Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:22][C:23]1[N:24]([CH3:32])[C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:3](/[CH:5]=[CH:6]/[C:7]1[CH:21]=[N:20][C:10]2[NH:11][C:12](=[O:19])[N:13]([CH2:15][C:16](O)=[O:17])[CH2:14][C:9]=2[CH:8]=1)=[O:4].[ClH:33].C[N:35]1[CH2:41][C:40]2C=C(/C=C/C(O)=O)C=N[C:39]=2[NH:38][C:37](=O)[CH2:36]1.CN1CCNCC1.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:33].[CH3:1][N:2]([CH2:22][C:23]1[N:24]([CH3:32])[C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:3](=[O:4])/[CH:5]=[CH:6]/[C:7]1[CH:21]=[N:20][C:10]2[NH:11][C:12](=[O:19])[N:13]([CH2:15][C:16]([N:35]3[CH2:36][CH2:37][N:38]([CH3:39])[CH2:40][CH2:41]3)=[O:17])[CH2:14][C:9]=2[CH:8]=1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)CN(CC(=O)O)C(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CCNCC1
Agent: Cl
Product: CN1CCN(C(=O)CN2Cc3cc(/C=C/C(=O)N(C)Cc4cc5ccccc5n4C)cnc3NC2=O)CC1
Yield: 43 %

Procedure:
According to the procedure of Example 1, except substituting (E)-(6-{2-[methyl-(1-methyl-1H-indol-2-ylmethyl)carbamoyl]vinyl}-2-oxo-1,4-dihydro-2H-pyrido[2,3-d]pyrimidin-3-yl)acetic acid for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting 1-methylpiperazine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (173 mg, 43%) was prepared as a off-white solid: 1H NMR (300 MHz, DMSO-d6) □ 10.78 (br s, 1H), 10.07-10.03 (m, 1H), 8.41-8.37 (m, 1H), 7.98-7.90 (m, 1H), 7.57-7.39 (m, 3H), 7.25-6.99 (m, 3H), 6.42-6.17 (m, 1H), 5.04-4.85 (m, 2H), 4.46-4.03 (m, 5H), 3.72-3.68 (m, 3H), 3.44-3.41 (m, 3H), 3.11-2.91 (m, 7H), 2.78 (s, 3H); MS (ESI) m/e 516 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[N+:18]([C:21]1[S:25][C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:23][CH:22]=1)([O-:20])=[O:19]>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:29]1[CH2:30][CH2:31][N:26]([C:24]2[S:25][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][N:23]=2)[CH2:27][CH2:28]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: O=[N+]([O-])c1cnc(N2CCNCC2)s1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc([N+](=O)[O-])s2)CC1
Yield: 67 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-nitro-thiazol-2-yl)-piperazine. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a yellow crystalline solid (yield 67%). MS (m/e): 455.4 (M+H+, 100%), 472.0 (M+NH4+, 100%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH2:13]([C@H:20]1[CH2:24][NH:23][C@H:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C@H:20]1[CH2:24][N:23]([C:10](=[O:12])[CH2:9][S:8][C:5]2[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=2)[C@H:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)CSc1ccncc1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)CSc1ccncc1
Yield: 12.3 %

Procedure:
Proceeding as in Example 1, but substituting 2-(pyridin-4-ylthio)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 96, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(pyridin-4-ylthio)acetyl)pyrrolidine-2-carboxamide (4 mg, 12.3%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.97 (s, 1H), 8.34 (d, 2H), 7.55 (m, 2H), 7.33-7.28 (m, 5H), 7.25-7.18 (m, 6H), 6.95 (m, 2H), 4.49 (m, 1H), 4.14 (m, 2H), 3.86 (m, 1H), 3.56 (m, 1H), 2.69 (m, 3H), 1.95 (m, 2H). MS (EI) for C31H28FN3O3S. found 542.6 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:36])[C:5]([CH:34]=O)=[CH:6][N:7]2[CH2:32][CH3:33].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)Cl>ClCCCl>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:36])[C:5]([CH2:34][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)=[CH:6][N:7]2[CH2:32][CH3:33]
Reactant: C1CCNC1
Reactant: CCn1cc(C=O)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCn1cc(CN2CCCC2)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
To a solution of 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydro quinoline-3-carbaldehyde (21.3 g, 34.4 mmol) in 1,2-Dichloroethane (DCE) (200 mL) was added pyrrolidine (3.13 mL, 37.8 mmol) and sodium triacetoxyborohydride (10.93 g, 51.6 mmol). The mixture was stirred at r.t. for 3 h. Then reaction mixture was concentrated, partitioned between DCM and brine, and extracted with DCM twice. The combined organic extracts were dried over sodium sulfate and the solvent was removed in vacuo. The crude product was then purified through normal phase chromatography (CombiFlash Rf), eluting with [DCM/MeOH/NH4OH (v:v:v=80:20:2)]:DCM (0% to 60%) to afford 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-3-(pyrrolidin-1-ylmethyl)quinolin-4(1H)-one (17 g, 30.2 mmol, 88% yield) as a light yellow solid. LCMS: (M+H)+: 563.2.
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[CH:42]=[CH:41][C:18]([O:19][C:20]3[CH:21]=[C:22]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:40])[CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH:28]=3)[C:23]([OH:25])=O)=[C:17]([F:43])[CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:44][C:45]1[CH:50]=[N:49][C:48]([CH3:51])=[CH:47][N:46]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[CH:42]=[CH:41][C:18]([O:19][C:20]3[CH:21]=[C:22]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:40])[CH2:31][O:32][Si:33]([C:36]([CH3:38])([CH3:39])[CH3:37])([CH3:35])[CH3:34])[CH:28]=3)[C:23]([NH:44][C:45]3[CH:50]=[N:49][C:48]([CH3:51])=[CH:47][N:46]=3)=[O:25])=[C:17]([F:43])[CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: Cc1cnc(N)cn1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)O)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3F)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Temperature: 25 °C
Reaction time: 11 h
Yield: 101.6 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.86 g, 6.56 mmol) was added to a solution of 3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (3 g, 5.96 mmol) in DCM (100 mL) and stirred at RT for 11 hour. 2-Amino-5-methylpyrazine (1.3 g, 11.9 mmol) and pyridine (0.94 mL, 11.9 mmol) were added and the reaction stirred for a further 30 mins. The solvent was removed in vacuo. Water (100 mL) was added and the mixture extracted with ethyl acetate (3×50 mL). The extracts were combined and washed with water (1100 mL), brine (100 mL), dried (MgSO4), filtered, and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (3.6 g).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]2[C:7](=[O:16])[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1)#N.C(O)=[O:20]>[Ni]>[O:16]=[C:7]1[C:6]2[CH:17]=[CH:18][C:3]([CH:1]=[O:20])=[CH:4][C:5]=2[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[NH:8]1
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1NC2=O
Reactant: O=CO
Agent: [Ni]
Product: O=Cc1ccc2c(c1)Sc1ccccc1NC2=O
Temperature: 25 °C

Procedure:
Heat a mixture of 5.0 gm. of 3-cyano-10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepin and 4.0 gm. of Raney nickel alloy in 60 ml. of 75% (v/v) aqueous formic acid at reflux for 1.5 hours. Cool to room temperature and filter. Concentrate to small volume and extract with methylene chloride. Wash the extract with water and with 1 N sodium bicarbonate until neutral. Dry the neutral extract over sodium sulfate and concentrate to dryness to obtain the title product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:8]2=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.[NH:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](O)=[O:31].P(C#N)(OCC)(OCC)=O>ClCCl.O>[NH:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:8]2=[O:9])[CH2:3][CH2:2]1)=[O:31]
Reactant: O=C(O)c1ccc[nH]1
Reactant: O=C1CCc2ccccc2N1C1CCNCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1ccc[nH]1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reaction time: 1 h
Yield: 28.5 %

Procedure:
1-(4-Piperidinyl)-3,4-dihydrocarbostyril (500 mg), triethylamine (1.2 ml) and pyrrole-2-carboxylic acid (314 mg) are dissolved in dichloromethane (10 ml) and thereto is added dropwise diethyl cyanophosphate (0.82 ml) under ice cooling. The mixture is stirred with ice cooling for 1 hour and then stirred at room temperature for 2 hours. The mixture is poured into water, extracted with chlorform, dried with sodium carbonate and purified by silica gel column chromatography (solvent; dichloromethane:methanol=20:1). The resultant is recrystallized from n-hexane/diethyl ether to give 1-[1-(2-pyrrolylcarbonyl)-4-piperidinyl]-3,4-dihyrocarbostyril (0.2 g), as white powder, m.p. 161°-162° C. (decomposed).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:6]([CH3:11])=[N:7][NH:8][C:9]=1[CH3:10].Br[CH2:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:9]([CH3:10])=[N:8][N:7]([CH2:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[C:6]=1[CH3:11]
Reactant: COC(=O)Cc1c(C)n[nH]c1C
Reactant: O=Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1c(C)nn(Cc2ccc(C=O)cc2)c1C

Procedure:
(3,5-Dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester (1 g, 6.0 mmol), 4-(bromomethyl)-benzaldehyde (1.18 g, 6.0 mmol) and K2CO3 (1.73 g, 12.5 mmol) were refluxed in 5 ml acetonitrile for 12 h. After cooling, the mixture was filtered, and the solvent was removed under reduced pressure. The residue was purified by MPLC (silica gel, CH2Cl2/methanol 99:1).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH:38][C:39](=[O:68])/[C:40](/[C:43]2[N:44]=[C:45]([NH:48][C:49]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[S:46][CH:47]=2)=[N:41]\[OH:42])[C:19]3=[O:69])=[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.C(=O)([O-])[O-].[K+].[K+].[Cl:76][CH2:77][C:78]([O:80][C:81]1[C:89]([O:90][C:91](=[O:94])[CH2:92][Cl:93])=[CH:88][C:84]([C:85](Cl)=[O:86])=[C:83]([CH3:95])[CH:82]=1)=[O:79]>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH:38][C:39](=[O:68])/[C:40](/[C:43]2[N:44]=[C:45]([NH:48][C:49]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:62]4[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=4)[S:46][CH:47]=2)=[N:41]\[O:42][C:85](=[O:86])[C:84]2[CH:88]=[C:89]([O:90][C:91](=[O:94])[CH2:92][Cl:93])[C:81]([O:80][C:78](=[O:79])[CH2:77][Cl:76])=[CH:82][C:83]=2[CH3:95])[C:19]3=[O:69])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(=O)n2nc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)[C@@H](NC(=O)/C(=N\O)c5csc(NC(c6ccccc6)(c6ccccc6)c6ccccc6)n5)[C@H]4SC3)sc2n1
Reactant: Cc1cc(OC(=O)CCl)c(OC(=O)CCl)cc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(=O)n2nc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)[C@@H](NC(=O)/C(=N\OC(=O)c5cc(OC(=O)CCl)c(OC(=O)CCl)cc5C)c5csc(NC(c6ccccc6)(c6ccccc6)c6ccccc6)n5)[C@H]4SC3)sc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To an ice-cooled solution of the product obtained in Step 4 (0.6 g) in dry dichloromethane (15 ml) was added potassium carbonate (0.1 g) at once, followed by dropwise addition of a solution of 4,5-bis(chloroacetoxy)-2-methylbenzoyl chloride (0.25 g) in dry dichloromethane (10 ml). The mixture was stirred under ice cooling for one hour and then at room temperature for an additional two hours. After filtering off the insoluble matters, the filtrate was washed with water and with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, giving 0.47 g of the objective compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:3]=1>CO.C(OCC)(=O)C.[Pd]>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:4]1[N:3]=[CH:2][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cnc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1
Reaction time: 0.75 h

Procedure:
To a solution of methyl 2-chloro-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylate (750 mg, 1.76 mmol) from Step A in methanol (10 mL) and ethyl acetate (10 mL) was added 10% Pd/C (100 mg). The suspension was stirred under an atmosphere of hydrogen (balloon pressure) for 45 min and was then filtered to remove the catalyst. HPLC/MS indicated a mixture of starting material, desired product, and minor amounts of several possible phenyl ring dechlorination products. The filtrate was evaporated and the residue was purified by flash column chromatography on silica gel eluted with 5 to 20% ethyl acetate in hexanes. The fractions containing the title compound were repurified by preparative TLC eluted with 15% ethyl acetate in hexanes to give pure methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylate. HPLC/MS: 392 (M+1), 394 (M+3); Rt=4.29 min. 1HNMR (CDCl3): δ 4.024 (s, 3H), 7.11 (br d, J=8.6 Hz, 2H), 7.23-7.35 (m, 4H), 7.36 (d, J=2.0 Hz, 1H), 7.37 (d, J=1.9 Hz,, 1H), 9.286 (d, J=1.9 Hz, 1H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([N:13]3[CH2:16][CH:15]([OH:17])[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:19]1[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH3:28])=[O:26])=[N:23][CH:24]=1>CN(C=O)C>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([N:13]3[CH2:14][CH:15]([O:17][C:19]4[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH3:28])=[O:26])=[N:23][CH:24]=4)[CH2:16]3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N1CCN(C2CCC2)CC1)N1CC(O)C1
Reactant: CNC(=O)c1ccc(Cl)cn1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(OC2CN(C(=O)N3CCN(C4CCC4)CC3)C2)cn1
Yield: 66.7 %

Procedure:
In a similar fashion (Route 20, GP I; except using DMF instead of DMSO as solvent), 1-[(4-cyclobutylpiperazin-1-yl)carbonyl]azetidin-3-ol (150 mg, 0.63 mmol) and 5-chloro-N-methylpyridine-2-carboxamide (214 mg, 1.26 mmol) gave the title compound (156 mg, 0.42 mmol, 66%) as white solid after purification by FCC [SiO2 eluting with DCM/MeOH/NH3 98:2:0.5].
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][N:10]=[CH:11][C:12]2[CH:13]=[C:14](/[CH:18]=[CH:19]/[C:20]([NH:22][O:23]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[O:21])[CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:43]C(OCC)=O>C1COCC1>[ClH:43].[OH:23][NH:22][C:20](=[O:21])/[CH:19]=[CH:18]/[C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH:11]=[N:10][O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:13]=1
Reactant: CCOC(=O)Cl
Reactant: O=C(/C=C/c1cccc(C=NOCCN2CCOCC2)c1)NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Cl
Product: O=C(/C=C/c1cccc(C=NOCCN2CCOCC2)c1)NO
Yield: 98 %

Procedure:
Compound ST3576 was obtained (0.931 mg, 98% yield) after acid hydrolysis of (2E)-3-{3-[(2-Morpholin-4-yl-ethoxyimino)-methyl]-phenyl}-N-trityloxy-acrylamide obtained (1.500 g, 2.67 mmol, 65% yield) by reaction of intermediate C (1.400 g, 4.12 mmol) with ethyl chloroformate (472 μL, 4.94 mmol) and TEA (746 μL, 5.35 mmol) in 5 mL of anhydrous THF (according to procedure described in Mai A., Pezzi R. et all. J. Med. Chem. 2005, 48, 3344 and in Mai A., Pezzi R. et all. J. Med. Chem. 2003, 46, 4826).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:19])=[C:7]([CH:12]=[C:13](C(C)(C)C)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[N+:20]([O-])([OH:22])=[O:21].O>C(O)(=O)C>[C:1]([C:5]1[C:6]([OH:19])=[C:7]([CH:12]=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
Methyl 3,5-di-tert-butyl-2-hydroxybenzoate (28.66 g, 108.4 mmol) was dissolved with stirring in 430 mL glacial acetic acid and the resulting mixture was treated drop wise with fuming nitric acid (90%, 179.26 mL). When the addition was complete, the resulting mixture was stirred for 2.5 h. The reaction mixture was poured into a 2.0 L of crushed ice and allowed to stand 30 min. Afterwards, 1.0 L of water was added and the ice water mixture was allowed to melt. The mixture was then filtered, washed with water and dried to provide the title compound (24.57 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:22])([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:13]=O.[NH:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[N:24]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[N:23]1([CH:13]([NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:12]([CH3:22])([CH3:11])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[N:24]1
Reactant: CC(C)(C=O)Cc1ccccc1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)(Cc1ccccc1)C(NC(=O)c1ccc(Cl)cc1)n1nnc2ccccc21
Temperature: 25 °C
Yield: 43.3 %

Procedure:
A suspension of p-chlorobenzamide (3.02 g, 20.0 mmol), the product from Example 18A (3.24 g, 20.0 mmol), and benzotriazole (2.38 g, 20.0 mmol) in benzene (75 mL) was treated with p-toluenesulfonic acid (190 mg, 1.00 mmol). The solution was heated at reflux under Dean-Stark conditions for 10 hours, then cooled gradually to ambient temperature. The solvent was removed under vacuum and the residue was purified by flash chromatography (elution with 15% EtOAc/hexanes) to provide the title compound (3.63 g) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:17]([NH2:18])=[N:16][C:9]2[N:10]=[C:11](SC)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2].S(Cl)([Cl:22])(=O)=O.CCOCC>C(Cl)(Cl)Cl.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:17]([NH2:18])=[N:16][C:9]2[N:10]=[C:11]([Cl:22])[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cnc(SC)nc2nc1N
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc2cnc(Cl)nc2nc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a suspension of the product of Example 128 in 50 mL of chloroform is slowly added sulfuryl chloride, followed by 2 drops of ethanol. The reaction is stirred at room temperature for 16 hours, poured into ether, and the solid collected to give 0.50 g (98%) of the product.
Reaction SMILES: [CH3:1][S:2]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([OH:40])=O)=[CH:32][CH:31]=1)(=[N:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[O:25][CH:26]=[CH:27][C:28]=3[CH3:29])=[O:23])[CH:16]=2)[CH:12]=1)=[O:6])=[O:3].[N:41]1([CH2:47][CH2:48][O:49][CH2:50][CH2:51][OH:52])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[OH:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][N:41]1[CH2:46][CH2:45][N:44]([C:38](=[O:40])[CH2:37][CH2:36][C:33]2[CH:34]=[CH:35][C:30]([S:2]([CH3:1])(=[O:3])=[N:4][C:5](=[O:6])[C:7]3[CH:12]=[C:11]([C:13]#[C:14][C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]5[O:25][CH:26]=[CH:27][C:28]=5[CH3:29])=[O:23])[CH:16]=4)[CH:10]=[N:9][CH:8]=3)=[CH:31][CH:32]=2)[CH2:43][CH2:42]1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)O)cc3)c2)c1
Reactant: OCCOCCN1CCNCC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)N4CCN(CCOCCO)CC4)cc3)c2)c1
Yield: 46.8 %

Procedure:
In a manner similar to that described in Example 485, 3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)-phenyl]propanoic acid (0.050 g, 0.090 mmol) and 2-(2-piperazin-1-yl-ethoxy)-ethanol (0.030 mL, 0.180 mmol) were reacted to give the title compound (0.030 g, 47%).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32])(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[OH:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][NH:28][S:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][CH:4]=[C:5]2[C:16]3[C:8](=[CH:9][CH:10]=[C:11]4[C:15]=3[S:14][CH:13]=[N:12]4)[NH:7][C:6]2=[O:17])=[CH:20][CH:21]=1)(=[O:27])=[O:26]
Reactant: CC(C)(CO)CNS(=O)(=O)c1ccc(N)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: CC(C)(CO)CNS(=O)(=O)c1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1

Procedure:
The title compound was prepared from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-amino-N-(3-hydroxy-2,2-dimethyl-propyl)benzenesulfonamide according to Procedure J: mp>250° C.; 1H NMR (DMSO-d6): δ 0.74 (s, 6H), 2.52 (d, J=6.7 Hz, 2H), 3.06 (bs, 2H), 4.43 (bs, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.32 (t, J=6.7 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.81 (d, J=8.3 Hz, 1H), 8.07 (d, J=12.2 Hz, 1H), 9.26 (s, 1H), 10.91 (s, 1H), 11.16 (d, J=12.3 Hz, 1H); APCI-MS: m/z 457 (M−H)−. Anal. Calcd for C21H22N4O4S2: C, 55.01; H, 4.84; N, 12.22; S, 13.98. Found: C, 54.90; H, 4.86; N, 12.25; S, 13.94.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:16])[NH:4][N:5]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12]C=2)[CH:7]=1.C(OC1N=NC(CC2CCCCC2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1>C(OCC)(=O)C>[CH:9]1([CH2:8][C:6]2[CH:7]=[C:2]([OH:1])[C:3](=[O:16])[NH:4][N:5]=2)[CH2:10][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=c1[nH]nc(CCc2ccccc2)cc1O
Agent: c1ccc(COc2cc(CC3CCCCC3)nnc2OCc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(CC2CCCCC2)cc1O

Procedure:
Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(cyclohexylmethyl)pyridazine (Intermediate 50) except that the solvent used for the hydrogenation was ethyl acetate and the product was recrystallised from a mixture of MTBE and heptanes.