Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=S)[C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=1)[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1.[H-].[Na+].C(I)C.[N:41]#[C:42][NH2:43]>O1CCCC1>[C:42]([NH:43][C:19](=[N:18][CH2:17][CH2:16][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)[C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=1)#[N:41]
Reactant: N#CN
Reactant: CN(CCCNC(=S)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCOc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCI
Product: CN(CCCN=C(NC#N)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCOc1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a solution of N-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-3,5-di-tert-butyl-4-hydroxybenzothioamide (1.0 g) obtained in Example 60 in dry tetrahydrofuran was added sodium hydride (0.16 g) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hour. To the mixture was added ethyl iodide (0.31 g), followed by stirring at room temperature for 2 hours. The mixture was again cooled to 0° C., and cyanamide (0.84 g) was added thereto, followed by stirring at room temperature for 15 hours. After completion of the reaction, the mixture was poured into ice-water, and the product was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform-methanol, 99:1) to afford 0.70 g (69%) of the title compound as pale yellow crystals. mp 129-130° C. NMR (CDCl3) (200 MHz) δ: 1.45 (18H, s), 1.6-2.1 (2H, m), 2.20 (3H, s), 2.6-3.0 (4H, m), 3.6-3.8 (2H, m), 3.83 (2H, t, J=5.7 Hz), 5.56 (1H, s), 5.84 (2H, s), 5.8-6.8 (3H, m), 7.48 (2H, s), 8.44 (1H, brs)
Reaction SMILES: [C:1]([C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=O)[CH:7]=[CH:6]2)#[N:2].[F:20][C:21]1[CH:22]=[C:23]([CH:28]=[C:29]([F:31])[CH:30]=1)[C:24]([NH:26][NH2:27])=O>>[F:20][C:21]1[CH:22]=[C:23]([C:24]2[O:15][C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)=[N:27][N:26]=2)[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: NNC(=O)c1cc(F)cc(F)c1
Reactant: N#Cc1ccc2c(ccn2CC(=O)O)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2nnc(-c3cc(F)cc(F)c3)o2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 35C from [5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and 3,5-difluorobenzohydrazide: MS (ES) m/z 405 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[CH:16]1([CH2:19][NH:20][C:21](=[O:37])[C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])O.[Na+]>CC(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:8]1([NH:7][C:5]([C:4]2[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([NH:20][CH2:19][CH:16]4[CH2:18][CH2:17]4)=[O:37])=[CH:23][CH:24]=3)[C:13]([CH3:14])=[C:12]([CH3:15])[CH:11]=2)=[O:6])[CH2:10][CH2:9]1
Reactant: Cc1cc(C(=O)NC2CC2)cc(Br)c1C
Reactant: CC1(C)OB(c2ccc(C(=O)NCC3CC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1cc(C(=O)NC2CC2)cc(-c2ccc(C(=O)NCC3CC3)cc2)c1C
Temperature: 90 °C

Procedure:
3-Bromo-N-cyclopropyl-4,5-dimethylbenzamide (Intermediate 21, 30 mg), N-cyclopropylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (28 mg), tetrakis(triphenylphosphine)palladium (1 mg) and aqueous sodiumhydrogen carbonate (1M, 0.5 ml) were mixed in propan-2-ol (2 ml) and heated at 90° C. under nitrogen for 24 hrs. The reaction was absorbed onto silica and applied to a SPE (Si, 10 g) and eluted with an ethyl acetate/cyclohexane gradient (0–100% ethyl acetate). The product fractions were reduced to dryness under vacuum and the residue recrystallised from ethyl acetate to give N3-cyclopropyl-N4′-(cyclopropylmethyl)-5,6-dimethyl-1,1′-biphenyl-3,4′-dicarboxamide.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH:21][C:22](=[O:36])[C:23]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)=[N:24][O:25][C:26](=[O:30])[CH:27]([Cl:29])[Cl:28])[C:19](=[O:37])[N:10]2[C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH:21][C:22](=[O:36])[C:23](=[N:24][O:25][C:26](=[O:30])[CH:27]([Cl:29])[Cl:28])[C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:19](=[O:37])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)C(Cl)Cl)c3cccs3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)C(Cl)Cl)c3cccs3)[C@H]2SC1
Yield: 53 %

Procedure:
A solution of t-butyl 3-acetoxymethyl-7β-[2-dichloroacetoxyimino-(thien-2-yl)acetamido]ceph-3-em-4-carboxylate (syn-isomer) in anisole (20 ml.) was treated with trifluoroacetic acid (100 ml.). After 5 minutes at 20° the solution was concentrated under reduced pressure at 35°. Ethyl acetate was added and the solution was again concentrated, whereupon a solid separated out. Ethyl acetate was evaporated from the residue three more times and the solid was collected and washed with ether to give 3-acetoxymethyl-7β-[2-dichloroacetoxyimino-2-(thien-2-yl)acetamido]ceph-3-em-4-carboxylic acid (syn-isomer) (37 g., 53%) λmax. (ethanol) 263 nm (ε14,800), τ(DMSO-d6) values include -0.19 (doublet, J 8 Hz; NH), 3.02 (singlet, CHCl2), 7.94 (singlet, OCOCH3).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[OH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=O.[CH:40]([C:43]1[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]([CH3:52])[CH3:51])[C:44]=1[NH2:45])([CH3:42])[CH3:41]>O.CN(C=O)C>[CH:50]([C:46]1[CH:47]=[CH:48][CH:49]=[C:43]([CH:40]([CH3:42])[CH3:41])[C:44]=1[NH:45][C:37](=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][OH:22])([CH3:52])[CH3:51]
Reactant: O=C(O)CCCCCCCCCCCCCCO
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCCCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 12 h
Yield: 22.7 %

Procedure:
WSC (4.2 g, 22 mmols) and HOBt (3.0 g, 22 mmols) were added to a DMF (40 ml) solution of the resulting carboxylic acid (5.2 g, 20 mmols) and 2,6-diisopropylaniline (5.3 g, 30 mmols), and stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the precipitate formed was taken out through filtration, and extracted with chloroform. The organic layer was washed with 1 N HCl and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. The residue was extracted with ether and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (developer: hexane/acetone=5/1) to obtain 1.9 g (yield: 23%) of N-(2,6-diisopropylphenyl)-15-hydroxypentadecanamide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[C:23]([C:25]([O:27]C)=[O:26])[CH:24]=4)[NH:21][C:20]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Li+].Cl>O1CCOCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=4)[NH:21][C:20]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)c1cc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc2cc(C(C)(C)C)[nH]c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc(C(=O)O)c2[nH]1
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
Methyl 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butyl-1H-indole-7-carboxylate (30 mg, 0.069 mmol) was dissolved in a mixture of 1,4-dioxane (1.5 mL) and water (2 mL) containing a magnetic star bar and lithium hydroxide (30 mg, 0.71 mmol). The resulting solution was stirred at 70° C. for 45 minutes. The crude product was then acidified with 2.6 M hydrochloric acid and extracted three times with an equivalent volume of dichloromethane. The dichloromethane extracts were combined, dried over sodium sulfate, filtered, and evaporated to dryness. The residue was dissolved in a minimum of N,N-dimethylformamide and then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butyl-1H-indole-7-carboxylic acid. ESI-MS m/z calc. 434.2, found 435.5. Retention time of 1.85 minutes. 1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 9.96 (d, J=1.6 Hz, 1H), 7.89 (d, J=1.9 Hz, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.02 (d, J=1.6 Hz, 1H), 6.96-6.88 (m, 2H), 6.22 (d, J=2.3 Hz, 1H), 6.02 (s, 2H), 1.43-1.40 (m, 2H), 1.37 (s, 9H), 1.06-1.02 (m, 2H).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][CH:13]=[CH:14][N:15]=2)[CH:8]=[CH:7][C:6]=1[C:16]1[C:17]([S:22]([NH:25][C:26]2[O:30][N:29]=[C:28]([CH3:31])[C:27]=2[CH3:32])(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C.[F:40][C:41]1[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=1[C:43](Cl)=[O:44]>>[CH3:31][C:28]1[C:27]([CH3:32])=[C:26]([NH:25][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[O:12][CH:13]=[CH:14][N:15]=3)=[CH:10][C:5]=2[CH2:4][N:3]([CH3:2])[C:43](=[O:44])[C:42]2[CH:46]=[CH:47][CH:48]=[CH:49][C:41]=2[F:40])(=[O:24])=[O:23])[O:30][N:29]=1
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2ccccc2F)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2'-[(methylamino)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide, monohydrochloride (25 mg, 0.053 mmol, prepared as described in Step (A) of Example 28), triethylamine (13.3 mg, 0.13 mmol) was added and followed by 2-fluorobenzoyl chloride (8.3 mg, 0.053 mmol). The reaction was stirred at room temperature overnight and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 29% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 71% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (20 mg, 68%) as a white solid, m.p. 127°-137° C. (amorphous).
Reaction SMILES: [C:1]([OH:22])(=O)[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:35][CH:36]([CH2:39][OH:40])[CH2:37][NH2:38]>CN(C=O)C.C(Cl)Cl>[OH:35][CH:36]([CH2:39][OH:40])[CH2:37][NH:38][C:1](=[O:22])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: NCC(O)CO
Reactant: CCCCCCCCC#CCC#CCC#CCCCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCC#CCC#CCC#CCCCC(=O)NCC(O)CO

Procedure:
In the same manner as in the above example, 8 g of 5,8,11-eicosatriynoic acid in 40 cm3 of anhydrous DMF are treated initially with 5.62 g of carbonyldiimidazole. 4.1 cm3 of 2,3-dihydroxypropylamine are then added at 0° C. At the end of the reaction, the reaction mixture is poured into ice-cold water. The precipitated product is drained and dissolved in 300 cm3 of methylene chloride. The solution is dried over sodium sulphate and then concentrated under reduced pressure. The solid obtained is directly recrystallized in acetonitrile. 9 g of N-(2,3-dihydroxypropyl)-5,8,11-eicosatriynamide are thereby obtained in the form of very pate beige crystals of melting point 87° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.Br[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:7][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[CH:9]=1
Reactant: CCOc1ccc(Br)cc1
Reactant: O=Cc1cc(Br)ccc1F
Product: CCOc1ccc(Cc2cc(Br)ccc2F)cc1

Procedure:
Preparation was performed in a similar manner as in Preparation Example 3 using 5-bromo-2-fluorobenzaldehyde and 4-bromophenetole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][CH2:11]Cl.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][CH2:11][N:27]1[CH2:28][CH2:29][CH:24]([C:20]2[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=2)[CH2:25][CH2:26]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: ClCCCOc1ccccc1Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOc3ccccc3Cl)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-chloro-2-(3-chloropropoxy)benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 415.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12]1([CH2:18][C:19](Cl)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>O1CCOCC1>[CH2:18]([C:19]1[O:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[N:1]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2oc(Cc3ccccc3)nc2c1
Temperature: 210 °C
Yield: 33.3 %

Procedure:
To 2-amino-4-nitrophenol (300 mg, 1.95 mmol) in dioxane (2.5 mL) was added 2-phenylacetyl chloride (290 μL, 2.15 mmol) at room temperature. The reaction vessel was heated in the microwave at 210° C. for 15 min. After cooling, the mixture was slowly poured into 1M aqueous sodium hydroxide (50 mL), and the resulting precipitate filtered and washed with water. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 1:7 v/v to ethyl acetate/hexanes 1:5 v/v) to afford 165 mg (33%) of the title compound (LCMS RT=6.47 min, MH+ 255.2)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[OH:8].[C:9](OC(=O)C)(=O)[CH3:10]>>[CH3:9][C:10]1[O:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1cnccc1O
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2cnccc2o1

Procedure:
3-Amino-4-hydroxypyridine was reacted with acetic anhydride to afford 4.7 g of 2-methyloxazolo[4,5-c]pyridine; mp 56°-58° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:31])[CH2:16][O:17][CH2:18][CH2:19][O:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([O:31][CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][O:32]2)[CH2:16][O:17][CH2:18][CH2:19][O:20][S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(O)c2ccc(OCc3ccccc3)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCC(OC2CCCCO2)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 0 °C

Procedure:
To a mixture of 20 g of 1-(4-benzyloxyphenyl)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethanol and 40 ml of methylene chloride containing 8.2 g of 3,4-dihydro-2H-pyrane was added 2.3 g of pyridinium p-toluenesulfonate at room temperature. The resulting mixture was refluxed for 30 minutes. The reaction mixture was cooled and added to a mixture of 100 ml of ice water and 100 ml of methylene chloride. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 18.6 g of light yellow oily 1-(4-benzyloxyphenyl)-1-(2-tetrahydropyranyloxy)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:18][CH:19](Cl)[CH3:20])[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>C(OC(C)C)(C)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:18][CH:19]([N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])[CH3:20])[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccc(C)c1N(CC(C)Cl)C(=O)c1ccccc1
Reactant: CCNCC
Solvent: CC(C)OC(C)C
Product: CCN(CC)C(C)CN(C(=O)c1ccccc1)c1c(C)cccc1C
Reaction time: 24 h
Yield: 64.3 %

Procedure:
A mixture of 6.0 g (20 mmoles) of 1-[N-(2,6-dimethylphenyl)-benzamido]-2-chloro-propane and 10.3 ml (7.3 g, 0.1 mole) of diethyl amine is heated at 160° C. for 12 hours in a steel bomb. The mixture is cooled and processed as described in Example 16. The resulting oily crude base, weighing 5.0 g, is dissolved in 30 ml of diisopropyl ether, the solution is allowed to stand for one day, and then the insolubles are filtered off. The filtrate is evaporated under reduced pressure. 4.35 g (64%) of 1-[N-(2,6-dimethylphenyl)-benzamido]-2-diethylamino-propane are obtained as a yellow oil.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][C:11]([NH:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20]2[N:21]=[C:22]([N:25]=[C:26]([NH2:28])[NH2:27])[S:23][CH:24]=2)[N:19]=1)=[O:12])=O)(C)(C)C>O1CCOCC1.CO>[ClH:1].[ClH:1].[NH2:9][CH2:10][C:11]([NH:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20]2[N:21]=[C:22]([N:25]=[C:26]([NH2:28])[NH2:27])[S:23][CH:24]=2)[N:19]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCc1nc(-c2csc(N=C(N)N)n2)cs1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCC(=O)NCc1nc(-c2csc(N=C(N)N)n2)cs1
Reaction time: 24 h

Procedure:
A solution of hydrogen chloride in dioxane (4N, 5 ml) was added slowly to a suspension of 4-(2-t-butoxycarbonylaminoacetylaminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole-(1.0 g) in methanol (5 ml) with cooling on an ice-water bath. The mixture was stirred for 24 hours with cooling on an ice-water bath. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and diisopropyl ether afforded 4-(2-aminoacetylaminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole dihydrochloride (0.58 g).
Reaction SMILES: [CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2]1.C(Cl)C1C=CC2OC[O:14][C:13]=2C=1.C1N2CN3CN(C2)CN1C3>>[CH:6]1[C:7]([CH:13]=[O:14])=[CH:8][C:3]2[O:2][CH2:1][O:9][C:4]=2[CH:5]=1
Reactant: c1ccc2c(c1)OCO2
Reactant: ClCc1ccc2c(c1)OCO2
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1ccc2c(c1)OCO2
Yield: 70 %

Procedure:
A typical process for preparing piperonal from 1,2-methylenedioxybenzene has been reported by P. P. Shorygin et al. [J. Gen. Chem. (U.S.S.R.), 8,975 (1938)]. This is a two-step process. In the first step, 1,2-methylenedioxybenzene is reacted with formalin in petroleum benzine under the influence of hydrogen chloride gas and zinc chloride to form piperonyl chloride (with a 70-78% yield based on the amount of 1,2-methylenedioxybenzene having reacted). This is followed by the second step in which the piperonyl chloride is reacted with an equimolar amount of hexamine in 60% alcohol to give a 70-80% yield of piperonal. By E. D. Laskina et al. [Chemical Abstracts, 57,9714 (1962)], another process has been described in which 1,2-methelenedioxybenzene is reacted with formalin in the presence of a large excess of the sodium salt of m-nitrobenzenesulfonic acid, hydrogen chloride, and an aluminum catalyst to give a 42.4% yield of piperonal.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([C:37]3([C:40]([O:42]C(C)C)=[O:41])[CH2:39][CH2:38]3)[N:36]=2)[N:33]=1>CN(C)C(=O)C>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([CH:34]=[C:35]([C:37]5([C:40]([OH:42])=[O:41])[CH2:39][CH2:38]5)[N:36]=4)[N:33]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)OC(=O)C1(c2cn3nc(Cl)ccc3n2)CC1
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(O)C1(c2cn3nc(OCCCN4CCC(OC(c5ccccc5)c5ccccc5)CC4)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
1.14 g of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 15 ml of N,N-dimethylacetamide; 140 mg of a 60% dispersion of sodium hydride in mineral oil was added, followed by stirring at room temperature under reduced pressure for 30 minutes. To the reaction mixture, 980 mg of isopropyl 1-(6-chloroimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxylate was added under ice cooling conditions, followed by stirring at constant temperature for 4 hours. Ice water was added, followed by saturation with sodium chloride and subsequent extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected and concentrated under reduced pressure to yield 496 mg of the title compound.
Reaction SMILES: [CH:1]([O:4][P:5]([CH2:11][O:12][C@H:13]([CH3:20])[CH2:14]OS(C)(=O)=O)([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2].[NH2:21][C:22]1[N:30]=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[C:24]([Cl:31])[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[NH2:21][C:22]1[N:30]=[C:29]2[C:25]([N:26]=[CH:27][N:28]2[CH2:14][C@H:13]([O:12][CH2:11][P:5]([O:4][CH:1]([CH3:2])[CH3:3])([O:7][CH:8]([CH3:9])[CH3:10])=[O:6])[CH3:20])=[C:24]([Cl:31])[N:23]=1
Reactant: CC(C)OP(=O)(CO[C@H](C)COS(C)(=O)=O)OC(C)C
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)OP(=O)(CO[C@H](C)Cn1cnc2c(Cl)nc(N)nc21)OC(C)C
Temperature: 25 °C
Yield: 34.8 %

Procedure:
(R)-2-O-[(Diisopropylphosphono)methyl]-1-O-methanesulfonyl-1,2-propanediol (2.0 g, 6.02 mmol) was mixed with 2-amino-6-chloropurine (1 23 g, 7.22 mmol) and cesium carbonate (3.92 g, 12.0 mmol) in 40 mL of acetonitrile. The mixture was gently refluxed under nitrogen atmosphere for 24 hours, then allowed to cool to room temperature, and filtered. The solvent was removed under reduced pressure The residue was purified by flash chromatography on silica gel twice (first time, methylene chloride:acetone=3:1 to 0:1; second time, methylene chloride:methanol=15:1 to 10:1). The title compound (0.85 g, 35% yield) was isolated as a glassy material which was crystallized from ethyl acetate-diethyl ether: mp 133°-135° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Br:12][C:9]1[CH:8]=[CH:7][C:6]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:10]=1
Reactant: [Br-]
Reactant: CC(C)(C)c1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: CC(C)(C)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 2-(tert-butyl)phenol (20 g, 133 mmol) in dry DCM (200 mL) was added tetrabutyl ammonium tribromide (64.3 g, 133 mmol) at 0° C. and the solution was stirred at rt for 2 h, concentrated and redissolved in Et2O, washed by brine (3×), dried over Na2SO4, filtered and concentrated to give compound P9a (36.6 g, 95%) as an oil.