of methyl 3-oxobutanoate, 790 mg (4.50 mmol) of 3-amino-1-(4-methylphenyl)but-2-en-1-one and 387 μl (6.72 mmol) of acetic acid in 10 ml of 2-propanol and heated under reflux under argon for 30 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 961 mg (44% of theory) of the title compound are obtained as a yellow solid.