Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)[CH:11]=[C:10]([C:25]([OH:27])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[F:52][C:53]1([F:58])[CH2:57][CH2:56][NH:55][CH2:54]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:52][C:53]1([F:58])[CH2:57][CH2:56][N:55]([C:25]([C:10]2[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:22]=[N:21][C:20]([CH3:23])=[N:19][CH:18]=3)=[O:24])[CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:9]=2)=[O:27])[CH2:54]1
Reactant: FC1(F)CCNC1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3cnc(C)nc3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(C(=O)N3CCC(F)(F)C3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-((2-methylpyrimidin-5-yl)methylcarbamoyl)-biphenyl-3-carboxylic acid (11 mg, 0.030 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (12 mg, 0.061 mmol), 1-hydroxybenzotriazole hydrate (5 mg, 0.030 mmol), CH2Cl2 (2 mL) were added 3,3-difluoropyrrolidine hydrochloride (9 mg, 0.061 mmol) and N,N-diisopropylethylamine (21 μL, 0.12 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-70% MeCN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: N.C([C:20]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]C)([OH:32])C(O)C(CC1C=CC=CC=1)O)CCCCCCC/C=C\CCCCCCCC.[CH3:51][CH2:52][OH:53].[CH2:54]1C[O:57][CH2:56][CH2:55]1>>[CH2:52]([O:53][CH2:54][CH:55]([CH2:56][OH:57])[O:32][CH2:20][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:51][CH2:20][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCC/C=C\CCCCCCCCC(O)(CCCCCCCC/C=C\CCCCCCCC)C(O)C(O)Cc1ccccc1
Reactant: C1CCOC1
Reactant: CCO
Agent: N
Product: CCCCCCCC/C=C\CCCCCCCCOCC(CO)OCCCCCCCC/C=C\CCCCCCCC
Temperature: -65 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A 250 ml flask equipped with a dry ice condenser and a dry ice-acetone bath was charged with anhydrous NH3 (140 ml). After cooling to -65° C. under N2 Li wire (1.35 g) was added in small pieces. Dioleylbenzylglycerol (10 g, 0.0146 mol) in THF (60 ml) and EtOH (12 g) was added over 30 minutes and then stirred at -65° C. for 15 minutes. The dry ice bath was removed and the reaction mass allowed to warm to room temperature, with evaporation of NH3. Water (100 ml) and heptane (150 ml) were added. The organic phase was washed with water, dried (MgSO4) and stripped of solvent yielding a light yellow oil (7.8 g, 90%).
Reaction SMILES: [C:1]1([CH:7]([NH:19][S:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:22])=[O:21])[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:30][CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33]>CCOC(C)=O>[Br-:30].[O:33]=[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][N+:13]12[CH2:18][CH2:17][CH:16]([CH2:15][CH2:14]1)[C@@H:11]([O:10][C:8](=[O:9])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[NH:19][S:20]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:22])=[O:21])[CH2:12]2
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)Cc1ccccc1)c1ccccc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(NS(=O)(=O)Cc1ccccc1)c1ccccc1)C2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-phenyl-2-(phenylmethylsulfonamido)-acetate (C80) (41 mg, 0.10 mmol) in EtOAc (2 ml), was added 2-bromo-1-phenylethanone (21.7 mg, 0.11 mmol), and the reaction was stirred at RT for 1 hour. The solvent was evaporated, and the crude was triturated with Et2O to obtain (3R)-1-(2-oxo-2-phenylethyl)-3-(2-phenyl-2-(phenylmethylsulfonamido)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (50 mg; 82% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:13])C(Cl)(Cl)Cl)[N:5]([CH3:7])[CH:6]=1.[O-][CH2:15][CH3:16].[Na+].C([OH:20])C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:13][CH2:15][CH3:16])=[O:20])[N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)cc1C(=O)C(Cl)(Cl)Cl
Reactant: CC[O-]
Reactant: CCO
Agent: [Na+]
Product: CCOC(=O)c1cc(Br)cn1C
Yield: 80 %

Procedure:
In ethanol (100 ml), 1-(4-bromo-1-methyl-1H-pyrrol-2-yl)-2,2,2-trichloroethanone (12.1 g, 40 mmol) prepared in the Step 10-1-1 was dissolved, and under an ice cooling a 20% sodium ethoxide-ethanol solution was added thereto. Thereafter, the mixture was heated under reflux for 3 hours. After the mixture was allowed to cool, the solvent was distilled off, and 3.5% hydrochloric acid (100 ml) and chloroform (150 ml) was added to the mixture. The organic phase was collected by separation, washed with a saturated sodium hydrogen carbonate aqueous solution and water in order, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5) to give the title compound (7.39 g, 80%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH:5]=[C:6]([OH:8])[CH:7]=1.[C:16](=[O:18])=[O:17].O[CH2:20]C(CO)O>>[CH3:20][O:17][C:16]([C:7]1[C:2]([OH:1])=[CH:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[CH:5][C:6]=1[OH:8])=[O:18]
Reactant: OCC(O)CO
Reactant: Oc1cccc(-c2cc(O)cc(O)c2)c1
Reactant: O=C=O
Product: COC(=O)c1c(O)cc(-c2cccc(O)c2)cc1O
Temperature: 120 °C
Reaction time: 96 h
Yield: 26 %

Procedure:
To 308 mg (1.52 mmol) of 3,5,3′-trihydroxybiphenyl was added 400 mg (4.0 mmol) of KHCO3, then 1 ml of glycerol. The reaction was stirred at 130° C. under 1 atm of CO2 for 1 hour. Following this period of heating, the thick mixture was transferred to a sealed tube, the space above the mixture was purged with CO2, then the reaction was heated at 120° C. for 15 hour, and at ambient temperature for 96 hours. The reaction was diluted with 10 mL of water, 5 mL of 1M HCl was added slowly, then the mixture was extracted with ethyl acetate (3×5 mL). The combined organic layers were back extracted with water (1×5 mL), and brine (1×5 mL), dried over MgSO4, filtered, and concentrated to a dark residue. This was taken up in ethyl acetate and methanol, and treated with ethereal diazomethane until the acid was no longer visible by TLC and a new, higher Rf spot appeared (40% ethyl acetate:hexanes). The product was purified by silica gel chromatography, eluting with 40% ethyl acetate:hexanes to give 100 mg (26%) of 3,5,3′-trihydroxy-biphenyl-4-carboxylic acid methyl ester as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.15 (bs, 2H), 9.56 (bs, 1H), 7.25 (t, 1H, J=7.8 Hz), 6.97 (dd, 1H, J=1.0, 9.2 Hz), 6.92 (t, 1H, J=2.0 Hz), 6.87 (dd, 1H, J=2.4, 8.0 Hz), 6.57 (s, 2H), 3.33 (s, 3H); MS (ESI) m/z=259 (M−H).
Reaction SMILES: C[O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[NH:12]([C:16]1[S:17][CH:18]=[C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])[N:20]=1)[C:13]([NH2:15])=[NH:14].N(C1SC=C(CSCCNC2C(OC)=NSN=2)N=1)C(N)=N.[OH-].[Na+]>>[NH:12]([C:16]1[S:17][CH:18]=[C:19]([CH2:21][S:22][CH2:23][CH2:24][NH:25][C:7]2[C:3]([OH:2])=[N:4][S:5](=[O:11])(=[O:10])[N:6]=2)[N:20]=1)[C:13]([NH2:15])=[NH:14]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: COC1=NS(=O)(=O)N=C1OC
Agent: COc1nsnc1NCCSCc1csc(NC(=N)N)n1
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)Nc1nc(CSCCNC2=NS(=O)(=O)N=C2O)cs1

Procedure:
When 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is reacted with one equivalent of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine and the resultant 3-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole, 1,1-dioxide is reacted with sodium hydroxide according to the procedure described in Example 17, Step B, the title compound is produced.
Reaction SMILES: [CH2:1]([NH:7][C:8]1[O:12][N:11]=[C:10]([CH3:13])[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[CH2:1]([N:7]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[N:9]=1)[C:14](=[O:16])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNc1nc(C)no1
Reactant: CC(=O)OC(C)=O
Product: CCCCCCN(C(C)=O)c1nc(C)no1

Procedure:
5-n-Hexylamino-3-methyl-1,2,4-oxadiazole (4.6 g, 0.025 mole) was dissolved in acetic anhydride (25 ml) and refluxed for 3 hours and then evaporated down to dryness under vacuum. The residue was taken up in CHCl3 (50 ml) and washed twice with 2 N HCl and twice with a saturated solution of NaHCO3 and dried over MgSO4. (b.p. 113°-114° C./1.0 mmHg).
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][OH:13].O>C(O)C.CCOC(C)=O>[C:1]1([CH:7]2[CH2:10][C:9](=[N:12][OH:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C1CC(c2ccccc2)C1
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: ON=C1CC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.49 %

Procedure:
To a solution of 3-phenylcyclobutanone (0.198 g, 1.354 mmol) in 95% ethanol (7 ml) was added 50% hydroxylamine in water (0.8300 ml, 13.54 mmol), and the reaction was stirred for 16 hours at ambient temperature. The reaction was diluted with EtOAc and washed with water and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 167 mg of the title compound (76.49% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[H-].[Na+].I[CH2:15][CH3:16]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[N:7][N:8]([CH2:15][CH3:16])[C:9]=2[CH:10]=1
Reactant: Nc1cc(Br)cc2[nH]ncc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1ncc2c(N)cc(Br)cc21
Reaction time: 0.25 h
Yield: 32.5 %

Procedure:
To a solution of 6-bromo-1H-indazol-4-amine (available from Sinova, 300 mg, 1.41 mmol) in THF (7 ml), cooled to 0° C. was added 60% sodium hydride in mineral oil (62 mg, 1.55 mmol) and the reaction was stirred for 15 mins. Iodoethane (0.124 ml, 1.55 mmol) was added and the reaction was stirred overnight. The reaction was quenched with MeOH (1 ml), diluted with water (10 ml), then extracted into ethyl acetate, which was separated and evaporated to dryness. The residue was purified by silica chromatography using 0-100% ethyl acetate in cyclohexane over 80 mins. Pure fractions were evaporated to give the title compound (110 mg).
Reaction SMILES: C([Cl:4])(=O)C.[CH3:5][C:6](/[CH:14]=[CH:15]/[CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[CH:7][C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]>>[Cl:4][C:21]([CH3:22])([CH3:23])[CH2:20][CH2:19][CH2:18][CH:17]([CH3:24])[CH2:16]/[CH:15]=[CH:14]/[C:6]([CH3:5])=[CH:7][C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)=CCCC(C)C/C=C/C(C)=CC(=O)OC(C)C
Reactant: CC(=O)Cl
Product: CC(=CC(=O)OC(C)C)/C=C/CC(C)CCCC(C)(C)Cl
Reaction time: 0.25 h

Procedure:
To 40 ml. of ice cold isopropanol is added 2.49 g. of acetyl chloride. The resulting solution is stirred at 0° for 15 min. and 1.0 g. of trans isopropyl 3,7,11-trimethyldodeca 2,4,10-trienoate added. The solution is stirred for 1 hour at 0° and for 48 hours at 25°. Solvent is removed under reduced pressure and the concentrate taken up in hexane. The hexane solution is washed with water until the aqueous wash is neutral and then with brine. The solution is dried over calcium sulfate and solvent evaporated to yield trans isopropyl 11-chloro-3,7,11-trimethyldodeca-2,4-dienoate.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC=C)(=O)C.C(Cl)Cl>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@H]1CCC[C@@H](OCc2ccccc2)C1
Solvent: ClCCl
Solvent: C=COC(C)=O
Product: OC1CCCC(OCc2ccccc2)C1
Reaction time: 26 h

Procedure:
100.0 g of cis-3-benzyloxycyclohexan-1-ol were dissolved in 170 ml of vinyl acetate and 630 ml of methylene chloride, admixed with 5.0 g of Novozym 435 and stirred at 20–23° C. for 26 h. The enzyme was filtered off, and a sample was withdrawn and concentrated by evaporation under reduced pressure. The enantiomeric excess of (1S,3R)-3-benzyloxycyclohexan-1-ol was >99% (HPLC on Chiralpak AD-H 250×4.6; 1 ml/min, 25:1:0.5 heptane/EtOH/CH3CN+0.1% TFA), and the enantiomeric excess of the (1R,3S)-acetate was 90% (HPLC on Chiralcel OD 250×4.6; 1 ml/min, 100:1:0.5 heptane/EtOH/CH3CN).
Reaction SMILES: [S:1]1[CH:9]2[C:4]([CH2:5][NH:6][CH2:7][CH2:8]2)=[CH:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:16][CH:17]=1.[C:22]([Si:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)Cl)([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>C(Cl)Cl>[Si:26]([O:10][C:2]1[S:1][C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1C=C2CNCCC2S1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1cc2c(s1)CCNC2)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A mixture of 2.00 g of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one-p-toluenesulfonate, 1.84 g of tert-butyldiphenylchlorosilane, 0.66 g of triethylamine and 7 ml of methylene chloride was stirred at room temperature (20° C.) for 3 hours. The produced 2-(tert-butyldiphenylsilyloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-p-toluenesulfonate was not isolated, and 0.96 g of 2-chlorobenzyl chloride and 1.21 g of triethylamine were added thereto. The mixture was allowed to react at room temperature (20° C.) for 1.5 hours by further stirring and then left to stand overnight to obtain a reaction mixture.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:26])([CH3:25])[C:21]([O:23]C)=O)[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[CH:27]=1)(=[O:3])[NH2:2].Cl.[NH:29]1[CH2:32][CH:31]([C:33]#[N:34])[CH2:30]1.C(N(CC)CC)C>CO>[C:33]([CH:31]1[CH2:32][N:29]([C:21](=[O:23])[C:20]([OH:26])([CH3:25])[C:19]#[C:18][C:14]2[C:15]([F:17])=[CH:16][C:11]3[O:10][CH2:9][CH2:8][N:7]4[CH:27]=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=[C:6]4[C:12]=3[CH:13]=2)[CH2:30]1)#[N:34]
Reactant: N#CC1CNC1
Reactant: COC(=O)C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)C(=O)N1CC(C#N)C1
Yield: 5.2 %

Procedure:
A solution methyl 4-(2-carbamoyl-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)-2-hydroxy-2-methylbut-3-ynoate (150 mg, 0.40 mmol, 1.00 equiv), azetidine-3-carbonitrile hydrochloride (237 mg, 2.00 mmol, 5.00 equiv), triethylamine (203 mg, 2.01 mmol, 5.00 equiv) in methanol (5 mL) was stirred for 12 h at 40° C. The resulting mixture was concentrated under vacuum and the residue was applied onto a silica gel column with dichloromethane/methanol (30:1) to give 8.8 mg (5%) the titled compound as an off-white solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>C(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1ccc(CN)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCCc1ccc(CNS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
To a solution of 4-butylbenzylamine (4.01 g, 24.6 mmol) in CH2Cl2 (75 mL) was added pyridine (4.0 mL, 49 mmol) followed by dropwise addition of methanesulfonyl chloride (2.5 mL, 32.3 mmol). The reaction was stirred at room temperature for 24 h and water was added. The product was extracted into CH2Cl2 (2×) and the organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (2:1 to 1:1 hexanes:EtOAc) provided the title compound as a white solid (3.4114 g). 1H NMR (400 MHz, CDCl3) δ 7.23 (d, 2H), 7.15 (d, 2H), 4.84 (m, 1H), 4.25 (d, 2H), 2.82 (s, 3H), 2.58 (t, 2H), 1.56 (m, 2H), 1.33 (m, 2H), 0.91 (t, 3H).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[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.[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][Br:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[Br-:30].[CH3:20][O:21][C:22]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:25][CH:24]=1)=[O:31]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]

Procedure:
3.44 g (13 mmol) Triphenylphosphine was dissolved in 100 ml dry toluene, in a 250 ml flask with an argon feed. 3 g (13 mmol) 4-(bromomethyl)benzoic acid methyl ester was added, and the mixture was heated 2 hr at reflux, with stirring. The white phosphonium salt which precipitated was separated out from the cooled mixture, washed with absolute toluene, and dried in a vacuum. The fine crystals melted at 251°-252° C. Yield: 5.85 g (91%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:32]1([CH3:63])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([C:53]([CH:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)=[O:54])[CH2:44][CH:43]([NH2:61])[C:42]2=[O:62])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1>O1CCCC1>[C:32]1([CH3:63])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([C:53]([CH:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)=[O:54])[CH2:44][CH:43]([NH:61][C:14]([NH:1][C:2]3[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=3)=[O:16])[C:42]2=[O:62])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(N)CN2C(=O)C1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C3CCCCC3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Reaction time: 2 h
Yield: 156.3 %

Procedure:
Ethyl 3-aminobenzoate (252 mg) was dissolved in tetrahydrofuran (40 ml), triphosgene (152 mg) was added under ice-cooling, subsequently, triethylamine (132 μl) was added five times every 3 minutes, a solution of 1-(2-toluoylmethyl)-2-oxo-3-amino-5-cyclohexylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (600 mg) in tetrahydrofuran (20 ml), and the reaction mixture was allowed to come to room temperature and additionally stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, water (50 ml) was added to the residue, extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 500 mg of the titled compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[C:37](O)=[O:38])[CH:28]=[CH:29][CH:30]=1>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[C:37]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH:2]([CH3:1])[CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:38])[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Reactant: COc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: COc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(3-methoxy-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][CH:30]=1>>[NH2:35][C:33]([C:32]1[CH:36]=[CH:37][C:29]([NH:28]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:30][CH:31]=1)=[O:34]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Reactant: NC(=O)c1ccc(N)cc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(C(N)=O)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-aminobenzamide
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[NH2:15][C:16]1[C:21]2=[C:22]([C:35]#[N:36])[CH:23]=[C:24]([C@@H:25]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@@:26]3([CH3:34])[OH:27])[N:20]2[N:19]=[CH:18][N:17]=1.O>CCO>[NH2:15][C:16]1[C:21]2=[C:22]([C:35](=[S:2])[NH2:36])[CH:23]=[C:24]([C@@H:25]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@@:26]3([CH3:34])[OH:27])[N:20]2[N:19]=[CH:18][N:17]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1c1cc(C#N)c2c(N)ncnn12
Solvent: CCO
Solvent: O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1c1cc(C(N)=S)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
to anhydrous EtOH (30 μl) was added P2S5 (7.30 mg, 0.02 mmol) and the mixture stirred in a sealed vial for 1 h at RT. To the reaction mixture was added a solution of Compound 14 (51 mg, 0.0033 mmol) in anhydrous EtOH. (30 μl). The mixture was heated in a sealed vial at 120° C. for 3 h and then cooled to RT, whereupon water was added and the mixture extracted with DCM. The aqueous layer was concentrated to dryness and the residue purified by column chromatography silica gel (elution gradient ethyl acetate to 17% methanol in ethyl acetate) to afford Compound 21: ESI-MS m/z 340 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][C:10]([N+:17]#[C-:18])([CH3:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O>Cl(O)(=O)(=O)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([C:18]([NH:17][C:10]([CH3:16])([CH3:9])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:23]([C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[O:20][CH3:19])[N:1]=2)[CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Reactant: COc1ccccc1C=O
Agent: [O-][Cl+3]([O-])([O-])O
Product: COc1ccccc1-c1nc2ccc(Br)cn2c1NC(C)(C)CC(C)(C)C

Procedure:
Compound (13) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-5-bromopyridine solution (0.1 M, DCM), 0.575 ml of 1,1,3,3-tetramethylbutyl isocyanide solution (0.2 M, DCM), 0.500 ml of 2-methoxybenzaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).