Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][C@H:5]([OH:11])[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[H-].[Na+].C([O-])(=O)C1C=CC=CC=1.[K+].F[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>CS(C)=O.C(OCC)(=O)C.CCCCCC.C(O)(=O)C.O>[CH3:12][N:2]([CH3:1])[CH2:3][CH2:4][C@H:5]([O:11][C:34]1[C:35]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][CH:33]=1)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN(C)CC[C@H](O)c1cccs1
Reactant: Fc1cccc2ccccc12
Agent: O=C([O-])c1ccccc1
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(C)CC[C@H](Oc1cccc2ccccc12)c1cccs1
Reaction time: 0.5 h

Procedure:
A 1.60 g portion of (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine was dissolved in 8 ml of dimethylsulfoxide at ambient temperature, to which was added 0.35 g of sodium hydride as a 60% dispersion in mineral oil with vigorous stirring. After 30 minutes of stirring, 0.28 g of potassium benzoate was added, and stirring was continued for 10 minutes more. Then 1.52 g of 1-fluoronaphthalene was added and the mixture was then stirred at 50° C. for 8 hours. The reaction mixture was poured slowly into 30 ml of cold water, and the pH was adjusted to 4.8 by addition of acetic acid. Fifteen ml of hexane was added, the mixture was stirred for 10 minutes, and the layers were separated. The aqueous phase was stirred again with 15 ml of hexane and the phases separated. The pH of the aqueous phase was adjusted to 12.5 by addition of aqueous sodium hydroxide, and 15 ml of ethyl acetate was added. The basic mixture was stirred at ambient temperature for 10 minutes, and the layers were separated. The aqueous phase was extracted with another 15 ml portion of ethyl acetate, and the organic extracts were combined, washed once with 30 ml of water, and dried over magnesium sulfate. The solvent was removed under vacuum to obtain a red-brown oil which was dissolved in the minimal amount of 1:1 ethyl acetate:hexane. The solution was flushed through a pad of silica gel using as eluant, ethyl acetate:hexane:methanol:amonium hydroxide, 47:47:5.8:0.2. The product fraction was evaporated under vacuum to obtain 2.3 g of the desired product as an amber oil.
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([C:44](=[O:54])[CH2:45][NH:46]C(=O)OC(C)(C)C)[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].FC(F)(F)C(O)=O>ClCCl>[NH2:46][CH2:45][C:44]([N:22]1[CH2:23][C@@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C@H:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:21]1)=[O:54]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(C(=O)CNC(=O)OC(C)(C)C)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(C(=O)CN)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
The resulting tert-butyl 2-((3R,4R)-3,4-bis((9Z,12Z)-octadec-9,12-dienyloxy)pyrrolidin-1-yl)-2-oxoethylcarbamate was dissolved in dichloromethane (2 mL), and stirred at room temperature for 1.5 hours after adding trifluoroacetic acid (0.256 mL, 3.33 mmol). The aqueous layer was extracted with chloroform after adding a saturated sodium bicarbonate aqueous solution to the reaction mixture. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 85/15) to give compound 61 (60.5 mg, 55.3%).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[CH2:36][CH2:35]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: COc1cccc(C)c1N1CCNCC1
Product: CCc1cc(NC(=O)N2CCN(c3c(C)cccc3OC)CC2)c(OC)nc1C
Yield: 67 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-methoxy-6-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[N:5][C:6]1[N:10]([C@@H:11]2[O:23][C@H:22]([CH2:24][O:25]C(=O)C)[C@@H:17]([O:18]C(=O)C)[C@H:12]2[O:13]C(=O)C)[CH:9]=[N:8][C:7]=1[C:29]#[N:30])[CH3:4].[H-].[Na+].N>O1CCOCC1>[NH2:30][C:29]1[CH:4]=[C:3]([N:2]([CH3:31])[CH3:1])[N:5]=[C:6]2[N:10]([C@@H:11]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:17]([OH:18])[C@H:12]3[OH:13])[CH:9]=[N:8][C:7]=12
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C#N)c2N=C(C)N(C)C)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)c1cc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
5-[1-(dimethylamino)-ethylideneamino]-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-imidazole-4-carbonitrile is reacted with sodium hydride in dioxane as described in Example 10 and the crude product is reacted with methanolic ammonia at room temperature over 18 hours. The mixture is concentrated to dryness and purified by silica gel chromatography to afford 7-amino-3-β-D-ribofuranosyl-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-5-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=2[CH:15]=1.[H][H]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][C:6]=2[CH:15]=1
Reactant: [H][H]
Reactant: COC(=O)C1=Cc2cc(Cl)ccc2OC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1COc2ccc(Cl)cc2C1
Reaction time: 8 h

Procedure:
700 mg of 5B was dissolved in 75 ml of ethyl acetate and the solution was treated with hydrogen (initial pressure of 30 psig), in the presence of a 10% palladium-on-carbon catalyst, for 8 hours. The reaction mixture then was filtered and stripped of solvent to give methyl 6-chloro-3,4-dihydro-2H-1-benzopyran-3-carboxylate (5C), as a yellow liquid, boiling point not determined.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(O[C:6](C)(C)[CH3:7])=O.[Cl:17][C:18]1[C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:43])=[CH:32][C:33]=3[O:35][CH:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)[N:28]=[CH:27][N:26]=2)=[C:22]2[O:44][CH2:45][O:46][C:21]2=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.N>C(Cl)Cl.C(OCC)C.C(O)C>[Cl:17][C:18]1[C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:43][CH2:6][CH3:7])=[CH:32][C:33]=3[O:35][CH:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)[N:28]=[CH:27][N:26]=2)=[C:22]2[O:44][CH2:45][O:46][C:21]2=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: CN1CCC(Oc2cc(O)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Agent: Cl
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCO
Solvent: ClCCl
Product: CCOc1cc(OC2CCN(C)CC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
A solution of di-tert-butyl azodicarboxylate (0.26 g) in methylene chloride (1 ml) was added dropwise to a stirred mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-(N-methylpiperidin-4-yloxy)quinazoline (0.12 g), ethanol (0.019 g), triphenylphosphine (0.15 g) and methylene chloride (2 ml) and the resultant mixture was stirred at ambient temperature for 1 hour. A 2M solution of hydrogen chloride in diethyl ether (3 ml) was added and the mixture was stirred at ambient temperature for 1.5 hours. Diethyl ether (1 ml) was added and the precipitate was isolated and dried under vacuum. The solid so obtained was dissolved in a 9:1 mixture of methylene chloride and a saturated methanolic ammonia solution. The mixture was filtered and the filtrate was evaporated. The residue was triturated under pentane and the resultant solid was isolated and dried under vacuum. There was thus obtained the title compound (0.092 g); NMR Spectrum: (CDCl3) 1.5 (t, 3H), 1.95–2.1 (m, 2H), 2.15–2.5 (m, 2H), 2.3 (s, 3H), 2.3–2.4 (m, 2H), 2.7 (br s, 2m), 4.15 (m, 2H), 4.6 (m, 1H), 6.05 (s, 2H), 6.5 (d, 1H), 6.7 (d, 1H), 6.8 (d, 1H), 6.95 (d, 1H), 8.5 (s, 1H), 9.25 (br s, 1H); Mass Spectrum: M+H+ 457 and 459.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[N:46]=[CH:45][C:44]3[C:39](=[C:40]([F:51])[CH:41]=[C:42]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH:43]=3)[C:38]2=[O:52])=[N:24][CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1)(=[O:19])[CH3:18]>>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[N:46]=[CH:45][C:44]3[C:39](=[C:40]([F:51])[CH:41]=[C:42]([C:47]([CH3:49])([CH3:48])[CH3:50])[CH:43]=3)[C:38]2=[O:52])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: Cn1cc(Nc2cc(Br)cn(C)c2=O)nn1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Product: CC(=O)OCc1c(-c2cc(Nc3cn(C)nn3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Yield: 49.9 %

Procedure:
Following the procedure in Example 147d, and starting with 149c (120 mg, 0.42 mmol, 1 eq.) and 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid (116c) (485 mg, 1.18 mmol, 2.8 eq.), afforded 149d as a yellow solid (120 mg, 50%). MS-ESI: [M+H]+ 573.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:20][CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[CH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15]C)=[O:14])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:20][CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[CH:9]\[C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(C=C(CCn2ccnc2)c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(/C=C(/CCn2ccnc2)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
A solution of Z isomer product from step D (0.64 g, 1.83 mmol) in MeOH (2 ml) was treated with 1N NaOH (2 ml). The resulting suspension was stirred at room temperature for 20 hrs and the acidity adjusted to pH 5 with 1N HCl. The solution was evaporated to dryness and the residue purified by chromatography isolute column (10 g, SiO2) with an eluent of dichloromethane/MeOH (9:1) to give 3-[(Z)-2-(4-fluorophenyl)-4-(imidazol-1-yl)-but-1-enyl]-benzoic acid 0.56 g, (91%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=4)[C:16]3=[O:32])=[CH:11][C:10]=2[CH3:33])=[N:6][CH:7]=1.[C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=1)#[CH:35].C(N(CC)CC)C.O>CN1CCCC1=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:31][O:30][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[O:28][CH3:29])[CH2:21][N:17]1[CH2:18][CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]3[CH:4]=[CH:3][C:2]([C:35]#[C:34][C:36]4[CH:41]=[CH:40][C:39]([C:42]([F:43])([F:44])[F:45])=[CH:38][CH:37]=4)=[CH:7][N:6]=3)=[C:10]([CH3:33])[CH:11]=2)[C:16]1=[O:32]
Reactant: COc1ccc(CN2CCCN(c3ccc(Oc4ccc(Br)cn4)c(C)c3)C2=O)cc1OC
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCCN(c3ccc(Oc4ccc(C#Cc5ccc(C(F)(F)F)cc5)cn4)c(C)c3)C2=O)cc1OC
Temperature: 115 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[4-(5-bromopyridin-2-yloxy)-3-methylphenyl]-3-(3,4-dimethoxybenzyl)tetrahydropyrimidin-2-one (0.3 g, 0.59 mmol) in N-methylpyrrolidone (10 mL) were added bis(triphenylphosphine)palladium dichloride (20 mg, 0.03 mmol), copper iodide (11 mg, 0.059 mmol), 4-ethynyl-α,α,α-trifluorotoluene (0.14 mL, 0.88 mmol) and triethylamine (0.14 mL, 10 mmol) under a nitrogen atmosphere. The resulting solution was stirred for 3 hours at 110 to 120° C. After being left to cool, water was added to the reaction solution. The resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then evaporated, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1→1:1), to thereby yield 0.28 g of the title compound.
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.[C:18](C#N)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[O:25]=[C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1
Reactant: N#CC(=O)c1ccccc1
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1nsc2nc3ccccc3n12
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.5 %

Procedure:
A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (6.0 g, 24.3 mmole) and benzoyl cyanide (6.36 g, 48.5 mmole) in 80 mL of dichloromethane was stirred at room temperature for 24 h. The precipitate was filtered and washed with dichloromethane. The crude product was recrystallized from acetone to give 6.48 g (96%) of 3-(oxophenylmethyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole as yellow crystals: mp 190-191° C.; 1H NMR (CDCl3)δ 8.35 (d, 3H), 7.82 (d, 1H), 7.73 (t, 1H), 7.59 (t, 2H), 7.50 (t, 1H), 7.36 (t, 1H) ppm; 13C NMR (CDCl3)δ 180.86, 163.69, 150.82, 146.70, 134.79, 134.34, 131.22 (2C), 129.46 (2C), 128.74, 125.82, 122.27, 119.49, 115.23 ppm; IR (KBr)ν 1671 cm-1 ; HRMS calcd for C15H9N3OS: 279.0466, found: 279.0475. Anal. Calcd for C15H9N3OS: C, 64.50;H, 3.25; N, 15.04. Found: C, 63.93;H, 3.10; N, 14.53.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6](=O)[C:7](=[CH:19]N(C)C)[CH2:8][N+:9]([O-:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[NH2:26][C:27]([NH2:29])=[S:28].C[O-].[Na+].O>CO>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:29]=[C:27]([SH:28])[N:26]=[CH:19][C:7]=3[CH2:8][N+:9]([O-:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: CN(C)C=C1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2C1=O
Reactant: NC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2-c2nc(S)ncc2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1.5 g (4 mmol) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one-2-oxide, 1.5 g (20 mmol) of thiourea and 5 ml of a 4M methanol solution of sodium methoxide in 30 ml of methanol was stirred at room temperature for 5 hr. The mixture was poured into water and extracted with ether. The aqueous solution was acidified with acetic acid and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue was triturated with methylene chloride to give an orange solid. Recrystallization from methylene chloride gave the product as orange crystals, mp 323°-325° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH:29]([CH2:32][CH3:33])[CH2:30][OH:31])[CH2:25][CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:13]=1>>[CH3:21][N:18]1[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][N:26]([C@@H:29]([CH2:32][CH3:33])[CH2:30][OH:31])[CH2:27][CH2:28]2)=[N:16][C:15]2[C:19]1=[N:20][C:12]([N:3]1[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]1[CH3:1])=[N:13][C:14]=2[N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: CCC(CO)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC1
Reactant: Cc1nc2ccccc2[nH]1
Product: CC[C@@H](CO)N1CCN(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and 2-(4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)butan-1-ol were reacted. The enantiomers were separated by SFC to give 382. LCMS m/z: 520.3 (MH+)
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH:8]([OH:19])[C:9]([F:18])([F:17])[C:10](O)([OH:15])[C:11]([F:14])([F:13])[F:12]>C1(C)C=CC=CC=1>[OH:19][CH:8]([CH:2]1[CH2:3][CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2)[C:9]([F:17])([F:18])[C:10](=[O:15])[C:11]([F:13])([F:14])[F:12]
Reactant: OC(C1CC2C=CC1C2)C(F)(F)C(O)(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(C(F)(F)F)C(F)(F)C(O)C1CC2C=CC1C2
Yield: 100 %

Procedure:
A mixture of 288 g of 1-(5-norbornene-2-yl)-2,2,4,4,4-pentafluorobutane-1,3,3-triol (synthesized according to [Synthetic example 1]) and 1500 g of toluene was heated under reflux for 2 hours, removing the water produced. After cooling, toluene was removed by evaporation under reduced pressure, and 270 g of 1-hydroxy-1-(5-norbornene-2-yl)-2,2,4,4,4-pentafluorobutane-3-one was obtained (quantitative yield).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]2[N:13]=[CH:12][NH:11][N:10]=2)[CH:3]=1.Cl[CH2:15][C:16](Cl)=[O:17].[OH-].[Na+].Cl>O1CCOCC1.N1C=CC=CC=1.C(OCC)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]2[NH:6][C:16](=[O:17])[CH2:15][N:10]3[N:11]=[CH:12][N:13]=[C:9]3[C:4]=2[CH:3]=1
Reactant: Nc1ccc(F)cc1-c1nc[nH]n1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C1Cn2ncnc2-c2cc(F)ccc2N1
Temperature: 12 °C
Reaction time: 0.08 h

Procedure:
5. 4.3 g of 4-fluoro-2-(1H-1,2,4-triazol-3-yl)aniline are dissolved in 200 ml of dioxan and 2.3 ml of absolute pyridine. The solution is stirred under argon and cooled to 12° C. A solution of 2.2 ml of chloroacetyl chloride in 8.0 ml of diethyl ether is then added dropwise thereto within 5 min. at 12° to 15° C. The resulting suspension is stirred at 10° to 12° C. for 15 min. and then treated within 5 min. with 28.8 ml of aqueous 2N sodium hydroxide solution. The mixture is stirred at room temperature overnight. The pH thereby drops to about 9. The mixture is adjusted to pH 8 with 3N hydrochloric acid and the solution is evaporated at about 40° C. in a vacuum. The residue in 150 ml of water and 5 ml of ethyl acetate is stirred at 15° C. for 30 min. The crystals are then filtered off, washed with cold water and dried at 50° C. in a vacuum. 3.78 g of 10-fluoro-5H-[1,2,4]triazolo[1,5-d][1,4]benzodiazepin-6(7H)-one of m.p. 232.5° to 238° C. are obtained. Further substance can be obtained from the aqueous phase by evaporation to dryness in a vacuum, The residue is stirred in 10 ml of trifluoroacetic acid at room temperature overnight. The mixture is evaporated in a vacuum, the residue is taken up in 60 ml of saturated aqueous sodium carbonate solution and 2 ml of ethyl acetate, stirred at room temperature for 1 h. and the crystals are then filtered off. A further 0.5 g of 10-fluoro-5H-[1,2,4]triazolo[1,5-d][1,4]benzo-diazepin-6(7H)-one is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([OH:6])=O.[NH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:12][C:7]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[O:6]
Reactant: Nc1ccncc1
Reactant: O=C(O)c1c(Cl)cc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccncc1)c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
A mixture of 2,4,6-trichlorobenzoic acid (224 mg, 10 mmol), 4-aminopyridine (141 mg, 1.5 mmol), HATU (1140 mg, 3 mmol), and DIPEA (646 mg, 5 mmol) in 5 mL anhydrous DMF was stirred under nitrogen at room temperature overnight. The reaction mixture was poured into ice-water (20 mL) and extracted EtOAc (2×50 mL). The combined organics were evaporated to dryness in vacuum and the residue was purified by silica gel column chromatography (EtOAc) to afford the desired product (72 mg, yield: 24%). 1HNMR: (CD3OD-d4, 400 MHz): δ 8.38 (d, J=6.0 Hz, 2H), 7.65 (d, J=6.0 Hz, 2H), 7.52 (s, 2H). LCMS (ESI) m/z: 301.1 [M+H+].
Reaction SMILES: [OH:1][CH:2]([CH2:12][OH:13])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:21][S:22]([CH2:24][CH2:25][C:26](Cl)=[O:27])=[O:23]>CN(C)C=O>[OH:1][CH:2]([CH2:12][OH:13])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:26](=[O:27])[CH2:25][CH2:24][S:22]([CH3:21])=[O:23])=[CH:7][CH:6]=1
Reactant: Nc1ccc(OCC(O)CO)cc1
Reactant: CS(=O)CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)CCC(=O)Nc1ccc(OCC(O)CO)cc1
Yield: 80.4 %

Procedure:
A 1.83 g quantity of 4-(2,3-dihydroxypropoxy)aniline and 1.53 g of triethylamine were dissolved in 30 ml of dimethylformamide. To the solution was added 1.55 g of 3-(methylsulfinyl)propionyl chloride with ice cooling. The same subsequent procedure as in Example 2 was repeated and recrystallization from ethanol was effected, giving 2.42 g of N-[4-(2,3-dihydroxypropoxy)phenyl]-3-(methylsulfinyl)propionamide in a yield of 80.4%. M.p. 139° to 141° C.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:27]=[CH:26][C:21]([CH2:22][CH2:23][C:24]#N)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.CC[O:31]CC>>[CH2:1]([NH:17][C:18]1[CH:27]=[CH:26][C:21]([CH:22]=[CH:23][CH:24]=[O:31])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC#N)cc1
Reactant: CCOCC
Agent: Cl
Product: CCCCCCCCCCCCCCCCNc1ccc(C=CC=O)cc1
Reaction time: 1 h

Procedure:
A solution of 10.0 g. of 4-hexadecylaminohydrocinnamonitrile in 100 ml. of dry ether is added rapidly to a mixture of 10.2 g. of anhydrous stannous chloride and 80 ml. of ether which has been saturated with dry hydrogen chloride for 2 hours. Dry hydrogen chloride is again bubbled through the reaction mixture which is stirred for 1 hour and allowed to stand for 20 hours. The ethereal solution is decanted from the semi-solid product which is washed again with ether and then treated with water and heated to reflux for 3 hours. Cooling and extraction of the reaction mixture with ether provides 4-(hexadecylamino)cinnamaldehyde.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([OH:31])[CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:32]1(O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:17][CH2:18]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Oc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc4c(c3)CCC4)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccccc3)c3ccc4c(c3)CCC4)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(2,3-dihydro-1H-inden-5-yl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenol: ESMS m/e: 497.2 (M+H)+.