Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[CH:24][N:25]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:26]=2[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH3:34])[N:28]=2)=[CH:18][CH:17]=1.[O:41]1[CH:45]=[CH:44][C:43]([CH:46]=O)=[N:42]1.C(OCC)C>C1COCC1>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[CH:24][N:25]([CH:35]3[CH2:40][CH2:39][N:38]([CH2:46][C:43]4[CH:44]=[CH:45][O:41][N:42]=4)[CH2:37][CH2:36]3)[C:26]=2[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH3:34])[N:28]=2)=[CH:20][CH:21]=1
Reactant: CNc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCNCC2)n1
Reactant: O=Cc1ccon1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(Cc3ccon3)CC2)n1
Reaction time: 1.5 h

Procedure:
Sodium triacetoxyborohydride (135 mg, 0.637 mmol) was added to a solution of 4-[4-(4-fluorophenyl)-1-piperidin-4-yl-1H-imidazol-5-yl]-N-methylpyrimidin-2-amine (C8) (150 mg, 0.426 mmol) and isoxazole-3-carbaldehyde (49.6 mg, 0.511 mmol) in THF (10 mL). After 90 minutes at room temperature, the reaction was concentrated in vacuo and partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a thick oil. Purification via silica gel chromatography (Eluants: ethyl acetate followed by 10% methanol in ethyl acetate) provided a viscous oil, which was reconcentrated from diethyl ether to afford the product as a white solid. Yield: 77 mg, 0.18 mmol, 42%. LCMS m/z 434.6 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.99-2.09 (m, 2H), 2.16-2.22 (m, 4H), 3.03 (m, 2H), 3.05 (d, J=5.1 Hz, 3H), 3.69 (s, 2H), 4.67 (br m, 1H), 5.17 (m, 1H), 6.41 (d, J=5.1 Hz, 1H), 6.41 (d, J=1.7 Hz, 1H), 7.00 (dd, J=8.7, 8.7 Hz, 2H), 7.46 (dd, J=8.7, 5.4 Hz, 2H), 7.77 (s, 1H), 8.16 (br d, J=4.5 Hz, 1H), 8.40 (d, J=1.6 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:18])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH:14]=[O:15])[O:11]C(C)(C)[O:9]1)[CH2:2][CH2:3][CH3:4].C(N)CCC>>[CH2:1]([NH:5][C:6](=[O:18])[CH2:7][C@H:8]([OH:9])[CH2:13][C@H:12]([OH:11])[CH2:14][OH:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1
Solvent: CCCCN
Product: CCCCNC(=O)C[C@H](O)C[C@H](O)CO

Procedure:
As per the PCT publication number WO2008/044243, the N-butyl-2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetamide compound of formula-3a prepared by the reaction of (3R,5S)-tert-butyl 3,5,6-trihydroxy hexanoate with n-butylamine at 70-80° C. to provide the (3R,5S)—N-butyl-3,5,6-trihydroxyhexanamide, which on further reaction with 2,2-dimethoxy propane to provide N-butyl-2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetamide followed by oxidation with oxalyl chloride provides the compound of formula-3a. The said process involves column chromatography purification in each stage and the amidation reaction take place without usage of solvent. When the present inventors were working on the same reaction, it was surprisingly found that the n-butyl amine reaction with protected dihydroxy compound i.e., tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate in presence of methanol solvent provides the compound with high purity and yield. However, it was observed that when ethanol is used in place of methanol the said reaction was not proceeded further.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:9]=2)[CH:5]=[C:4]([CH:19]=[O:20])[CH:3]=1.[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])[N:9]=2)[CH:5]=[C:4]([CH2:19][OH:20])[CH:3]=1
Reactant: Cc1cc(C=O)cc2cn(COCC[Si](C)(C)C)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(CO)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-5-carbaldehyde (150 mg, 0.516 mmol) in ethanol (4 mL) at room temperature was added sodium borohydride (19.5 mg, 0.516 mmol). The reaction was stirred at room temperature for 20 min, cooled to 0° C., and quenched by the cautious addition of saturated ammonium chloride. The reaction was poured into diethyl ether and washed with water (2×), then brine, dried over magnesium sulfate, and concentrated to give 139 mg (92%) as an oil. 1H-NMR (CDCl3, 500 MHz) δ 7.97 (s, 1H), 7.38 (s, 1H), 7.01 (s, 1H), 5.65 (s, 2H), 4.64 (s, 2H), 3.58 (m, 2H), 2.57 (s, 3H), 2.51 (bs, 1H), 0.89 (m, 2H), −0.07 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 148.9, 135.1, 128.2, 125.5, 122.9, 121.7, 115.4, 81.5, 67.2, 65.6, 17.7, 17.1, −1.5.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1([C:11](=[O:14])[C:12]#[CH:13])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH:16]([CH3:18])[CH3:17]>>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1([C:11](=[O:14])/[CH:12]=[CH:13]/[N:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC
Reactant: C#CC(=O)C1(NC(=O)OC(C)(C)C)CC1
Product: CN(C)/C=C/C(=O)C1(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
(1-Propynoyl-cyclopropyl)-carbamic acid tert-butyl ester (2.2 g, 10.5 mmol) was dissolved in a solution of Me2NH (2 M in THF, 21 mL, 42 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h and then the volatiles were removed in vacuo to give a crude solid. The solid was purified by washing with n-pentane and Et2O to give 1.8 g of the title compound as a yellow solid, m/z 255.36 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=O)=[CH:5][CH:4]=1.ClC1C=C(Cl)C=CC=1C1[C:27]([C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)=[CH:26][N:25]=[C:24]([NH:33][CH2:34][CH2:35][NH:36][C:37]2[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][N:38]=2)[N:23]=1>>[NH:29]1[CH:30]=[CH:31][N:32]=[C:28]1[C:27]1[C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:23][C:24]([NH:33][CH2:34][CH2:35][NH:36][C:37]2[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][N:38]=2)=[N:25][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(C(F)(F)F)cc3)n2)nc1

Procedure:
{5-imidazol-2-yl-4-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}{2-[(5-nitro(2-pyridyl))amino]ethyl}amine was prepared from 4-(trifluoromethyl)benzoyl chloride using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [F:1][C:2]1([F:15])[O:6][C:5]2[C:7]([CH3:14])=[CH:8][CH:9]=[C:10](B(O)O)[C:4]=2[O:3]1.[OH:16]O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1([F:15])[O:6][C:5]2[C:7]([CH3:14])=[CH:8][CH:9]=[C:10]([OH:16])[C:4]=2[O:3]1
Reactant: OO
Reactant: Cc1ccc(B(O)O)c2c1OC(F)(F)O2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(O)c2c1OC(F)(F)O2
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.1 %

Procedure:
(2,2-difluoro-7-methyl-1,3-benzodioxol-4-yl)boronic acid (Intermediate 36, 150 mg, 1.28 mmol) was dissolved in THF (1.5 mL) and a 30% w/w aqueous solution of H2O2 (2.56 mmol) and NaOH (51 mg, 1.28 mmol) were added and the reaction mixture stirred for 2 days at room temperature. The reaction was quenched with a 2N aqueous solution of HCl and diluted with ethyl acetate. Two phases were separated and the organic layer was washed twice with brine, dried over Na2SO4 and evaporated to dryness, affording the title compound (140 mg) as yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:14]1[CH2:18][CH2:17][CH2:16][N:15]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:8]=[C:7]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][C:3]=1[NH:4][C:14]1[CH2:18][CH2:17][CH2:16][N:15]=1
Reactant: ClC1=NCCC1
Reactant: CC(=O)Nc1ccc(N)c(C)c1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(NC2=NCCC2)c(C)c1
Reaction time: 4 h

Procedure:
The product aniline of Example 32 was added to a solution of 2-chloro-1-pyrroline, prepared by the method of Example 1 using toluene, and the mixture was stirred for four hours at reflux. The solvent was removed by decanting and the residual solid was dissolved in water. The acidic solution (ca. pH 1.5) was washed with ethyl acetate and then made strongly basic (ca. pH 13) with aqueous sodium hydroxide. The crude product compound was immediately extracted into ethyl acetate. The extract was filtered and concentrated in vacuo to an oil, which solidified on standing. The solid was triturated with diethyl ether, collected, and dried under vacuum to give the title compound, the free base of the compound prepared by the methods of Example 16 and 17. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1.NC(N)=[S:16]>C(O)C>[SH:16][C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1
Reactant: Clc1cc2c(nn1)CCCCCC2
Reactant: NC(N)=S
Solvent: CCO
Product: Sc1cc2c(nn1)CCCCCC2
Reaction time: 20 h

Procedure:
59.1 g of 3-chloro-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine and 25.2 g of thiourea are heated at reflux in 250 cc of absolute ethanol while stirring for 20 hours. The reaction mixture is subsequently concentrated and divided between chloroform and water. After concentrating the chloroform phase, crude 3-mercapto-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine is obtained and is recrystallized from 250 cc of absolute ethanol with the addition of carbon. M.P. 167°-170° (decomp.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH:11]([CH3:13])[CH3:12].[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[O:15]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:22]([C:19]1[CH:18]=[CH:17][C:16]([CH:14]=[O:15])=[CH:21][CH:20]=1)(=[O:24])=[O:23]
Reactant: O=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(NCC(C)C)c(C)c1
Solvent: c1ccncc1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C=O)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
To a solution of (2,4-dimethylphenyl)(2-methylpropyl)amine (400 mg, 2.256 mmol) in pyridine (5 mL), stirred in air at room temperature, was added 4-formylbenzene-1-sulfonyl chloride (760 mg, 3.71 mmol) in one charge. The reaction mixture was stirred at 20° C. for 30 minutes, then left to stand 6 hours. The solvent was removed in vacuo and the crude material purified by flash (Si) chromatography (using a 0-25% ethyl acetate-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the required product (794 mg) as a colourless gum. LCMS (M+1) 346, RT 1.33 mins.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH2:8][N:9]=[C:10]=[O:11])=[O:5]>C1(C)C=CC=CC=1>[C:4]([O:6][CH2:7][CH2:8][N:9]=[C:10]=[O:11])(=[O:5])[CH:3]=[CH2:2]
Reactant: O=C=NCCOC(=O)CCCl
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCN=C=O
Temperature: 50 °C
Yield: 85.3 %

Procedure:
A three-necked flask was charged with 500 ml of toluene, 60 g (0.34 mol) of (2-isocyanatoethyl) 3-chloropropionate obtained in Synthesis Example 2, and 200 g of a dried strongly basic ion-exchange resin, followed by heating at 50° C. for 6 hours with stirring. After cooling to room temperature, the ion-exchange resin was filtered off. Subsequently, the toluene was evaporated, and the remainder was distilled (at 62-67° C. and 0.7 kPa) to yield 41 g (0.29 mol) of acryloyloxyethyl isocyanate (boiling point: 200° C.) (86% yield). The hydrolyzable chlorine concentration was 270 ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.C([O:17][B:18](OC(C)C)[O:19]C(C)C)(C)C.Cl>O1CCCC1>[F:1][C:2]1[C:3]([F:8])=[CH:4][CH:5]=[CH:6][C:7]=1[B:18]([OH:19])[OH:17]
Reactant: Fc1ccccc1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(F)c1F
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 86.7 %

Procedure:
After 7.5 g of o-difluorobenzene was dissolved in 80 ml of dried tetrahydrofuran (THF), the solution thus formed was cooled down to -70° C. under a nitrogen atmosphere and then added dropwise with 42 ml of butyllithium (1.6 mol/liter hexane solution) at a temperature lower than -55° C. The solution was continuously stirred at the same temperature for 1.5 hours and added dropwise with a THF solution containing 24.8 g of triisopropylborate at a temperature of -65° C. to -60° C. After the dropping of the solution was finished, the solution was continuously stirred at an ambient temperature for 12 hours, added further with 60 ml of a 10% aqueous hydrochloric acid solution, and continuously stirred for 1 hour. The reaction mixture thus obtained was subjected to extraction with an ether, washed with water, dried, and subjected to distillation under a reduced pressure to separate the solvent to obtain 9.0 g of 2,3-difluorophenyl boronic acid.
Reaction SMILES: [CH2:1]([C:3]([CH2:10][CH3:11])([CH2:6][CH2:7][C:8]#[N:9])[CH2:4][OH:5])[CH3:2].C(Cl)(=O)C(Cl)=O>CS(C)=O>[CH2:10]([C:3]([CH:4]=[O:5])([CH2:1][CH3:2])[CH2:6][CH2:7][C:8]#[N:9])[CH3:11]
Reactant: CCC(CC)(CO)CCC#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Product: CCC(C=O)(CC)CCC#N

Procedure:
2,2-Diethyl-4-cyanobutanol, oxalyl chloride and dimethylsulfoxide were processed as described in Example 18A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[OH:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]2[C:32]([CH3:39])=[C:33]([CH:37]=O)[NH:34][C:35]=2[CH3:36])[CH2:25]1>C(O)C.N1CCCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:37]\[C:33]1[NH:34][C:35]([CH3:36])=[C:31]([CH2:30][N:26]2[CH2:27][CH2:28][CH2:29][CH:24]([OH:23])[CH2:25]2)[C:32]=1[CH3:39])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CN1CCCC(O)C1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1CCCC(O)C1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-(3-hydroxy-piperidin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde in ethanol and piperidine to give the titled compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[CH:17][S:16][C:10]=2[N:11]=[C:12]([NH2:15])[CH2:13][N:14]=1.[Cl:19]Cl.[OH-].[Na+]>CO.ClCCl>[Cl:19][C:17]1[S:16][C:10]2[N:11]=[C:12]([NH2:15])[CH2:13][N:14]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:9]=2[CH:18]=1
Reactant: NC1=Nc2sccc2C(c2ccccc2F)=NC1
Reactant: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: NC1=Nc2sc(Cl)cc2C(c2ccccc2F)=NC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
19 g of 5-(2-fluoro-phenyl)-3H-thieno[2,3-e][1,4]diazepin-2-ylamine were dissolved in 730 ml of 5% methanol in dichloromethane, treated while stirring well with 327 g of a 2.8% solution of chlorine gas in 5% methanol in dichloromethane and stirred at room temperature under argon for 5 minutes. Thereafter, the reaction mixture was poured into 600 ml of 0.2N sodium hydroxide solution while cooling with ice and extracted. The dichloromethane extracts were dried with sodium sulphate, filtered and the solvent was evaporated in a vacuum. After two fold boiling of the residue in 5% methanol in dichloromethane and filtration there were obtained 7.4 g of 7-chloro-5-(2-fluoro-phenyl)-3H-thieno[2,3-e][1,4]diazepin-2-ylamine of m.p. 215-217° C. (dec.).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=1[O:19][CH3:20].[OH:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][C:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:26][C:25]2=[O:38]>>[CH3:18][O:17][CH:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[O:28][C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][C:25]3=[O:38])=[C:7]([O:19][CH3:20])[CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Reactant: COc1cc(CC(OC)C(=O)O)ccc1OCCCBr
Product: COc1cc(CC(OC)C(=O)O)ccc1OCCCOc1ccc2oc(-c3ccccc3)cc(=O)c2c1

Procedure:
The title compound was prepared from 3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid (Example 175, Step B) and 6-Hydroxy-2-phenyl-chromen-4-one following the Standard Procedure J. 1H-NMR (200.15 MHz, CDCl3): 8.0–7.9 (m, 2H), 7.6–7.5 (m, 5H), 7.30 (dd, 1H, J=9.0, 3.0), 6.9–6.8 (m, 4H), 4.3–4.2 (m, 4H), 4.00 (dd, 1H, J=7.2, 4.6), 3.83 (s, 3H), 3.41 (s, 3H), 3.09 (dd, 1H, J=14.2, 4.6), 2.96 (dd, 1H, J=14.2, 7.2), 2.33 (qn, 2H, J=6.2) ppm.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[N:6]([C:15]([N:19]=[C:20]=[O:21])([CH2:17][CH3:18])[CH3:16])=[N:7][C:8]([N:12]=[C:13]=[O:14])([CH2:10][CH3:11])[CH3:9]>CCCCC>[N:6]([C:15]([NH:19][C:20]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:21])([CH2:17][CH3:18])[CH3:16])=[N:7][C:8]([NH:12][C:13]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:14])([CH2:10][CH3:11])[CH3:9]
Reactant: CCC(C)(N=C=O)N=NC(C)(CC)N=C=O
Reactant: CCNCC
Solvent: CCCCC
Product: CCN(CC)C(=O)NC(C)(CC)N=NC(C)(CC)NC(=O)N(CC)CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3.95 grams (0.054 moles) of diethylamine in 30 ml pentane in a 50 ml erlenmeyer flask cooled in a water bath was added 6.05 grams (0.027 moles) of 2,2'-azobis(2-isocyanatobutane) (from Example XXXVI) dropwise over 20 minutes while holding the reaction temperature below 30° C. After the addition was complete, the reaction was stirred for an additional 60 minutes at room temperature and filtered. The filter cake was washed with pentane and dried. The dry white solid weighed 1.8 grams (18% crude yield) and melted at 215°-220° C. with decomposition. The product had a broad carbonyl band at 1650 cm-1 and a strong NH band at 3400 cm-1 in its infrared spectrum and the isocyanate band at 2200 cm-1 was absent.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:15][CH2:16][OH:17])[C@H:8]1[CH2:13][CH2:12][C@H:11]([CH3:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br.[H-].[Na+].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[N:7]([CH2:15][CH2:16][O:17][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=1[Cl:19])[CH:8]1[CH2:9][CH2:10][CH:11]([CH3:14])[CH2:12][CH2:13]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N(CCO)[C@H]1CC[C@H](C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCC(N(CCOCc2ccccc2Cl)C(=O)OC(C)(C)C)CC1
Reaction time: 16 h

Procedure:
To a mixture of (2-hydroxy-ethyl)-(trans-4-methyl-cyclohexyl)-carbamic acid tert-butyl ester (0.75 g, 2.91 mmol) and 2-chlorobenzylbromide (0.90, 4.37 mmol) in DMF (8 mL) was added NaH (60% in mineral oil, 0.23 g, 5.83 mmol) and the reaction mixture was stirred for 16 h. H2O (4 mL) was added and the mixture was extracted with diethyl ether (3×5 mL). The organic phase was collected and the solvent was removed in vacuo to give the crude product of [2-(2-chloro-benzyloxy)-ethyl]-(4-methyl-cyclohexyl)-carbamic acid tert-butyl ester. This was dissolved in DCM (4 mL) and TFA (4 mL) was added and the mixture was stirred for 2 hs before the volatiles were removed in vacuo.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[Br:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17].BrC1C=CC=CC=1C=O.CNC>>[Br:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[CH:15]([N:16]([CH3:18])[CH3:17])[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1ccc2ccccc21
Reactant: C[N+](C)=Cc1ccccc1Br
Agent: CNC
Agent: O=Cc1ccccc1Br
Agent: [Cl-]
Product: CN(C)C(c1ccccc1Br)c1cn(C)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methylindole and (2-bromo-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 2-bromo-benzaldehyde and dimethylamine.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]([CH2:21][CH2:22][O:23][CH3:24])[CH3:20])=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:29][O:30][CH2:31][CH2:32][NH:33][CH3:34]>>[ClH:1].[ClH:1].[CH3:29][O:30][CH2:31][CH2:32][N:33]([CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]([CH2:21][CH2:22][O:23][CH3:24])[CH3:20])=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1)[CH3:34]
Reactant: CNCCOC
Reactant: COCCN(C)c1ccc(OC)c2nc(NC(=O)c3ccc(CCl)cc3)sc12
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(N(C)CCOC)c3s2)cc1
Product: Cl
Yield: 168 %

Procedure:
A mixture of 100 mg (0.24 mmol) 4-chloromethyl-N-{4-methoxy-7-[(2-methoxy-ethyl)-methyl-amino]-benzothiazol-2-yl}-benzamide and 212 mg (2.38 mmol) N-(2-methoxyethyl)methylamine was ultrasonicated at room temperature for 30 minutes. The reaction mixture was then concentrated it vactio and the residue purified by flash chromatography (ethyl acetate). The product-containing fractions were concentrated in vactio and the residue stirred with HCl in ether and ethyl acetate. The resulting crystals were collected by filtration and washed with ether to afford 110 mg (91%) 4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-{4-methoxy-7-[(2-methoxy-ethyl)-methyl-amino]-benzothiazol-2-yl}-benzamide dihydrochloride as a white crystalline solid. ES-MS m/e (%): 473 (M+H+, 100).
Reaction SMILES: C(Cl)(C(Cl)=O)=O.OCC1(CO)O[C@@H]([N:14]2[CH:22]=[C:20]([CH3:21])[C:18](=[O:19])[NH:17][C:15]2=[O:16])CC1.ON=C[C@]1(CO)O[C@@H](N2C=C(C)C(=O)NC2=O)CC1>C(Cl)Cl.CS(C)=O>[NH:14]1[CH:22]=[C:20]([CH3:21])[C:18](=[O:19])[NH:17][C:15]1=[O:16]
Reactant: Cc1cn([C@H]2CCC(CO)(CO)O2)c(=O)[nH]c1=O
Agent: Cc1cn([C@H]2CC[C@@](C=NO)(CO)O2)c(=O)[nH]c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1c[nH]c(=O)[nH]c1=O
Temperature: -55 °C
Reaction time: 0.25 h

Procedure:
To a solution of DMSO (170μl, 2.34 mM) and CH2Cl2 (0.5 ml) at -60° C., was added 135 ml of (COCl)2 in 1 ml of CH2Cl2 dropwise over a period of 5 minutes. After 15 minutes, 3'-deoxy-4'-hydroxymethylthymidine (0.3 g, 1.17 mM), prepared, e.g., as described in Preparation 15, in 0.5 ml DMSO/0.5 ml CH2Cl2 was added slowly and the mixture stirred at -55° C. for 3 hours. After the addition of 0.65 ml TEA, the solution was removed from the cooling bath and allowed to warm to 24° C. at which temperature it was stirred for 15 minutes. The solution was filtered and the solvent was removed by evaporation. The residue was dissolved in pyridine; treated with H2NOH HCl (0.2 g, 2.9 mM), and stirred at 24° C. for 48 hours. The solvent was removed by evaporation and the residue was chromatographed on silica gel using 8% CH3OH/CH2Cl2, yielding a mixture of the 4'-α and 4'-β isomers of 3'-deoxy-4'-hydroxyiminomethylthymidine (140 mg, 0.52 mM).
Reaction SMILES: [CH:1]1([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.[C:16]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]([C:22](O)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1>>[C:16]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]([C:22]([N:2]2[CH2:3][CH:4]3[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:1]2[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: CCOC(=O)CC1NCC2CCCCC21
Product: CCOC(=O)CC1C2CCCCC2CN1C(=O)c1ccccc1-c1ccccc1

Procedure:
Ethyl 2-(2-(biphenylcarbonyl)octahydro-1H-isoindol-1-yl)acetate was prepared according to general procedure A using ethyl 2-(octahydro-1H-isoindol-1-yl)acetate and biphenyl-2-carboxylic acid.