Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:40])[CH2:25][CH2:26][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(O[N:64]1[C:69](=[O:70])[CH2:68][CH2:67][C:65]1=[O:66])=[N+](C)C)C>C1COCC1>[C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:40])[CH2:25][CH2:26][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28][CH2:29][C:30]([O:32][N:64]1[C:69](=[O:70])[CH2:68][CH2:67][C:65]1=[O:66])=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCNC(=O)CCN(CCC(=O)O)C(=O)OC(C)(C)C
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCNC(=O)CCN(CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
17-{3-[tert-Butoxycarbonyl (2-carboxyethyl)amino]propionylamino}heptadecanoic acid tert-butyl ester (0.122 g, 0.2 mmol) was dissolved in THF (5 mL). DIEA (39 ul) was added and the mixture was cooled to 0° C. TSTU (66 mg, 0.22 mmol) was added. The mixture was stirred at 0° C. for 30 min, then for 16 h at RT. The mixture was concentrated under vacuum. AcOEt (15 mL) and the solution was washed with 0.2 N HCl (5 ml) and sat. NaCl (5 ml), dried over MgSO4, and dried under vacuum. The residue was purified by flash chromatography (silica) eluting with AcOEt/heptane (9:1) and AcOEt. The appropriate fractiones were pooled and concentrated under vacuum to yield 58 mg.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:20][CH2:21][NH2:22])[CH:16]=[CH:17][C:18]=1[Cl:19].[BH4-].[Na+].[OH-].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][NH:22][CH2:21][CH2:20][C:15]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1cc2ccccc2o1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Clc1ccc(CCNCc2cc3ccccc3o2)cc1Cl
Temperature: 25 °C

Procedure:
A solution of 150 mg (1.03 mmol) of benzofuran-2-carbaldehyde and 195 mg (1.03 mmol) of 2-(3,4-dichloro-phenyl)-ethylamine in methanol (4 ml) was heated to reflux for 3 h. Then the reaction mixture was allowed to cool to RT and 58 mg (1.54 mmol) of sodium borohydride were added. The mixture was heated to reflux over night. After cooling to RT, 0.1 N sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography (silica gel; dichloromethane and dichloromethane/methanol 95:5). The title compound was isolated as yellow oil (249 mg, 76%). MS (ISP) 320.2 (M+H)+.
Reaction SMILES: N.[Na].[C:3](#[N:5])[CH3:4].[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10]>O1CCCC1.C(OCC)C>[NH2:10][C:9]([C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[Cl:6])=[CH:4][C:3]#[N:5]
Reactant: N#Cc1ccccc1Cl
Reactant: CC#N
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CC=C(N)c1ccccc1Cl

Procedure:
A 150 ml. portion of ammonia is condensed in a reaction flask and a small piece of sodium is added. The blue color is discharged by the addition of ferric chloride and 3.22 g. of sodium are added. After the color is discharged, 5.75 ml. of acetonitrile in 10 ml. of diethyl ether are added. The reaction is cooled in a dry ice-acetone bath and 13.3 g. of 2-chlorobenzonitrile in 25 ml. of tetrahydrofuran are added dropwise. The ammonia is allowed to evaporate, the solvent is blown off with nitrogen and water is added. The mixture is extracted with methylene chloride. The organic extracts are dried over sodium sulfate and filtered through Magnesol®. The filtrate is evaporated with the addition of hexanes giving β-amino-2-chlorocinnamonitrile as a white crystalline solid.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Br:20][CH2:21][C:22](OC)=[O:23]>>[Br:20][CH2:21][C:22]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:23]
Reactant: COC(=O)CBr
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Product: CCCCCCCC/C=C\CCCCCCCCOC(=O)CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Technical grade oleyl alcohol (85 wt %; 10 g; 37.2 mmol) was combined with Novozym 435 (200 mg) in an amber bottle. Methyl bromoacetate (6.84 g; 44.7 mmol; 1.2 equiv.) was added, and the mixture was sealed and stirred at room temperature overnight to afford about 50% conversion to oleyl bromoacetate. The mixture was then purged with a subsurface stream of nitrogen 2.5 days to afford 98.5% conversion of oleyl alcohol to oleyl bromoacetate according to GC analysis. The mixture was filtered, and the solid was washed with toluene. The filtrate was concentrated to give the desired product as a viscous colorless oil (13.19 g, 91%). The product was used in the subsequent reactions without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6].[C:15]1([CH3:27])[CH:20]=[CH:19][C:18]([S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:15]1([CH3:27])[CH:16]=[CH:17][C:18]([S:21]([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=2)[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6])=[O:26])(=[O:22])=[O:23])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCCCOC(=O)c1cccc(N)c1
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1cccc(NC(=O)NS(=O)(=O)c2ccc(C)cc2)c1

Procedure:
In a three-necked flask equipped with a dropping funnel, a thermometer and a reflux condenser 15.4 g of n-butyl 3-aminobenzoate was placed and 150 ml of toluene was added thereto with stirring to dissolve n-butyl 3-aminobenzoate therein. With stirring the resultant mixture by a magnetic stirrer, 17.3 g of p-toluenesulfonylisocyanate was added dropwise to the mixture through the dropping funnel at room temperature. Continuous stirring of the reaction mixture caused an exothermic reaction, thereby precipitating a large amount of white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH:4]([OH:7])[CH2:5][OH:6].[OH-].[K+].S(O[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=O)(=O)C>C1(C)C(C)=CC=CC=1>[CH2:16]([O:7][CH:4]([CH2:5][O:6][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:3][N:2]([CH3:8])[CH3:1])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CN(C)CC(O)CO
Reactant: CCCCCCCC/C=C\CCCCCCCCOS(C)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CCCCCCCC/C=C\CCCCCCCCOCC(CN(C)C)OCCCCCCCC/C=C\CCCCCCCC
Reaction time: 3 h
Yield: 76 %

Procedure:
To a three-necked, 2-liter round bottom flask equipped with a Dean-Stork trap were added 3 -dimethylamino-1,2 -propanediol (6.08 g, 51.1 mmoles), xylene (1300 ml) and KOH (8.0 g). The solution was refluxed for 2 hours while removing water azeotropically via the Dean-Stork trap. Oleyl mesylate (40.0 g, 115.6 mmoles) in 100 ml xylene was added to the reaction mixture drop-wise in 30 minutes. Refluxing was continued for 3 hours and the reaction mixture concentrated to a gum. The gum was triturated with 400 ml hexane and filtered. The solid was washed with 100 ml hexane followed with 200 ml ethyl acetate. The filtrates were combined, concentrated and subjected to f lash chromatography. 2,3-dioleyloxy-1- (N, N-dimethylamino) propane was obtained as a colorless oil in 76% yield, TLC: Rf =0.37 (Silica gel: 5% EtOAc: hexane); IR: 2925, 2850, 1469, 1120, 1040 cm-1 ; HNMR (CDCl3) δ 5.35 (t, 4H) , 4.13 (q, 1H) 3.4-3.65 (m, 6H), 2.35-2.45 (m, 2H) , 2.25 (S, 6H) , 1.95-2.05 (m, 8H) , 1.5-1.65 (m, 4H) , 1.2-1.45 (m, 4H) 0.9 (t, 6H).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([NH2:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:21]([NH:27][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCN
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Product: CCCCCCNCc1ccc(Oc2ccc(C(N)=O)cn2)c(OC)c1
Yield: 72.8 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and hexylamine (0.0186 g, 0.184 mmol) gives the title compound (0.0479 g, 73.0%): TOF MS ES+ 358.2 (M+H)+, HRMS calcd for C20H28N3O3 358.2131 (M+H)+, found 358.2124, time 0.41 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.4 min, 100% purity.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:26]1([S:30](C2C=CC(C3C=C4N=C(CCC5NC(=S)CCCC5)NC4=NC=3)=CC=2)(=[O:32])=[O:31])[CH2:29][CH2:28][CH2:27]1.N>CO>[N:26]1([S:30]([C:4]2[CH:3]=[CH:2][C:1]([C:7]3[CH:8]=[C:9]4[N:15]=[C:14]([CH2:16][CH2:17][CH:18]5[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]5)[NH:13][C:10]4=[N:11][CH:12]=3)=[CH:6][CH:5]=2)(=[O:32])=[O:31])[CH2:29][CH2:28][CH2:27]1
Reactant: O=S(=O)(c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1)N1CCC1
Reactant: NC1=NC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)CCCC1
Agent: N
Solvent: CO
Product: NC1=NC(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCC5)cc4)cnc3[nH]2)CCCC1

Procedure:
The title compound is synthesized as described for 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine (compound 1) from 92 mg of 7-(2-{6-[4-(azetidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepane-2-thione (compound A6) and 4.50 ml of methanol containing ammonia (strength: 7.0 M) at 50° C. for 70 hours. Purification by flash chromatography on LiChroprep-NH2® (eluent gradient: dichloromethane/0-100 vol. % methanol) affords 56 mg of the title compound as an amorphous solid of m.p. 154° C. (decomp.). ESI-MS: 453.2 (MH+). TLC: Rf=0.23 (LiChroprep-NH2® HPTLC, neat methanol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.S([O-])(=O)(=O)C.CS(O[CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:41][CH2:42][CH2:43][CH3:44])=[C:25]([C:27]2[NH:28][C:29](=[O:40])[C:30]3[N:35]([CH3:36])[N:34]=[C:33]([CH2:37][CH2:38][CH3:39])[C:31]=3[N:32]=2)[CH:26]=1)(=O)=O>C(#N)C>[CH3:36][N:35]1[C:30]2[C:29](=[O:40])[NH:28][C:27]([C:25]3[CH:26]=[C:21]([CH2:20][O:19][CH2:18][CH2:17][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:22]=[CH:23][C:24]=3[O:41][CH2:42][CH2:43][CH3:44])=[N:32][C:31]=2[C:33]([CH2:37][CH2:38][CH3:39])=[N:34]1
Reactant: CCCOc1ccc(COCCOS(C)(=O)=O)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Reactant: C1COCCN1
Agent: CS(=O)(=O)[O-]
Solvent: CC#N
Product: CCCOc1ccc(COCCN2CCOCC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 49.7 %

Procedure:
Morpholine (0.19 g, 0.0021 mol) was added to a solution of the above mesylate, namely 5-[5-(2-methanesulphonyloxyethoxymethyl)-2-n-propoxyphenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, (0.20 g, 0.00042 mol) in acetonitrile (25 ml) and the stirred mixture was heated under reflux for 18 hours. The solvent was removed by evaporation under vacuum, the residue dissolved in saturated aqueous sodium carbonate solution and the solution extracted with ethyl acetate (3×20 ml). The extracts were combined, dried (Na2SO4) and evaporated under vacuum, and the residue was chromatographed on silica gel (4 g) using an elution gradient of methanol in dichloromethane (0-2% methanol). Evaporation under vacuum of the appropriate fractions, followed by crystallisation from hexane, gave the title compound as white crystals (0.098 g, 48%), m.p. 65°-66° C. Found: C,64.17; H,7.69; N,14.96; C25H35N5O5 requires C,63.94; H,7.51; N,14.91%.
Reaction SMILES: [Cl:1][C:2]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]=[C:7](OCC)[C:6]1=[O:15].[F:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=O)=[CH:27][CH:26]=1>C(O)CCC>[Cl:1][C:2]1[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]2[C:29]([C:28]3[CH:33]=[CH:34][C:25]([F:24])=[CH:26][CH:27]=3)=[N:31][N:32]=[C:7]2[C:6]1=[O:15]
Reactant: CCOC1=NC[C@H](C)N(Cc2cccc(C(F)(F)F)c2Cl)C1=O
Reactant: NNC(=O)c1ccc(F)cc1
Solvent: CCCCO
Product: C[C@H]1Cn2c(nnc2-c2ccc(F)cc2)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Yield: 58.1 %

Procedure:
A solution of (6S)-1-(2-chloro-3-(trifluoromethyl)benzyl)-3-ethoxy-6-methyl-5,6-dihydropyrazin-2(1H)-one (216 mg, 0.62 mmol) and 4-fluorobenzohydrazide (105 mg, 0.68 mmol) in 1-butanol (6.2 mL) was heated at 130° C. for 16 h. After cooling to rt, the solvent was removed in vacuo. Purification by chromatography (SiO2; 0-10% IPA/EtOAc) afforded the desired product as a white solid (158 mg, 58%). MS (ESI): mass calcd. for C20H15ClF4N4O, 438.1; m/z found, 439.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.77-7.70 (m, 3H), 7.68-7.59 (m, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.25-7.15 (m, 2H), 5.33 (d, J=15.7 Hz, 1H), 4.66 (dd, J=13.0, 4.5 Hz, 1H), 4.55 (d, J=15.7 Hz, 1H), 4.23 (dd, J=13.0, 2.0 Hz, 1H), 4.11 (dt, J=14.3, 4.8 Hz, 1H), 1.27-1.24 (m, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][NH:3]1.[O:14]1[CH:18]=[CH:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[O:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[N:3]1[CH:4]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6](=[O:8])[NH:7][C:2]1=[O:1]
Reactant: C1=COCC1
Reactant: CCOC(=O)c1c[nH]c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(C2CCCO2)c(=O)[nH]c1=O
Temperature: 75 °C
Yield: 40.6 %

Procedure:
A mixture of 5.52 g. (30 mmoles) of ethyl 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylate, 15 g. of 2,3-dihydrofuran and 15 ml. of pyridine is heated at 135° C. for 6 hours. The reaction mixture is concentrated to dryness under reduced pressure and, with the addition of 20 ml. of water, the pyridine is azeotropically removed. The residue is dissolved in 50 ml. of 50% ethanol and heated at 75° C. for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure and the residue is stirred well with 40 ml. of chloroform. Then, 0.9 g. of insoluble ethyl 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylate is recovered. The mother liquor is concentrated to dryness and the residue is recrystallized from 15 ml. of ethanol to give 3.1 g. (yield: 40.6%) of ethyl 1-(2-tetrahydrofuryl)-1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylate, melting point: 125° C.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@:11]1([C:26]#[CH:27])[O:15][C@@H:14]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][C@H:12]1[OH:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[C:1]([O:9][CH2:10][C@@:11]1([C:26]#[CH:27])[O:15][C@@H:14]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][C@H:12]1[O:25][S:29]([CH3:28])(=[O:31])=[O:30])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: C#C[C@]1(COC(=O)c2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O
Solvent: c1ccncc1
Product: C#C[C@]1(COC(=O)c2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OS(C)(=O)=O
Reaction time: 6 h
Yield: 78.2 %

Procedure:
To a pyridine (3.5 mL) solution of 4 (110.9 mg, 0.30 mmol) was added MsCl (0.12 mL, 1.5 mmol) at 0° C. under Ar atmosphere, and the mixture was stirred for 6 h. The reaction mixture was partitioned between CHCl3/sat. aqueous NaHCO3. Silica gel column chromatography (1.5% MeOH in CH2Cl2) of the organic layer gave 5 (105.2 mg, 78%) as a foam: 1H NMR (CDCl3) δ1.92 (3H, d, JMe,6=1.2 Hz, Me-5), 2.43 (1H, dd, J1′,2′a=3.6 and J2′a,2′b=16.0 Hz, H-2′a), 2.72 (1H, s, C≡CH), 3.07 (3H, s, SO2Me), 3.23 (1H, ddd, J1′,2′b=8.2, J2′b,3′=5.2 and J2′a,2′b=16.0 Hz, H-2′b), 4.72 (1H, d, J5′a,5′b=11.2 Hz), 4.76 (1H, d, J5′a,5′b=11.2 Hz), 5.37 (1H, d, J2′b,3′=5.2 Hz, H-3′), 6.56 (1H, d, J1′,2′a=3.6 and J1′,2′b=98.2 Hz, H-1′), 7.36 (1H, d, JMe,6=1.2 Hz), 7.47-7.51, 7.60-7.64 and 8.07-8.10 (5H, each as m, Ph), 8.32 (1H, br); FAB-MS (m/z) 449 (M++H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][S:30][CH2:31][C@@H:3]12.[CH2:32]([N:34](C(C)C)C(C)C)C.Cl.CN>CN(C=O)C>[CH3:32][NH:34][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][S:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
In a vial equipped with a stir bar was charged (R)-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (50 mg, 0.114 mmol) was taken up in DMF (1.14 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (59 μl, 0.34 mmol), O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (64.9 mg, 0.171 mmol), and methanamine hydrochloride (8.45 mg, 0.125 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were collected and lyophilized to yield 25.1 mg (49%) of the product as a white solid. 1H NMR (CHLOROFORM-d) δ: 8.37 (br. s., 1H), 7.58-7.89 (m, 3H), 7.15 (br. s., 1H), 6.87 (d, J=8.8 Hz, 2H), 6.07 (d, J=4.5 Hz, 1H), 5.06 (dt, J=13.6, 2.5 Hz, 1H), 4.42 (dd, J=10.1, 3.8 Hz, 1H), 3.55 (br. s., 2H), 3.36 (br. s., 4H), 3.08-3.24 (m, 1H), 2.56-3.08 (m, 8H), 2.40 (dd, J=13.5, 1.1 Hz, 1H), 1.74 (br. s., 2H). [M+H] calc'd for C, 23; H, 28; N, 6; O, 2; S, 453; found, 453.
Reaction SMILES: [C:1](=[O:11])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:2].O.[C:13]([OH:17])(=[O:16])[CH:14]=[O:15]>CCOCC>[OH:15][CH:14]([C:13]([OH:17])=[O:16])[NH:2][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:11]
Reactant: NC(=O)OCc1ccccc1
Reactant: O=CC(=O)O
Solvent: O
Solvent: CCOCC
Product: O=C(NC(O)C(=O)O)OCc1ccccc1
Yield: 69.4 %

Procedure:
Benzyl carbamate (63 g, 0.05 mol) was stirred with glyoxylic acid monohydrate (5.09 g, 0.055 mol) in dry ether (50 mL). The crystalline product 22A (7.81 g, 73%) formed was filtered and washed with ether.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22](Cl)=[O:23])[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:22](=[O:23])[CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=1
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Reactant: COc1cccc(CC(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(CC(=O)Nc2ccc3sc(C)nc3c2Cl)c1
Yield: 44 %

Procedure:
Reaction of 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in THF (1.5 mL) with 3-methoxyphenylacetyl chloride (47 μL, 0.30 mmol) in presence of triethylamine (42 μL, 0.30 mmol) according to method A gave N-(4-chloro-2-methyl-benzothiazol-5-yl)-2-(3-methoxy-phenyl)-acetamide (40 mg, 0.11 mmol, 48% yield) as a white powder after crystallisation in hexane/DCM.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([Cl:42])[CH:41]=1)[C:36](Cl)=[O:37]>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:36](=[O:37])[C:35]2[CH:34]=[C:33]([Cl:32])[CH:41]=[C:40]([Cl:42])[CH:39]=2)[C@H:10]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCN[C@H](Cc3ccc4ccccc4c3)C2)cc1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CCN(Cc2ccccc2)C[C@H]1Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3R)-1-benzyl-3-(2-naphthylmethyl)piperazine (3.23 g) and triethylamine (4.3 ml) in dichloromethane (60 ml) was added a solution of 3,5-dichlorobenzoyl chloride (6.0 g) in dichloromethane (10 ml) at 0° C. After stirring at room temperature for 3 hours, the mixture was quenched with water and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, and evaporated under reduced pressure. The obtained residue was triturated with a mixture of dichloromethane and hexane to give (2R)-4-benzyl-1-(3,5-dichlorobenzoyl)-2-(2-naphthylmethyl)piperazine.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.[O-:16][C:17]#[N:18].[K+]>O.CN(C)C1C=CN=CC=1>[NH:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:8]=1)[C:17]([NH2:18])=[O:16]
Reactant: N#C[O-]
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-(4-Aminophenyl)-2(1H)-pyrazinone hydrochloride (1.0 g) was dissolved in water (25 ml), to which solution potassium cyanate (0.4 g) and 4-dimethylaminopyridine (about 0.005 g) were added. The mixture was stirred at room temperature for 18 hours and the resulting suspended material collected by filtration. This was washed in hot dimethylformamide (30 ml), the insoluble material being collected and washed with water to afford the title compound, m.p. >300° C.; n.m.r. δ (DMSO-d6) 5.90 (s, 2H, --CONH2), 7.98, 8.10 (2d, 2H, pyridine H's); ν (liquid paraffin) 1710, 1665 cm-1.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](O)([CH3:12])[CH3:11])[CH:5]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:15][O:14][CH:3]([O:2][CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:12])=[CH2:11])[CH:5]=1
Reactant: COC(OC)c1cccc(C(C)(C)O)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)c1cccc(C(OC)OC)c1
Yield: 95.7 %

Procedure:
0.4 g of the alcohol compound obtained above was dissolved in 8 ml of purified methylene chloride, and with stirring under ice cooling, 0.24 g of methanesulfonyl chloride and 0.38 g of triethylamine were added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporatd under reduced pressure and then extracted by adding ethyl ether and water. The extract was worked up in a customary manner to give 0.35 g of crude 3-isopropenylbenzaldehyde dimethyl acetal as a pale yellow oil.