Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]([OH:6])[CH3:5].[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)[CH3:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:8][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:1][CH2:2][CH2:3][CH:4]([CH3:5])[O:6]1
Reactant: CC(O)CCS
Reactant: CC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1CCSC(C)(c2ccccc2)O1

Procedure:
74 ml of dichloromethane is placed into a 100 ml round-bottom flask. To the dichloromethane is added 5.3 grams (0.05 moles) of 4-mercapto-2-butanol. 6.6 grams (0.055 moles) of acetophenone is then added followed by 0.1 grams of p-toluene sulfonic acid. Boiling chips are added to the flask. A Dean-Starke distilling receiver is placed on the flask, and a reflux condenser is placed on the receiver. The flask is then heated slowly until reflux occurs, and then the temperature is increased for a more vigorous reflux. The refluxing lasts for a period of 3 hours before water of reaction ceases to be formed. The reaction mass is then cooled and neutralized with 10% aqueous sodium bicarbonate to a pH of 8. The reaction mass is filtered through fluted filter paper, and the dichloromethane solvent is removed by means of rotary evaporation. 10.4 grams of crude product are recovered after the rotary evaporation operation. The crude product is then distilled by means of vacuum distillation yielding the following 3 fractions:
Reaction SMILES: [CH2:1]1[CH2:5]OC[CH2:2]1.NN.S1C=CC=[C:9]1CC(Cl)=O.[CH3:17][C:18]([O:20][CH2:21][C:22]1[CH2:39][S:38][C@@H:25]2[C@H:26]([NH:29][C:30]([CH2:32][C:33]3[S:37][CH:36]=[CH:35][CH:34]=3)=[O:31])[C:27](=[O:28])[N:24]2[C:23]=1[C:40]([OH:42])=[O:41])=[O:19]>C(Cl)(Cl)Cl.CC#N>[S:37]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:32][C:30]([NH:29][CH:26]1[C:27](=[O:28])[N:24]2[C:23]([C:40]([O:42][C:1]([CH3:2])([CH3:5])[CH3:9])=[O:41])=[C:22]([CH2:21][O:20][C:18](=[O:19])[CH3:17])[CH2:39][S:38][C@H:25]12)=[O:31]
Reactant: C1CCOC1
Reactant: O=C(Cl)Cc1cccs1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 0.08 h

Procedure:
A solution of 1.37 g. (3 mmol.) of t-butyl 7-phthalisoimido-3-acetoxymethyl-3-cephem-4-carboxylate in 10 ml. of dry THF was cooled in an ice water bath, and 0.12 ml. of anhydrous hydrazine was added. After the mixture was stirred for 5 min., 0.75 ml. of 2-thienylacetyl chloride was added, and the mixture was refluxed for 8 min., cooled and evaporated to dryness. The residue was dissolved in ethyl acetate, and the solution was washed successively with NaHCO3 solution, 1N HCl, water and brine. The crude mixture was chromatographed over silica gel using a gradient mixture of benzene and ethyl acetate. Fractions 16-73 were collected giving 340 mg. of t-butyl ester of cephalothin [α]D + 40.0° (MeCN); λEtOH 238 and 262 mμ (ε 14,200 and 8300); ir (CHCl3) 1785, 1740, 1730 and 1690 cm-1 ; nmr (CDCl3) δ 1.55 (s, 9, t-Bu), 2.1 (s, 3, CH3), 3.25 and 3.6 (ABq, 2, J = 17 Hz), 3.82 (s, 2, CH2), 4.75 and 5.14 (ABq, 2, CH2), 4.92 (d, 1, J = 4.5 Hz), 5.82 (dd, 1, J = 4.5 and 9 Hz), and 7.2 (m, 3, ArH).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5](/[CH:9]=[CH:10]/[S:11]([NH2:14])(=[O:13])=[O:12])[CH:4]=1.[Cl:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].O>O1CCOCC1>[Cl:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18]([NH:14][S:11](/[CH:10]=[CH:9]/[C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)(=[O:12])=[O:13])=[O:19]
Reactant: NS(=O)(=O)/C=C/c1cccnc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NS(=O)(=O)/C=C/c1cccnc1)c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (36 mg, 0.9 mmol) was added to a solution of (E)-2-Pyridin-3-yl-ethenesulfonic acid amide (56 mg, 0.3 mmol) in dioxane (1 mL) and the mixture was shaken for 30 minutes. A solution of 2,4-dichlorobenzoyl chloride (63 μL, 0.45 mmol) in dioxane (0.5 mL) was added to the mixture and the whole was shaken at room temperature for 18 hours. Water (0.1 mL) was added to the mixture and the whole was concentrated in vacuo. The resultant residue was purified by preparative HPLC to give (E)-2-pyridin-3-yl-ethenesulfonic acid 2,4-dichloro-benzoylamide (29.1 mg, 26%) as sodium salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19](C2C=CC(F)=CC=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH2:35]([CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1)[C:36]#[CH:37]>>[C:25]([C:22]1([C:20]([NH:19][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]4[CH:15]=[C:16]([C:37]#[C:36][CH2:35][CH:38]5[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]5)[S:17][C:10]=34)=[C:2]([F:1])[CH:3]=2)=[O:21])[CH2:24][CH2:23]1)(=[O:26])[NH2:27]
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(CC#Cc2cc3nccc(Oc4ccc(NC(=O)C5(C(N)=O)CC5)cc4F)c3s2)CC1
Yield: 49.9 %

Procedure:
Prepared from N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Example 12, Step A, 50 mg, 0.0845 mmol) and tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (37.8 mg, 0.169 mmol) using the procedure described for Example 6, Step B. The reaction was purified by preparative TLC (1 mm thickness, Rf=0.52), eluting with 10% MeOH/DCM. The product was subject to a second preparative TLC purification (0.5 mm thickness, Rf=0.09), eluting with 1:1 EtOA/hexanes. The product was obtained as a beige powder (25 mg, 31%). LRMS (APCI−): m/z 685 (M−1) detected.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][C@@H:21]([CH3:23])[N:11]2[C:12]3[CH:13]=[C:14]([CH3:20])[C:15](Br)=[CH:16][C:17]=3[CH:18]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:22][C@@H:21]([CH3:23])[N:11]2[C:12]3[CH:13]=[C:14]([CH3:20])[C:15]([CH3:24])=[CH:16][C:17]=3[CH:18]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2c(cc1Br)cc1n2[C@H](C)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc2cc3n(c2cc1C)[C@H](C)CN(C(=O)OC(C)(C)C)C3
Yield: 63.4 %

Procedure:
To a solution of 1.18 g (R)-8-bromo-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester in 12 ml dioxane were added 0.36 g tetrakistriphenylphosphinpalladium, 1.29 g potassium carbonate and 0.39 trimethylboroxine and the mixture was heated 1 h at reflux. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was washed with 10% sodium bicarbonate, 10% citric acid and brine, dried over magnesium sulfate and purified by chromatography on silica gel with hexane:ethyl acetate=3:1 to yield 0.62 g (R)-4,7,8-trimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester as slightly yellow foam. MS: (M+H)=315.4
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][C@H:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][OH:19])=[N:4][C:5]([NH:8][C:9]2[NH:13][C:12]([S:14][CH3:15])=[N:11][N:10]=2)=[N:6][CH:7]=1.C([O-])(O)=[O:24].[Na+].OOS([O-])=O.[K+]>CO.O.O>[Br:1][C:2]1[C:3]([NH:16][C@H:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][OH:19])=[N:4][C:5]([NH:8][C:9]2[NH:13][C:12]([S:14]([CH3:15])=[O:24])=[N:11][N:10]=2)=[N:6][CH:7]=1
Reactant: CSc1nnc(Nc2ncc(Br)c(N[C@@H](CO)C(C)C)n2)[nH]1
Reactant: O=C([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)[C@H](CO)Nc1nc(Nc2nnc(S(C)=O)[nH]2)ncc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., 159 mg (0.41 mmol) of (R)-2-[5-bromo-2-(5-methylsulfanyl-4H-[1,2,4]triazol-3-ylamino)-pyrimidin-4-ylamino]-3-methyl-butan-1-ol in 4 ml of MeOH/water (4:1) is mixed with 80 mg (0.95 mmol) of NaHCO3 and 98 mg (0.95 mmol) of oxone. The reaction mixture is stirred for 2 hours at room temperature, then another 50 mg (0.5 mmol) of oxone is added, and it is stirred for 1 hour at 30° C. The batch is diluted with water and extracted with ethyl acetate. The organic phase is concentrated by evaporation and purified by chromatography (methylene chloride-(methylene chloride/ethanol: 9/1); Flashmaster II). After the recrystallization, 45 mg (0.11 mmol, 27% of theory) of the product (R)-2-[5-bromo-2-(5-methanesulfinyl-4H-[1,2,4]triazol-3-ylamino)-pyrimidin-4-ylamino]-3-methyl-butan-1-ol is obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].C(Cl)(Cl)[Cl:55]>CO>[ClH:55].[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([CH2:33][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]4[N:19]5[C:20]6[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=6[N:16]=[CH:17][C:18]5=[O:21])[CH2:10]4)[CH2:4][CH2:3]3)=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Reactant: ClC(Cl)Cl
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=c1ccc2ncc(=O)n3c2n1C[C@H]3CN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Reaction time: 1.5 h
Yield: 58.4 %

Procedure:
A suspension of (2R)-2-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (for a preparation see Example 16A(j)) (60 mg, 0.199 mmol) and 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde (commercially available) (29.4 mg, 0.179 mmol) in chloroform (2 ml) and methanol (0.100 ml) at rt under nitrogen was treated with sodium triacetoxyborohydride (127 mg, 0.597 mmol) and stirred for 90 min, LC-MS after 90 min showed reaction complete. This was treated with saturated aqueous NaHCO3 (10 ml) and extracted with 20% methanol/DCM (3×25 ml). The combined organic extracts were dried (MgSO4), filtered, evaporated and chromatographed (0-20% methanol/DCM) to give the free base of the title compound (46.8 mg, 58.4%) as a yellow gum.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[N:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH:67]([C:69]1[CH:88]=[CH:87][C:72]([CH2:73][N:74]2[CH2:79][CH2:78][N:77]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[CH2:76][CH2:75]2)=[CH:71][CH:70]=1)=O>C(O)C.CN(C=O)C>[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[N:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:67]([C:69]3[CH:70]=[CH:71][C:72]([CH2:73][N:74]4[CH2:75][CH2:76][N:77]([C:80]([O:82][C:83]([CH3:84])([CH3:86])[CH3:85])=[O:81])[CH2:78][CH2:79]4)=[CH:87][CH:88]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3cncnc3)CC2)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C=O)cc2)CC1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3nc4c(N5CCN(Cc6cncnc6)CC5)c(Cl)cnc4[nH]3)cc2)CC1
Reaction time: 6 h
Yield: 44.3 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-chloro-3-nitro-4-(4-(pyrimidin-5-ylmethyl)piperazin-1-yl)pyridin-2-amine (25 mg, 0.071 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.21 mmol, 0.21 mL) and tert-butyl 4-(4-formylbenzyl)piperazine-1-carboxylate (1.2 eq, 0.085 mmol, 28 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (19 mg, 44%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.39 (s, 9H, C(CH3)3), 2.34 (t, J=4.9 Hz, 4H, piperazine N(CH2)2), 2.64 (t, J=4.4 Hz, 4H, piperazine N(CH2)2), 3.32 (s, br, 4H, piperazine N(CH2)2), 3.55 (s, 2H, NCH2), 3.65 (s, 2H, NCH2), 3.71 (s, br, 4H, piperazine N(CH2)2), 7.46 (d, J=8.2 Hz, 2H, phenyl H-3 & H-5), 8.11 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.13 (d, J=8.1 Hz, 2H, phenyl H-2 & H-6), 8.80 (s, 2H, pyrimidine H-4 & H-6), 9.12 (s, 1H, pyrimidine H-2), 13.34 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]#[N:10])[CH2:5][CH2:4]1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].O.Cl>N1C=CC=CC=1>[S:11]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[N:10])[CH2:5][CH2:4]1)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: N#CC1CCC(CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](C#N)CC2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 1.20 g of the 4-(hydroxymethyl)cyclohexanecarbonitrile obtained in 5 ml of pyridine was treated portionwise with 2.46 g of tosyl chloride at room temperature and while gassing with argon. After stirring at room temperature for 3.5 hours (formation of a white precipitate), the mixture, cooled to 0° C., was treated with about 2 ml of water, cautiously made acid with about 7 ml of concentrated hydrochloric acid and extracted three times with 30 ml of diethyl ether each time. The organic phases were washed with 50 ml of water and 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated, there remaining behind 2.31 g of a semi-crystalline oil. Low-pressure chromatography (0.5 bar) on 480 g of silica gel using 30% ethyl acetate/petroleum ether as the eluant gave 1.06 g (42%) of trans-4-(tosyloxymethyl)cyclohexanecarbonitrile as a colourless, crystallizing oil (m.p. 84°-85° C.) and 1.03 g (41%) of cis-4-(tosyloxymethyl)cyclohexanecarbonitrile as a colourless, viscous oil. Rf values (30% ethyl acetate/petroleum ether): trans product 0.25, cis product 0.20.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[CH3:25][Si:26]([CH3:35])([CH3:34])NC(=O)C(C)(C)C.[Br:36]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:36][CH2:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([O:10][Si:26]([CH3:35])([CH3:34])[CH3:25])=[O:9]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Reactant: CC(C)(C)C(=O)N[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Yield: 40 %

Procedure:
352 mg (1.01 mmoles) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide were silylated in 40 ml of chloroform at 60° C. in half an hour with 0.28 g (1.8 mmoles) of N-trimethylsilyl-2,2-dimethylpropanamide and the clear, pale yellow solution obtained was cooled in an ice-bath. Bromination was carried out in half an hour using 0.24 g (1.35 mmoles) of N-bromosuccinimide as the brominating agent to obtain a 40% yield of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[NH4+:5].I.CS[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:34])[NH:19][C:20]([C:22]2[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=2)=[O:21])=[CH:13][CH:12]=1)=[NH:10]>CO.ClCCl>[C:1]([OH:4])(=[O:3])[CH3:2].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:34])[NH:19][C:20]([C:22]2[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=2)=[O:21])=[CH:13][CH:12]=1)(=[NH:5])[NH2:10]
Reactant: CC(=O)[O-]
Reactant: COC(=O)COc1ccc(C(=O)NC(=O)Nc2ccc(C(=N)SC)cc2)cc1
Reactant: [NH4+]
Agent: I
Solvent: CO
Solvent: ClCCl
Product: CC(=O)O
Product: COC(=O)COc1ccc(C(=O)NC(=O)Nc2ccc(C(=N)N)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.1 %

Procedure:
Ammonium acetate (1 g) was added to a stirred suspension of methyl 4-[4-(4-methylthiocarbonimidoylphenyl)allophanoyl]phenoxyacetate, hydroiodide salt (340 mg), in methanol (6 ml) and dichloromethane (4 ml). The reaction mixture was stirred at ambient temperature for 3 days and then heated to reflux for 30 hours. The solvents were removed in vacuo and the resultant solid residue was stirred under methanol for 1 hour. The solid was collected and washed with methanol to give the title compound (249 mg) as a white solid; m.p. 225°-229° C. (decomposes); NMR Spectrum (DMSO-d6) 1.75 (3H, s), 3.71 (3H, s), 4.92 (2H, s), 7.07 (2H, d), 7.80 (4H, s), 8.04 (2H, d); Mass Spectrum m/Z 371 (M+H)+ ; Elemental Analysis: calculated for C18H18N4O5. 1.0 CH3CO2H. 0.2 H2O: C, 55.3%; H, 5.2%; N, 12.9%; found: C, 55.4%; H, 5.1%; N, 12.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15](=[S:24])[NH:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][C:28]=1[Cl:37]>>[Cl:37][C:28]1[CH:29]=[C:30]([S:33]([NH2:36])(=[O:34])=[O:35])[CH:31]=[CH:32][C:27]=1[CH2:26][S:24][C:15]1[N:16]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:12]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)([CH3:11])[CH3:10])=[CH:13][N:14]=1
Reactant: NS(=O)(=O)c1ccc(CBr)c(Cl)c1
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1c[nH]c(=S)n1-c1ccc(F)cc1
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(SCc2ccc(S(N)(=O)=O)cc2Cl)n1-c1ccc(F)cc1

Procedure:
Similarly the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2(3H)-thione and 4-(bromomethyl)-3-chlorobenzenesulfonamide. MS (EI) m/z 584 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]([C:11]([OH:13])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH3:14][Si](C=[N+]=[N-])(C)C>CO.C(OCC)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1cc2c(cn1)C(C(=O)O)CC2
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1CCc2cc(N)ncc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-amino-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic acid from Step F in methanol (10 mL) was treated dropwise with a solution of trimethylsilyl diazomethane in diethyl ether (2.0 M, 1.96 mL) at 0° C. After complete addition, the reaction warmed to room temperature and stirred 30 min, then was concentrated. The resulting residue was dried under high vacuum to afford methyl 3-amino-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylate. 1H NMR (500 MHz, CDCl3), δ 8.26 (s, 1H), 8.19 (s, 1H), 8.05 (br s, 2H), 4.00 (m, 1H), 3.75 (s, 3H), 3.01 (m, 1H), 2.83 (m, 1H), 2.44 (m, 1H), 2.32 (m, 1H); LC/MS (M+1)+=193.0;
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH:20]([CH3:22])[CH3:21])[C:12]2=[O:23])=[O:10])[CH2:3][CH2:2]1.[Cl:24][CH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](OC)=[CH:31][CH:30]=1)=[O:28]>>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH:20]3[CH2:21][CH2:22]3)[C:12]2=[O:23])=[O:10])[CH2:3][CH2:2]1.[Cl:24][CH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]
Reactant: CC(C)n1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Reactant: COc1ccc(C(=O)CCCl)cc1
Product: O=C(CCCl)c1ccccc1
Product: O=C(NCC1CCNCC1)n1c(=O)n(C2CC2)c2ccccc21

Procedure:
The procedure given in Example 135 was followed using 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 3-chloro-4′-methoxypropiophenone as a reactant, instead of 3-cyclopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 3-chloropropiophenone, to give the title compound.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:24]#[C:25][C:26]4[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:50])=O>ClCCl>[C:1]12([C:11]3[CH:12]=[C:13]([C:24]#[C:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([Cl:50])=[O:31])=[CH:28][CH:27]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COCCOCOc1ccc(C#Cc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=S(Cl)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: COCCOCOc1ccc(C#Cc2ccc(C(=O)Cl)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 1 h

Procedure:
A solution of 3.14 g (6.8 mmol) of 4-[3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl]benzoic acid in 100 ml of anhydrous dichloromethane was introduced into a round-bottomed flask, 1.4 ml (6.8 mmol) of dicyclohexylamine was added and stirring was carried out for one hour. 500 μl (6.8 mmol) of thionyl chloride were then added and stirring was carried out for one hour. Evaporation was carried out to dryness, the residue was taken up in anhydrous ethyl ether, the dicyclohexylamine salt was filtered and the filtrate was evaporated. 3.3 g (100%) of the crude acid chloride were collected, which chloride was used as is in the continuation of the synthesis to follow.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][CH3:5].Br[CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1>CN(C=O)C>[CH2:3]([O:6][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:4][CH3:5]
Reactant: CCCO
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOCc1ccc(C(=O)O)cc1
Reaction time: 4 h

Procedure:
Sodium hydride (50% in oil; 0.42 g) was cautiously added to a solution of propanol (0.6 g) in DMF (8 ml). After gas evolution ceased, methyl 4-bromomethylbenzoate (1.0 g) was added. After 4 hours, the mixture was partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was hydrolyzed by method P-a. This resulted in the product with the molecular weight of 194.23 (C11H14O3); MS (ESI): 195 (M+H+).