Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:11]=3[C:12]=2[C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9](=[O:34])[C:10]3[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:11]=3[C:12]=2[C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: O=C(C1=C(c2ccc(O)cc2)S(=O)c2cc(O)ccc21)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
A mixture of 1.0 gram (3.26 mmoles) of 2-(4-hydroxyphenyl)-3-benzoyl-6-hydroxybenzothiophene in 50 ml. of ethyl acetate was prepared and cooled to 0° C. The mixture was stirred, and 620 mg. (3.59 mmoles) of m-chloroperbenzoic acid were added. The mixture was stirred for one hour and then was allowed to stand overnight under refrigeration. The product was chromatographed rapidly over silica gel in a fritted glass funnel, elution being carried out with a 7:3 mixture of benzene and ethyl acetate followed by pure ethyl acetate to obtain 220 mg. (19 percent) of the title compound. Mass spectrum: Theory, 362; Found, 362.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C[CH2:45][N:46](C(C)C)[CH:47](C)C.CNC>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][N:46]([CH3:47])[CH3:45])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Agent: CNC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CN(C)C)c3)c3ccccc23)cc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 37.1 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (0.1 mL) and DIPEA (17 μl, 0.1 mmol) was added dimethylamine (2.0M solution in THF) (41 μl, 0.08 mmol). The reaction mixture was heated to 40° C. and stirred for 12 hr. The crude reaction mixture was purified by column chromatography (12 g silica, 0-10% MeOH in DCM, gradient elution). Product fractions were concentrated in vacuo and the residue triturated with a mixture of diethyl ether, DCM and iso-hexane (2:1:2, 5.0 mL) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(dimethylamino) acetamide (Example 12) as an orange solid (18 mg, 35%): m/z 607 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.31 (6H, s), 2.39 (3H, s), 3.14 (2H, s), 5.39 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.29 (1H, d), 7.35 (2H, d), 7.44 (2H, d), 7.65-7.55 (3H, m), 7.94 (1H, m), 8.38-8.28 (3H, m), 8.59 (1H, s), 8.79 (1H, s), 9.93 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]([C:15]([O:17][CH3:18])=[O:16])([CH2:8][CH2:9][CH:10]([O:13][CH3:14])[O:11]C)[CH2:6]O)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH3:14][O:13][CH:10]1[O:11][CH2:6][C:5]([C:3]([O:2][CH3:1])=[O:4])([C:15]([O:17][CH3:18])=[O:16])[CH2:8][CH2:9]1
Reactant: COC(=O)C(CO)(CCC(OC)OC)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: COC(=O)C1(C(=O)OC)CCC(OC)OC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of dimethyl-1-hydroxy-5,5-dimethoxypentane-2,2-dicarboxylate made in accordance with Example I (8.4 g, 0.032 mol), p-toluenesulfonic acid (0.052 g, 0.027 mmol) in dry benzene (600 ml) was allowed to reflux through a Soxhlet extractor for 2 hours. The Soxhlet thimble was charged with Type 4 A molecular sieves (ca 20 g). After the mixture was cooled to room temperature, anhydrous potassium carbonate (7 g, 0.05 mol) was added, and the mixture was stirred for 30 min. The mixture was filtered and the solvent was removed by a rotary evaporator. The residual amber oil was distilled under reduced pressure. Yield of the product, which had a bp of 95°-100° C. (1 mmHg), was 84%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:12][O:13][CH2:14][CH2:15][OH:16].O[C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]2=[O:48])=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:12][O:13][CH2:14][CH2:15][O:16][C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]2=[O:48])=[CH:20][CH:19]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCON=Cc1ccc2ccccc2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1SC(Cc2ccc(OCCON=Cc3ccc4ccccc4n3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 78.6 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 478 mg of 2-(2-quinolylmethyleneaminooxy)ethanol (prepared as described in Preparation 2), 1.00 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 638 mg of triphenylphosphine and 423 mg of diethyl azodicarboxylate, 1.12 g of the title compound were obtained as a crystalline powder, melting at 127°-130° C.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C[C:14]([N:16](C)C)=O>C(OC(=O)C)C.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[C-]#N.[Zn+2]>[O:12]=[C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:14]#[N:16])[CH:11]=2)[CH2:6][CH2:7][NH:8]1
Reactant: O=C1NCCc2ccc(I)cc21
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)C(=O)NCC2
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 63.48 %

Procedure:
7-Iodo-3,4-dihydro-2H-isoquinolin-1-one (I-32b: 200 mg, 0.7326 mmol) in DMA (1 mL) was added to a stirred solution of Pd(dba)3 (4.02 mg, 0.0043 mmol), Zn dust (1.9 mg, 0.0293 mmol), Dppf (7.77 mg, 0.0095 mmol) in DMA (1 mL) previously degassed with argon for 15 mins. The reaction mixture was stirred for 5 mins. This was followed by the addition of Zn(CN)2 (51.6 mg, 0.4395 mmol) and the resulting mixture was heated to 120° C. for 4 hrs. The reaction was monitored by TLC (80% ethylacetate). The reaction mixture was diluted with ethylacetate and washed with 2N NH4OH solution. The organic layer was dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (70% ethylacetate in hexane) afforded 80 mg of the product (63.48% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23].C(O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6](=[N:22][NH2:23])[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)Cc1ccc(C(=NN)c2ccc(Cl)cc2)cc1
Reaction time: 6 h
Yield: 95.7 %

Procedure:
4-chloro-4'-methylsulfonylmethylbenzophenone (10.0 g) and hydrazine monohydrate (4.9 g) were added to ethanol (200 ml) and acetic acid (10 ml), and the mixture was stirred for 6 hours under reflux. The reaction mixture was concentrated, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the desired product (10.0 g, melting point: 52° to 54° C., yield: 97%)
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]([C:11]3[CH:16]=[CH:15][C:14]4[O:17][CH2:18][O:19][C:13]=4[CH:12]=3)=[C:3]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc(OC)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl(1RS)-1-hydroxy-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (0.80 g, 1.9 mmol) in CH2Cl2 (10 ml) at 0° C. under an argon atmosphere was added triethylsilane (0.28 g, 2.4 mmol), followed by boron trifluoride etherate (1 ml, 8.1 mmol). The resulting solution was stirred at 0° C. for 10 min, and was then partitioned between EtOAc and 3M HCl. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was filtered through a pad of silica gel, eluting with CH2Cl2. The title compound (mixture of Δ1 and Δ2 double bond isomers) was obtained as a glassy, yellow solid (0.72 g, 94%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[C:8]3[S:14][CH2:13][CH2:12][N:9]32)=[CH:4][C:3]=1[F:19].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[F:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)[N:9]1[CH2:12][CH2:13][S:14][C:8]1=[C:7]([C:15]([OH:17])=[O:16])[C:6]2=[O:18]
Reactant: O=C(O)c1c2n(c3cc(Br)c(F)cc3c1=O)CCS2
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)c2n3CCS2)CC1
Yield: 22 %

Procedure:
A mixture of 500 mg (1.45 mmol) of 8-bromo-7-fluoro-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a) quinoline-4-carboxylic acid, 730 mg (7.25 mmol) of N-methylpiperazine and 10 ml of pyridine was heated to reflux for twelve hours on an oil bath. The conent was then concentrated under reduced pressure, water was added to the residue, insoluble matters were collected by filtration, washed with water, dried, and the resulting powder was recrystallized from dimethyl formamide to give 116 mg (22.0 percent) of the title compound. Melting point was 267° to 271° C. (decomposition).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:56])[C@@H:24]([NH:25][C:26](=[O:55])[C@H:27](C4C=CC(C(OC(C)(C)C)=O)=CC=4N)[NH:28][C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[C:33](=[O:39])[C:32]4=[O:40])=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:57][O:58][C:59](=[O:61])[CH3:60])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:63]1([CH3:73])[CH:68]=[CH:67][C:66]([S:69]([OH:72])(=[O:71])=[O:70])=[CH:65][CH:64]=1.[C:74](#[N:76])[CH3:75]>>[C:63]1([CH3:73])[CH:64]=[CH:65][C:66]([S:69]([OH:72])(=[O:70])=[O:71])=[CH:67][CH:68]=1.[C:8]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:56])[C@@H:24]([NH:25][C:26](=[O:55])[C@H:27]([C:63]4[CH:64]=[CH:65][C:74]([NH2:76])=[CH:75][CH:68]=4)[NH:28][C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[C:33](=[O:39])[C:32]4=[O:40])=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:57][O:58][C:59](=[O:61])[CH3:60])=[O:16])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC#N
Reactant: CCN1CCN(C(=O)N[C@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(COC(C)=O)CS[C@H]23)c2ccc(C(=O)OC(C)(C)C)cc2N)C(=O)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCN1CCN(C(=O)N[C@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(COC(C)=O)CS[C@H]23)c2ccc(N)cc2)C(=O)C1=O

Procedure:
In the manner described in Example 11, 3.883 g of 3-acetoxymethyl-7β-[(2S)-2-(4-BOC-aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted with 1.75 g of p-toluenesulphonic acid monohydrate in 30 ml of acetonitrile and worked up. 3-Acetoxymethyl-7β-[(2S)-2-(4-aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonate is obtained. [α]D20 =+32°±1° (0.90% in CH3OH).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:5]2([CH3:6])[C:4](=[O:21])[CH2:3]1)[C@@H:16]1[C:11](=[CH:12][C:13](=[O:20])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>N1C=CC=CC=1>[C:22]([O:1][C@@H:2]1[C@H:7]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:5]2([CH3:6])[C:4](=[O:21])[CH2:3]1)[C@@H:16]1[C:11](=[CH:12][C:13](=[O:20])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](O)CC2=O
Solvent: O
Solvent: c1ccncc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(=O)c1ccccc1)CC2=O
Reaction time: 1 h

Procedure:
A solution of 69.2 g of 15α-hydroxy-4-estrene-3,17-dione in 408 ml of pyridine is combined under ice cooling with 46.4 ml of benzoyl chloride and stirred for one hour under cooling. Then the mixture is combined with 5.7 ml of water and agitated for 3 hours at room temperature and precipitated into ice water. The thus-formed precipitate is filtered off, washed with water, and dried, thus yielding 98.7 g of 15α-benzoyloxy-4-estrene-3,17-dione.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](Cl)=[O:12].[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:42])[CH2:35][CH2:36][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:17][N:16]=1>ClCCl.N1C=CC=CC=1>[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:11]([C:3]4[N:2]([CH3:1])[C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:12])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:42])[CH2:35][CH2:36][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:17][N:16]=1
Reactant: COc1cc(-c2csc3c(NC(=O)CCN4CCCC4)cnc(N)c23)ccc1N
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2csc3c(NC(=O)CCN4CCCC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Methyl-1H-indole-2-carbonyl chloride (109 mg, 0.6 mmol) in dichloromethane (2 mL) was added to N-[4-amino-3-(4-amino-3-methoxyphenyl)thieno[3,2-c]pyridin-7-yl]-3-pyrrolidin-1-ylpropanamide (0.5 mmol) in pyridine (3 mL) at about 0° C. The ice-water bath was removed and the reaction mixture was stirred at room temperature overnight. The solvent was removed and residue was purified by reverse phase preparative HPLC to give the title compound as the acetate salt (116 mg, 37%). 1H NMR (DMSO, d6) δ 1.75 (m, 4H), 1.90 (s, 3H), 2.55 (m, 6H), 2.77 (t, 2H), 3.91 (s, 3H), 4.04 (s, 3H), 5.44 (s, 2H), 7.08 (d, 1H), 7.15 (t, 1H), 7.20 (s, 1H), 7.33(t, 1H), 7.35 (s, 1H), 7.55 (s, 1H), 7.59 (d, 1H), 7.71 (d, 1H), 7.91 (s, 1H), 7.99 (d, 1H), 9.51 (s, 1H), 10.14 (s, 1H). LCMS: MH+=567.3, Rt =2.579 min. (a).
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:14]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:13][N:12]=[N:11]2)[CH:5]=1.N(C1C=C(C=CC=1)C(OC)=O)=[N+]=[N-].O=S(Cl)Cl.CNC.[C:40]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])(=[O:42])[CH3:41].[Li]>C1COCC1>[C:44]([O:43][C:40](=[O:42])[CH2:41][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:14]([CH2:15][N:16]([CH3:17])[CH3:18])=[CH:13][N:12]=[N:11]2)[CH:5]=1)=[O:19])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-n2nncc2CN(C)C)c1
Agent: CNC
Agent: COC(=O)c1cccc(N=[N+]=[N-])c1
Agent: [Li]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CN(C)Cc1cnnn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from 3-(5-dimethylaminomethyl-[1,2,3]triazol-1-yl)-benzoic acid methyl ester [prepared from methyl 3-azidobenzoate following the synthetic steps i.) to iii.) as described in the preparation of Example K5 and reacting the obtained product with SOCl2 in THF at 0 to 23° C. for 1 h, followed by addition of dimethylamine (7.9 M in H2O) and stirring at 23 to 70° C. for 1 h.] (2.14 g, 8.22 mmol) by treatment with lithium tert.-butyl acetate according to general procedure K (method b). Obtained as a yellow oil (2.90 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Br[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC#N)c1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C(C#N)CCc2ccccc2)c1
Yield: 63.7 %

Procedure:
By working in a way similar to that described in example 16 but using 3-methoxy-phenyl-acetonitrile (4.4 g, 30 mmoles), anhydrous DMF (30 ml), NaH (55-65%, 1.44 g, 36 mmoles) and 2-bromoethylbenzene (6.7 g, 36.3 mmoles), 4.8 g of the title compound were obtained (yield: 64%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][N:7]=1)=[O:5])[CH3:2].[I:16]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH2:14]([O:13][C:11]([C:9]1[C:10]([I:16])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:7][N:8]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1n[nH]c(C(=O)OCC)c1I
Temperature: 25 °C

Procedure:
To a solution of 10 g 1H-Pyrazole-3,5-dicarboxylic acid diethyl ester in 400 ml acetonitrile 13 g ammonium cerium(iv) nitrate (CAN) and 7.17 g iodine were added and the mixture was heated to reflux for 5 h. Then, after cooling to RT, 30 ml sat. sodium thiosulfate solution were added. The mixture was extracted with ethyl acetate (3×100 ml), the combined organic layers were washed with water and then dried over MgSO4, filtered and the solvents were removed under reduced pressure. The residue was filtered through a pad of silica gel eluting with heptane/ethyl acetate 1:1. Yield: 13 g.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH3:16])[C:13](=O)[NH:14][C:10]=2[C:9]([C:17]([F:20])([F:19])[F:18])=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:13]1[N:12]([CH3:16])[C:11]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=[C:9]([C:17]([F:20])([F:19])[F:18])[C:10]=2[N:14]=1
Reactant: CCC(CC)c1ccc(C(F)(F)F)c2[nH]c(=O)n(C)c12
Reactant: O=P(Cl)(Cl)Cl
Product: CCC(CC)c1ccc(C(F)(F)F)c2nc(Cl)n(C)c12
Temperature: 110 °C
Yield: 91 %

Procedure:
A mixture of 7-(1-ethylpropyl)-1-methyl-4-(trifluoro-methyl)-1,3-dihydro-2H-benzimidazol-2-one (310 mg, 1.08 mmol) and phosphoryl chloride (5 ml) was heated at 110° C. for 1 h and concentrated in vacuo. Toluene was added and concentrated again to remove excess reagent. Aqueous saturated sodium bicarbonate was added to the residue and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 20% ethyl acetate/n-hexane to give 300 mg (0.99 mmol, 91%) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:27]=[CH:26][C:16]([C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C(NC2C=CC(C(N3CCN(C)CC3)=[O:44])=CC=2)=CC=1.ClC1C=C2C(C(NC3C=CC(C(N4CCN(CCCC)CC4)=O)=CC=3)=CC=N2)=CC=1.ClC1C=C2C(C(NC3C=CC(C(N4CCN(CC5C=CC=CC=5)CC4)=O)=CC=3)=CC=N2)=CC=1.COC1C=C2C(=CC=1)N=CC=C2NC1C=CC(C(N2CCN(C)CC2)=O)=CC=1.C(OC1C=CC=C2C=1C(NC1C=CC(C(N3CCN(C)CC3)=O)=CC=1)=CC=N2)C(C)C.CC1C=C2C(C(NC3C=CC(C(N4CCN(C)CC4)=O)=CC=3)=CC=N2)=CC=1.C(C1C=C2C(=CC=1)N=CC=C2NC1C=CC(C(N2CCN(C)CC2)=O)=CC=1)(C)C>>[N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:11]=2)[C:6]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([N:19]3[CH2:24][CH2:23][N+:22]([O-:44])([CH3:25])[CH2:21][CH2:20]3)=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CN1CCN(C(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)CC1
Reactant: CN1CCN(C(=O)c2ccc(Nc3ccnc4ccccc34)cc2)CC1
Agent: CC(C)COc1cccc2nccc(Nc3ccc(C(=O)N4CCN(C)CC4)cc3)c12
Agent: CC(C)c1ccc2nccc(Nc3ccc(C(=O)N4CCN(C)CC4)cc3)c2c1
Agent: CCCCN1CCN(C(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)CC1
Product: C[N+]1([O-])CCN(C(=O)c2ccc(Nc3ccnc4ccccc34)cc2)CC1

Procedure:
Similarly, following the above procedure but replacing the 1-[p-[ (7-chloro-4-quinolyl)amino]benzoyl]-4-methylpiperazine as used therein with an equal molar proportion of 1-[p-[ (4-quinolyl)amino]benzoyl]-4-methylpiperazine; 1-[p-[(7-chloro- 4-quinolyl)amino]benzoyl]-4-butylpiperazine; 1-[p-[ (7-chloro-4-quinolyl)amino]benzoyl]-4-benzylpiperazine; 1-[p-[(6-methoxy-4-quinolyl)amino]benzoyl]-4-methylpiperazine; 1-[p-[(5-isobutoxy-4-quinolyl)amino]benzoyl]-4-methylpiperazine; 1-[p-[(7-methyl-4-quinolyl)amino]benzoyl]- 4-methylpiperazine; 1-[p-[(6-isopropyl-4-quinolyl)amino] benzoyl]-4-methylpiperazine; 1-[p-[[(7-trifluoromethyl)- 4-quinolyl]amino]benzoyl]-4-isobutylpiperazine; 1-[p-[ [(7-trifluoromethyl)-4-quinolyl]amino]benzoyl]-4-benzylpiperazine; 1-[p-[[(7-trichloromethyl)-4-quinolyl]amino] benzoyl]-4-methylpiperazine; and 1-[p-[(7-chloro-4 -quinolyl)-N-ethylamino]benzoyl]-4-methylpiperazine,respectively, there is obtained 1-[p-[(4 -quinolyl)amino]benzoyl]-4-methylpiperazine-4-oxide; 1-[p-[(7-chloro-4-quinolyl)amino]benzoyl] -4-butylpiperazine-4-oxide; 1-[p-[(7-chloro-4-quinolyl)amino] benzoyl]-4-benzylpiperazine-4-oxide; 1-[p-[(6-methoxy- 4-quinolyl)amino]benzoyl]-4-methylpiperazine-4-oxide; 1-[p-[(5-isobutoxy-4-quinolyl)amino]benzoyl]-4-methylpiperazine-4-oxide; 1-[p-[(7-methyl-4-quinolyl)amino]benzoyl]- 4-methylpiperazine-4-oxide; 1-[p-[(6-isopropyl-4 -quinolyl)amino]benzoyl]-4-methylpiperazine-4-oxide; 1-[p-[[(7-trifluoromethyl)-4-quinolyl]amino]benzoyl]-4-isobutylpiperazine-4-oxide; 1-[p-[[(7-trifluoromethyl)-4-quinolyl]amino] benzoyl]-4-benzylpiperazine-4-oxide; 1-[p-[[(7-trichloromethyl)- 4-quinolyl]amino]benzoyl]-4-methylpiperazine-4-oxide; and 1-[p-[(7-chloro-4-quinolyl)-N-ethylamino] benzoyl]-4-methylpiperazine-4-oxide, respectively.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[N:11][C:6]=2[S:5][C:4]([NH:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=2)=[N:3]1.[H-].[Li+].[CH3:26]I>>[CH3:26][N:3]1[C:2](=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[N:11][C:6]=2[S:5][C:4]1=[N:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1
Reactant: CI
Reactant: CCOC(=O)c1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Agent: [H-]
Agent: [Li+]
Product: CCOC(=O)c1ccc(N=c2sc3ncccc3c(=O)n2C)cc1

Procedure:
The reaction procedure of Example 11 was followed except that 1.31 g of ethyl 4-[(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]benzoate, 36 mg of lithium hydride and 0.25 ml of methyl iodide were used. As a result, 656 mg of ethyl 4-[(3-methyl-4-oxo-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-2-ylidene)amino]benzoate was obtained.