Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[C@H:5]([CH2:6][O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C:3]1=O.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:16]([NH:23][CH:3]1[CH2:4][CH:5]([CH2:6][O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:2]1[F:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1C[C@@H](COCc2ccccc2)[C@@H]1F
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: FC1C(COCc2ccccc2)CC1NCc1ccccc1
Reaction time: 0.08 h

Procedure:
In a 25 mL flask with trans-2-fluoro-3-(benzyloxymethyl)cyclobutanone (0.20 g, 0.96 mmol) inside, dry 1,2-DCE 3.4 mL was added under argon to give a colorless solution. To this, benzylamine (0.11 mL, 1.01 mmol) was added to give still a colorless solution. After stirring for 5 min, sodium triacetoxyborohydride (0.29 g, 1.37 mmol) was added all at once to give a white emulsion. Then AcOH (0.06 mL, 1.05 mmol) was added drop by drop. After 5 min, it gave a yellow solution and this was left stirring for 2 hr and then the reaction was quenched by sat. NaHCO3. The organic phase was separated and the aqueous phase was extracted with EtOAc twice. The combined organic phase was dried over MgSO4 and the crude product was purified by silica gel flash chromatography (Hexane: EtOAc=3:1) to give 0.19 g (65%, Rf=0.18) of the product. 1H NMR (CDCl3, 600 MHz): δ 1.81-1.95 (m, 3H), 2.80-2.89 (m, 1H), 3.46-3.56 (m, 3H), 3.76-3.84 (m, 3H), 4.51-4.55 (m, 2H), 4.89-5.00 (td, 1H, J=54.6, 4.8), 7.25-7.37 (m, 10H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+].[F:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]=C=O)=[CH:42][CH:41]=1>C(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([NH:46][C:43]4[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=4)=[O:7])[CH2:13][CH2:12]3)=[CH:15][C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:17]2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1
Reactant: O=C=Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-7-chloroquinoline-2-carboxylate (1.0 g, 2.4 mmol) in CH2Cl2 (5 mL) is added trifluoroacetic acid (5 mL). After 1 h at room temp., the reaction mixture is adjusted to pH 10–11 with 10% aq. NaOH and extracted with EtOAc. The combined extracts are dried (Na2SO4) and concentrated. The residue is dissolved in CH2Cl2 (70 mL) and treated with 4-fluorophenyl isocyanate (0.32 mL, 2.8 mmol) for 15 h at room temp. The reaction mixture is washed with water and brine, dried (Na2SO4), and concentrated. The residue is purified by column chromatography with CH2Cl2-MeOH yielding the title product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([C:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH:32]=2)=[N:24][C:25]=1[CH3:26].O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:30]1[CH2:31][CH:32]=[C:27]([C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[C:25]([CH3:26])[N:24]=2)[CH2:28][CH2:29]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: Cc1ccc(C2=CCNCC2)nc1C
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C2=CCN([C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CC2)nc1C
Yield: 44.7 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.83 g, 3.3 mmol) and 5,6-dimethyl-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine (5.18 g, 27.5 mmol) were dissolved in acetonitrile (50 ml), and lithium perchlorate trihydrate (7.48 g, 46.6 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.67 g of the intended substance (yield 44.7%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][CH2:15][CH2:14]2)[N:5]=[C:4]([NH:23][CH2:24][C:25]([CH3:37])([CH3:36])[CH2:26][CH2:27][CH:28]2[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][CH2:30][CH2:29]2)[N:3]=1.[CH2:38]([NH:41][CH2:42][CH2:43][CH3:44])[CH2:39][CH3:40].[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:38]([N:41]([CH2:42][CH2:43][CH3:44])[C:2]1[N:3]=[C:4]([NH:23][CH2:24][C:25]([CH3:37])([CH3:36])[CH2:26][CH2:27][CH:28]2[CH2:33][C:32]([CH3:34])([CH3:35])[NH:31][CH2:30][CH2:29]2)[N:5]=[C:6]([NH:8][CH2:9][C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][CH2:15][CH2:14]2)[N:7]=1)[CH2:39][CH3:40]
Reactant: CCCNCCC
Reactant: CC(C)(CCC1CCNC(C)(C)C1)CNc1nc(Cl)nc(NCC(C)(C)CCC2CCNC(C)(C)C2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CCCN(CCC)c1nc(NCC(C)(C)CCC2CCNC(C)(C)C2)nc(NCC(C)(C)CCC2CCNC(C)(C)C2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
53.6 g of 2-chloro-4,6-bis-(2,2,6,6-tetramethyl-4-piperidylbutylamino)-1,3,5-triazine, together with 15.0 g of dipropylamine in 250 ml of xylene, are stirred under reflux for 16 hours. After cooling to room temperature, 100 ml of 2N sodium hydroxide solution are added, the mixture is stirred vigorously for 15 minutes and the aqueous phase is then separated off. The xylene solution is dried over sodium sulfate and evaporated in vacuo. Crystallisation of the resulting residue from acetonitrile gives 2-dipropylamino-4,6-bis-(2,2,6,6-tetramethyl-4-piperidylbutylamino)-1,3,5-triazine, melting point 95°-96° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]([C:19]([OH:21])=O)=[CH:13][CH:14]=[CH:15][C:16]=1[O:17][CH3:18])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>C(Cl)Cl>[CH2:26]([N:28]([CH2:29][CH3:30])[C:19]([C:12]1[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])=[C:16]([O:17][CH3:18])[CH:15]=[CH:14][CH:13]=1)=[O:21])[CH3:27]
Reactant: COc1cccc(C(=O)O)c1-c1ccccc1OC(C)C
Reactant: CCNCC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1cccc(OC)c1-c1ccccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 111.3 %

Procedure:
Prepare a stirred solution of 2'-isopropoxy-6-methoxy-biphenyl-2-carboxylic acid (1.432 g, 0.0050 mole) in methylene chloride (50 mL) at -50° C. and under argon. Warm to ambient temperature then add thionyl chloride (0.8415 g, 0.516 mL). Continue stirring for about 45 minutes, observing the color change to light brown. Cool to 0° C. and dropwise add diethylamine (6.00 mL, 4.242 g, 0.058) mole, keeping the temperature of the reaction below 26° C. Continue stirring for about 30 minutes once the addition is complete. Dilute to 150 mL with additional methylene chloride. Wash the methylene chloride layer with water, separate, and extract twice with 100 mL 5% sodium bicarbonate. Separate, wash again with brine , separate and dry over MgSO4. Filter through celite and condense on a rotary evaporator to a light brown, viscous liquid. Elute via chromatography with 30% ethyl acetate/70% hexane to give a clear viscous liquid (1.90 g). Concentrate under high vacuum to give a waxy solid of the title compound. (1.40 g, 82%).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[S:13](Cl)(=[O:16])(=[O:15])[NH2:14].ClS(N=C=O)(=O)=O.C(N(CC)CC)C>C(#N)C>[N:1]1([C:6]2[CH:7]=[C:8]([O:12][S:13](=[O:16])(=[O:15])[NH2:14])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NS(=O)(=O)Cl
Reactant: Oc1cccc(-n2ccnc2)c1
Agent: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NS(=O)(=O)Oc1cccc(-n2ccnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3(1H-imidazol-1-yl)phenol (8 g, 0.05 mole) in acetonitrile was treated in an ice bath with sulfamoyl chloride generated from 0.075 mole of chlorosulfonyl isocyanate (Preparation 19) followed by 0.075 mole of triethylamine. After stirring overnight at room temperature, TLC, and 1H NMR of a sample showed starting material still present. The reaction was then treated with another 0.075 mole each of sulfamoyl chloride and triethylamine for another night.
Reaction SMILES: [CH3:1][N:2]1[C:13]2[C:5](=[CH:6][CH:7]=[C:8]3[C:12]=2[CH:11]=[N:10][NH:9]3)[C:4]([C:14]([OH:16])=O)=[CH:3]1.C1C=CC2N(O)N=[N:23]C=2C=1.N.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:1][N:2]1[C:13]2[C:12]3[C:8](=[N:9][NH:10][CH:11]=3)[CH:7]=[CH:6][C:5]=2[C:4]([C:14]([NH2:23])=[O:16])=[CH:3]1
Reactant: Cn1cc(C(=O)O)c2ccc3[nH]ncc3c21
Reactant: On1nnc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(N)=O)c2ccc3n[nH]cc3c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
To a solution of 1-methyl-1,6-dihydro-1,6,7-triaza-as-indacene-3-carboxylic acid B2 (0.232 mmol) dry DMF (2 mL), HOBT.NH3 (0.464 mmol), TBTU (0.464 mmol) and DIEA (0.08 mL) were added. The mixture was stirred at rt for 24 h. The reaction mixture was concentrated and the residue was chromatographed on silica gel (eluant: DCM/MeOH 20:1). The title compound was obtained in 60% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([NH:13]/[C:14](/[CH3:21])=[CH:15]\[C:16]([O:18]CC)=O)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[O:18]=[C:16]1[CH:15]=[C:14]([CH3:21])[NH:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][NH:10][C:11]1=2
Reactant: CCOC(=O)/C=C(/C)Nc1c[nH]nc1-c1ccc(Cl)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1cc(=O)c2[nH]nc(-c3ccc(Cl)cc3)c2[nH]1
Yield: 76.5 %

Procedure:
Ethyl 3-[3-(4-chlorophenyl)-pyrazol-4-ylamino]crotonate (D14) (0.6 g) was added to refluxing Dowtherm A (20 ml) under nitrogen and heated for 20 min. The cooled solution was diluted with petroleum ether (40°-60°; 100 ml) and the resulting solid was collected and washed well with petroleum ether to afford the title compound (0.39 g) m.p. 324°-327° C. (Found: C, 60.06; H, 3.74; N, 16.14% C13H10N3OCl requires C, 60.13; H, 3.88; N, 16.18%)
Reaction SMILES: [CH:1]1([CH:4]([C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[O:5][C:6]2[CH:26]=[CH:25][C:9]([CH2:10][NH:11][C:12]3[C:17]([NH2:18])=[CH:16][C:15]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:14][N:13]=3)=[CH:8][C:7]=2[O:27][CH3:28])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:44]([N:49]=[C:50]=S)(=[O:48])[O:45][CH2:46][CH3:47].C1(S(Cl)(=O)=O)C=CC=CC=1>O1CCCC1>[CH:1]1([CH:4]([C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[O:5][C:6]2[CH:26]=[CH:25][C:9]([CH2:10][N:11]3[C:12]4=[N:13][CH:14]=[C:15]([C:19]5[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=5)[CH:16]=[C:17]4[N:18]=[C:50]3[NH:49][C:44](=[O:48])[O:45][CH2:46][CH3:47])=[CH:8][C:7]=2[O:27][CH3:28])[CH2:3][CH2:2]1
Reactant: COc1ccc(C(Oc2ccc(CNc3ncc(-c4cnn(C)c4)cc3N)cc2OC)C2CC2)cn1
Reactant: CCOC(=O)N=C=S
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Nc1nc2cc(-c3cnn(C)c3)cnc2n1Cc1ccc(OC(c2ccc(OC)nc2)C2CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
To a stirred solution of N2-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.55 g, 1.13 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.799 g, 7.90 mmol). The resulting mixture was allowed to stir at room temperature. After 15 min, the mixture was treated with ethyl carbonisothiocyanatidate (0.444 g, 3.39 mmol), and the resulting mixture was allowed to stir at room temperature. After 30 min, the mixture was filtered, and the filtrate was concentrated. The residue was dissolved in tetrahydrofuran (5 mL) and was treated with triethylamine (0.799 g, 7.90 mmol) and benzenesulfonyl chloride (0.259 g, 1.43 mmol). The resulting mixture was allowed to stir at room temperature. After 16 h, the mixture was concentrated. Chromatographic purification of the residue (neutral alumina, 50% ethyl acetate in petroleum ether elute) afforded 0.45 g (68%) of ethyl (3-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[O:50]1[CH2:55][CH2:54][N:53]([CH:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:52][CH2:51]1>>[CH3:47][O:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:59]6[CH2:60][CH2:61][CH:56]([N:53]7[CH2:54][CH2:55][O:50][CH2:51][CH2:52]7)[CH2:57][CH2:58]6)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:45][CH:44]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Reactant: C1CC(N2CCOCC2)CCN1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCC(N5CCOCC5)CC4)cc3)cn2)cc1
Yield: 83.5 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (80.0 mg, 0.121 mmol) obtained in Step A in Example 1-D-19 and 4-morpholinopiperidine (41.3 mg, 0.242 mmol) instead of 3-(aminomethyl)pyridine, amidation was carried out in the same manner as Step B in Example 1-D-19, to obtain a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-(4-morpholin-4-yl-piperidin-1-yl)-methanone as a yellow solid (82.0 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-307) as a yellow powder (32.0 mg, 55%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].Cl[CH2:23][CH:24]1[O:28][C:27](=[O:29])[NH:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:29]=[C:27]1[NH:26][CH2:25][CH:24]([CH2:23][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])[O:28]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: O=C1NCC(CCl)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1NCC(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)O1
Temperature: 25 °C
Reaction time: 11 h
Yield: 30.1 %

Procedure:
A mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.37 g, 4.89 mmol), 5-(chloromethyl)-1,3-oxazolidin-2-one (1.34 g, 5.38 mmol) and cesium carbonate (2.39 g, 7.34 mmol) in N,N-dimethylformamide (8.0 mL) was stirred at ambient temperature for 11 h and filtered. The solid was washed with ethyl acetate and the filtrate was washed with water (3×15 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography to afford 1′-[(2-oxo-1,3-oxazolidin-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1H)-one (0.56 g, 25%): mp 195-202° C.; 1H NMR (300 MHz, CDCl3) δ 7.35-7.30 (m, 1H), 7.17-7.04 (m, 3H), 6.50 (s, 1H), 6.12 (s, 1H), 5.84 (s, 2H), 5.27 (br, 1H), 5.02-4.96 (m, 1H), 4.91-4.87 (m, 1H), 4.68-4.64 (m, 1H), 4.14-3.96 (m, 2H), 3.75-3.68 (m, 1H), 3.55-3.44 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 178.9, 158.5, 155.9, 149.0, 142.4, 142.2, 131.7, 129.4, 124.0, 123.9, 119.2, 109.6, 102.8, 101.6, 93.7, 80.3, 74.9, 58.1, 43.5, 43.1; MS (ES+) m/z 403.2 (M+23), 381.2 (M+1).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[I:21].N([Cl:24])=O>C(#N)C.ClCCl>[Cl:24][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[I:21]
Reactant: O=NCl
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Cl)c1I

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (1 g) in acetonitrile (15 ml) at 0° C. was added dropwise nitrosyl chloride (2.7 ml of a ˜1M solution in dichloromethane). The reaction mixture was heated under reflux for 10 minutes. The reaction mixture was then evaporated and the residue was purified by column chromatography on silica gel eluted with hexane: toluene (2:1) and then toluene. Combination and evaporation of suitable fractions gave the title compound as a pale orange solid, m.p. 115.7-116.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCC)[NH:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][NH:36][CH3:37]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:36]([CH2:35][CH2:34][N:33]([CH3:38])[CH3:32])[CH3:37])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CNCCN(C)C
Reactant: CCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(C)CCN(C)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(2-dimethylamino-ethyl)-methyl-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazolidin-4-one and N,N,N′-Trimethyl-ethane-1,2-diamine following General Procedure C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18]1[N:27]([CH3:28])[C:26](=[O:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1>CN(C=O)C.CCOC(C)=O>[CH3:28][N:27]1[C:26](=[O:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]1[CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cn1c(CCl)nc2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(COc2ccc(C=O)cc2)nc2ccccc2c1=O
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (3.21 g, 26.3 mmol) and K2CO3 (3.64 g, 26.3 mmol) in dry DMF (50 ml) was stirred for 15 min at 30° C. To the above stirred mixture a solution of 2-chloromethyl-3-methyl4-oxo-3,4-dihydroquinazoline (5.0 g, 24.0 mmol) was added and stirred further for 90 minutes at the same temperature. The reaction mixture was diluted with EtOAc (200 ml), washed with aqueous Na2CO3 solution (3×50 ml) and then with brine, dried over anhydrous Na2SO4 and concentrated to yield the title compound (5.08 g, 72%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8]/[N:9]=[C:10]1/[C@H:11]2[S:16][CH2:15][C:14]([CH3:17])=[C:13]([C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19])[N:12]2[C:26]/1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][NH:9][C@@H:10]1[C:26](=[O:27])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]([Cl:23])([Cl:24])[Cl:25])=[O:19])=[C:14]([CH3:17])[CH2:15][S:16][C@H:11]12)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)/C(=N\NC(=O)OC(C)(C)C)[C@H]2SC1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NNC(=O)OC(C)(C)C)[C@H]2SC1
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
In tetrahydrofuran (20 ml) is dissolved 2,2,2-trichloroethyl (E)-7-t-butoxycarbonylhydrazono-3-methyl-3-cephem-4-carboxylate (4.60 g), and under ice-cooling, a 1 M tetrahydrofuran solution of borane-tetrahydrofuran complex (23 ml) is added dropwise. The mixture is stirred at that temperature for 30 minutes. The reaction mixture is poured in a mixture of ethyl acetate (150 ml) and aqueous sodium chloride (200 ml). The organic layer is taken, dried over magnesium sulfate and concentrated. The residual oil is subjected to silica gel (50 g) column chromatography and elution is carried out with ethyl acetate-benzene. The above procedure gives crystals of 2,2,2-trichloroethyl 7β-t-butoxycarbonylhydrazino-3-methyl-3-cephem-4-carboxylate (2.49 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15](Cl)[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.[C-:25]#[N:26].[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15]([C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)[C:25]#[N:26]
Reactant: N#Cc1ccc(C(Cl)=NNc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CC(=NNc1c(Cl)cc(C(F)(F)F)cc1Cl)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
55 g of solid 4-{1-[(2,6-dichloro-4-trifluoromethylphenyl)hydrazono]chloromethyl}benzonitrile are added in portions in the course of approximately one hour to 11.4 g of sodium cyanide in 270 ml of water and 400 ml of ethanol. After the mixture has been stirred for three hours at room temperature, 200 ml of ethanol and 135 ml of water are added and the mixture is stirred for a further 5 hours. 100 ml of water are added slowly, the precipitate is filtered off and washed with water, and the filter residue is dried in vacuo at 40°. This gives the title compound of melting point 186-187° (compound no. 3.4).
Reaction SMILES: COC1C=C(C=CC=1C1SC=CC=1)[NH2:6].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.O>C(O)(=O)C>[C:18]1(=[O:19])[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:20])[NH:6]1
Reactant: COc1cc(N)ccc1-c1cccs1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)c2ccccc21

Procedure:
A stirred mixture of 5.1 g (0.025 mole) of 3-methoxy-4-(thien-2-yl)aniline (prepared in Example 4) and 4.1 g (0.03 mole) of phthalic anhydride in 20 ml of glacial acetic acid was heated at reflux for approximately 18 hours. The hot reaction mixture was poured into 700 ml of distilled water forming a precipitate. The precipitate was collected by filtration and the filter cake dissolved in methylene chloride. The methylene chloride solution was washed first with a 10% aqueous potassium carbonate solution and then with an aqueous sodium chloride solution. The washed organic solution was dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by evaporation under reduced pressure to yield 8.2 g of 2-[4-thien-2-yl)-3-methoxyphenyl]-1H-isoindol-1,3-(2H)-dione as a solid (mp 153°-155° C.).