Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[Si](C)(C)C.[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)[NH:14][CH:13]=1)=O.C(#N)C.C([BH3-])#N.[Na+]>O>[Cl:6][CH2:7][CH2:8][CH2:9][CH2:10][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)[NH:14][CH:13]=1
Reactant: N#Cc1ccc2[nH]cc(C(=O)CCCCl)c2c1
Agent: C[Si](C)(C)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc2[nH]cc(CCCCCl)c2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Chlorotrimethylsilane (137 g) was added to a mixture of 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile (50 g) and acetonitrile (750 ml) at 25-30° C. The resulting mixture was cooled to 0° C., followed by portion wise addition of sodium cyanoborohydride (75 g) while maintaining the temperature at 0-5° C. during the time period of 30 minutes to 1 hour. The resulting mass was stirred for 1 hour at the same temperature. The temperature of the reaction mass was then raised to 25-30° C., followed by stirring for 6-16 hours at the same temperature. The reaction mass was slowly poured into water (5 Lt) at 25-30° C. and then stirred for 30 minutes to 1 hour at the same temperature. The separated solid was filtered and then dissolved in dichloromethane (900 ml) and the resulting organic layer was washed with 20% sodium chloride solution (400 ml×10). The resulting organic layer was subjected to carbon treatment, followed by distillation of the organic layer at 50-55° C. under vacuum to produce the titled compound as a residue. The resulting residue was dissolved in 5% aqueous methanol (4 to 5 times to the weight of the residue), followed carbon treatment at 50-55° C. The resulting filtrate was finally cooled to 25-30° C., the separated solid was filtered, washed with chilled 5% aqueous methanol (50 ml) and then dried the material at 60-65° C. to produce 31 g of 3-(4-chlorobutyl)-1H-indole-5-carbonitrile (First Crop). The resulting filtrate was cooled to 0-5° C. and then stirred for 30 minutes at the same temperature. The separated solid was filtered, washed with chilled 5% aqueous methanol and then dried the material at 60-65° C. to produce 10.5 g of the titled compound (Second Crop) (Purity by HPLC: 99.3; Total yield: 87.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:17][C:18]=1[CH3:19])[CH:6]=[O:7].OC1C=CC(C=O)=CC=1OC.CC1OC(C2C=CC=CC=2)=NC=1CCOS(C)(=O)=O.[CH2:56]([C@H:63]1[CH2:67][O:66][C:65](=[O:68])[N:64]1[C:69](=[O:74])[CH2:70][O:71][CH2:72][CH3:73])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC>>[CH2:56]([C@H:63]1[CH2:67][O:66][C:65](=[O:68])[N:64]1[C:69](=[O:74])[C@@H:70]([O:71][CH2:72][CH3:73])[C@H:6]([OH:7])[C:5]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: COc1cc(C=O)ccc1OCCc1nc(-c2ccccc2)oc1C
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Agent: COc1cc(C=O)ccc1O
Agent: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)c(OC)c1

Procedure:
In analogy to the procedures described in examples 11 a] to 11 c], 3-methoxy-4-[2-(5-methyl2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (prepared from 4-hydroxy-3-methoxy-benzaldehyde and methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester in analogy to the procedure described in example 114 b]) was reacted with (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one and nBu2BOTf to yield (S)-4-benzyl-3-((2S,3R) -2-ethoxy-3-hydroxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one (according to NMR, one of the four isomers is strongly predominating; the configuration was tentatively assigned as 2S, 3R according to Tetrahedron Asymmetry 1999, 1353). Reduction of (S)-4-benzyl-3-((2S,3R)-2-ethoxy-3-hydroxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one with triethylsilane in trifluoroacetic acid then gave (S)-4-benzyl-3-((2S)-2-ethoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one. The (S)-4-benzyl-3-((2S)-2-ethoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one was subsequently saponified with 1N NaOH in THF to yield (2S)-2-ethoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless solid. The enantiomeric excess was judged according to chiral HPLC (Chiralcel-OJ) to be 98.7%.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:9]=[C:10]([CH3:24])[C:11]3[CH:15]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:14][B:13]([OH:22])[C:12]=3[CH:23]=2)=[N:4][N:3]=1.CCN(CC)CC.[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([NH:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:9]=[C:10]([CH3:24])[C:11]3[CH:15]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:14][B:13]([OH:22])[C:12]=3[CH:23]=2)=[N:4][N:3]=1)(=[O:34])[CH3:33]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(N)s3)cc(C)c21
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(NC(C)=O)s3)cc(C)c21
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(6-(5-amino-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (70 mg, 0.2 mmol) in DCM (10 mL) was added Et3N (0.11 ml) and acetic anhydride (0.08 mL). The mixture was stirred at room overnight. The mixture was concentrated and precipitate was filtered and washed with a mixture of hexane and ethyl acetate to afford the product as a light yellow solid (59 mg). 1H NMR (DMSO-d6) δ 12.44 (s, 1H), 9.28 (s, 1H), 7.4 (s, 1H), 7.26 (s, 1H), 5.54 (d, 1H), 4.03 (q, H) 3.14 (dd, 1H), 2.48 (d, 1H), 2.35 (s, 3H), 2.13 (s, 3H), 1.11 (t, 3H); MS found: (M+H)+=392.1.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:34]([O:38][C:39]([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55](O)=[O:56])=[O:40])([CH3:37])([CH3:36])[CH3:35].[Cl:58][C:59]1[N:63]([CH3:64])[N:62]=[CH:61][C:60]=1[NH2:65].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:58][C:59]1[N:63]([CH3:64])[N:62]=[CH:61][C:60]=1[NH:65][C:55]([C:43]1[N:44]=[C:45]([C:47]2[C:48]([F:54])=[CH:49][CH:50]=[CH:51][C:52]=2[F:53])[S:46][C:42]=1[NH:41][C:39](=[O:40])[O:38][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:56]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
A solution of PyBOP (4.08 g, 7.84 mmol) and 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (2.20 g, 6.16 mmol) in DCM (50 mL) was stirred at room temperature for 30 min. A solution of 5-chloro-1-methyl-1H-pyrazol-4-amine (737 mg, 5.60 mmol) and DIPEA (1.6 mL, 9.0 mmol) in DCM (50 mL) was then added and the mixture stirred at room temperature for 16 hr. The mixture was diluted with DCM (50 mL) and washed with water (3×50 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel chromatography (0-100% EtOAc/isohexane) followed by trituration with MeCN gave tert-butyl 4-(5-chloro-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate as an off-white solid (1.71 g, 65%). 1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H), 8.73 (s, 1H), 8.06 (s, 1H), 7.42-7.33 (m, 1H), 7.09-7.01 (m, 2H), 3.87 (s, 3H), 1.54 (s, 9H).
Reaction SMILES: CN(C[N:5]=[CH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22]Br)=[CH:16][CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH2:5][CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([CH2:22][CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[CH2:11][CH2:12]1
Reactant: Fc1ccc(OCCBr)cc1
Reactant: CN(C)CN=CC1CCNCC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: NCC1CCN(CCOc2ccc(F)cc2)CC1

Procedure:
In a similar manner to Example 3, a mixture of 4-(dimethylaminomethyliminomethyl)piperidine (6.42 g), 2-bromoethyl 4-fluorophenyl ether (8.3 g), triethylamine (5.3 ml) and toluene (20 ml) was heated on a steam bath for 16 hours to give 4-aminomethyl-1-[2-(4-fluorophenoxy)ethyl]piperidine as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@@H:5]([NH2:18])[C@@H:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[OH:7])[CH3:2].Cl.C(O[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=N)C.C(N(CC)CC)C>O>[CH2:1]([O:3][C:4]([C@@H:5]1[C@@H:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[O:7][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:18]1)=[O:19])[CH3:2]
Reactant: CCOC(=N)c1ccccc1
Reactant: CCOC(=O)[C@@H](N)[C@H](O)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1N=C(c2ccccc2)O[C@@H]1c1ccc(S(C)(=O)=O)cc1

Procedure:
(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound VIc) (10 g, 0.0348 moles) is reacted at about 0° C. in a reaction vessel with benzenecarboximidic acid ethyl ester hydrochloride (Compound IV hydrochloride salt wherein R2 is phenyl and R4 is ethyl) (about 7.1 g, 0.03828 moles) in 1,2-dichloromethane (about 650 mL) containing triethylamine (3.9 g, 0.03828 moles). Thereafter, water is added (about 500 mL). Next, the organic layer is separated and washed with dilute hydrochloric acid (about 1 N) and dilute sodium bicarbonate (about 1N). The washed organic layer is dried over anhydrous sodium sulfate. The dried organic layer is heated to evaporate the 1,2-dichloromethane to yield (4S-trans)-4,5-dihydro-5-[4-(methylsulfonyl)phenyl]-2-phenyl-4-oxazolecarboxylic acid ethyl ester (Compound IIIk).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:27]1[C:28]([F:38])=[CH:29][C:30]([F:37])=[C:31]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:32]=1>>[F:37][C:30]1[CH:29]=[C:28]([F:38])[C:27]([C:2]#[C:1][C:3]2[N:7]3[CH:8]=[C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)[CH:10]=[C:11]([C:12]([F:14])([F:13])[F:15])[C:6]3=[N:5][CH:4]=2)=[CH:32][C:31]=1[S:33]([NH2:36])(=[O:34])=[O:35]
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Product: NS(=O)(=O)c1cc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)cn23)c(F)cc1F

Procedure:
The title compound was prepared from 3-ethynyl-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.18) (310 mg, 0.88 mmol) and 5-Bromo-2,4,-difluorobenzenesulfonamide (226 mg, 0.83 mmol) according to general procedure II. Obtained as an off-white solid (56 mg, 12%). MS (ISP) 546.2 [(M+H)+]; mp 306–307° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CON(C)C(=O)Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)Cc1cccc(-c2ccccc2)c1
Temperature: 80 °C
Yield: 91.6 %

Procedure:
The mixture of 2-(3-bromophenyl)-N-methoxy-N-methylacetamide (2.0 g, 7.7 mmol), phenylboronic acid (1.42 g, 11.6 mmol), 1-1′-bis(diphenylphosphino)derrocene palladium dichloride (500 mg, 0.77 mmol), and saturated aqueous sodium carbonate solution (1 mL) in N,N-dimethylformamide (20 mL) was heated at 80° C. under N2 overnight. The mixture was poured into water, extracted with EA, dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE: EtOAc=30:1-10:1) to afford 2-(biphenyl-3-yl)-N-methoxy-N-methylacetamide (1.8 g, yield 94.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH:19]([CH3:20])[C:18]2[C:13](=[N:14][C:15]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][CH:17]=2)[N:12]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])[C:11]1=[O:36].[OH-:37].[Na+].OO.O>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH:19]([CH3:20])[C:18]2[C:13](=[N:14][C:15]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:16][CH:17]=2)[N:12]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]([NH2:32])=[O:37])[C:11]1=[O:36]
Reactant: [OH-]
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4ccccc4)ncc3C2C)c(F)c1
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(N2C(=O)N(c3cccc(C(N)=O)c3)c3nc(Nc4ccccc4)ncc3C2C)c(F)c1
Reaction time: 0.75 h

Procedure:
(±)-3-[3-(2-Fluoro-4-methoxy-phenyl)-4-methyl-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile (0.80 g; 1.67 mmol) (from Example 9b supra) was dissolved in dimethyl sulfoxide (25 mL). Most of the material went into solution. Aqueous sodium hydroxide (1.0 N; 3.34 mL; 3.34 mmol) was added followed by hydrogen peroxide (30% in water; 0.51 mL, 4.99 mmol) at room temperature. After stirring for 45 minutes, water was added and a white solid precipitated out of solution. The solid was collected, washed with water and dried. Dissolution of the solid required significant volumes of dichloromethane-methanol-acetonitrile. The solvent mixture was then distilled off until solid began to crystallize out of solution. Cooling and filtration gave (±)-3-[3-(2-fluoro-4-methoxy-phenyl)-4-methyl-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzamide as a white solid. (Yield 0.56 g; 67.6%).
Reaction SMILES: Br[C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3.CCCC[N+](CCCC)(CCCC)CCCC.[OH-].O.CC1C=CC2C(=C([OH:63])C=CC=2)N=1>CS(C)=O.[Cu]I>[NH2:25][C@@H:20]([CH2:21][CH:22]([CH3:23])[CH3:24])[CH2:19][O:18][C:17]1[C:2]([OH:63])=[CH:3][C:4]2[C:13]3[C:8](=[CH:9][N:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[CH:16]=1
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)C[C@H](N)COc1cc2c(cc1O)c1ccncc1c(=O)n2C
Temperature: 120 °C
Reaction time: 14 h
Yield: 55 %

Procedure:
A mixture of (S)-tert-butyl (1-((9-bromo-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.05 g, 0.099 mmol) (as prepared in Ex. 3, Part A), tetra-N-butylammonium hydroxide. 30H2O (0.463 g, 1.784 mmol) and water (1.5 mL) was added over 0.1 h to a stirred solution of copper(I) iodide (1.89 mg, 9.91 μmol) and 2-methyl 8-quinolinol (3.16 mg, 0.020 mmol) in DMSO (1 mL). The reaction mixture was heated to 120° C. and stirred for 14 h. The resulting mixture was cooled to room temperature. The crude product was purified by reverse phase HPLC (10 mM ammonium acetate) to afford a (S)-8-((2-amino-4-methylpentyl)oxy)-9-hydroxy-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (0.004 g, 0.011 mmol, 12% yield) as a brown solid. LC/MS (ESI) m/e 342.2 [(M+H)+, calcd for C19H24N3O3, 342.2]; HPLC retention time (method F): tR=1.62 min. HPLC retention time (method B): tR=5.88 min. 1H NMR (400 MHz, CD3OD) δ 9.39 (s, 1H), 8.62 (d, J=6.00 Hz, 1H), 7.96 (d, J=5.60 Hz, 1H), 7.56 (s, 1H), 6.73 (s, 1H), 3.80 (s, 3H), 3.67-3.70 (m, 1H), 3.49-3.59 (m, 2H), 1.81-1.85 (m, 1H), 1.56-1.63 (m, 2H), 1.05 (d, J=6.80 Hz, 3H), 0.98 (d, J=6.80 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:63]1([NH:69][CH2:70][C@H:71]2[CH2:75][CH2:74][CH2:73][NH:72]2)[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:72]1[CH2:73][CH2:74][CH2:75][C@@H:71]1[CH2:70][NH:69][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1ccc(NC[C@H]2CCCN2)cc1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@@H]3CNc3ccccc3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (R)-2-(phenylaminomethyl)-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]1[CH:30]=[CH:29][C:17]([CH2:18][C:19]2[CH:28]=[C:27]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=[CH:26]3)[CH:20]=2)=[CH:16][C:15]=1Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:32]([O:39][C@@H:40]1[C@@H:46]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@H:45]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@@H:44]([CH2:63][O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[O:43][C:41]1=[O:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH:20]1[C:21]2[C:27]([CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:28][C:19]=1[CH2:18][C:17]1[CH:29]=[CH:30][C:14]([O:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:15]([C:41]2([O:43][C@H:44]([CH2:63][O:64][CH2:65][C:66]3[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=3)[C@@H:45]([O:55][CH2:56][C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[C@H:46]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C@H:40]2[O:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[OH:42])[CH:16]=1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: Brc1cc(Cc2cc3cccccc-3c2)ccc1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2cc(Cc3cc4cccccc-4c3)ccc2OCc2ccccc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 0.17 h
Yield: 468.1 %

Procedure:
A 1.6 M n-hexane solution of n-butyl lithium (0.32 ml) was added dropwise to a solution of 2-[4-(benzyloxy)-3-bromobenzyl]azulene (0.17 g) in THF (3.0 ml) at −55° C. and the mixture was stirred at the same temperature for 10 minutes. A solution of 2,3,4,6-tetra-O-benzyl-glucono-1,5-lactone (0.12 g) in THF (3.0 ml) was added dropwise to the reaction mixture and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain 1-C-[5-(azulen-2-ylmethyl)-2-(benzyloxy)phenyl]-2,3,4,6-tetra-O-benzyl-D-glucopyranose (0.9 g).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:22])[CH2:20][CH3:21])=[CH:15][CH:14]=1>C1COCC1>[CH2:20]([C:19]1([C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=2)[CH2:8][O:22]1)[CH3:21]
Reactant: C[S+](C)C
Reactant: CCC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCC1(c2ccc(F)cc2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(4-fluorophenyl)propan-1-one (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH:11]([OH:22])[CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([O:22][CH:11]([CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:9][CH2:8]/[CH:7]=[CH:6]\[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC/C=C\CCCC(O)CCC/C=C\CCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution (0° C.) of 6Z,15Z)-henicosa-6,15-dien-11-ol 4 (5.6 g, 18.2 mmol) and triethylamine (3.8 mL, 27.2 mmol) in anhydrous dichloromethane (50 mL) was slowly added methanesulfonyl chloride (2.1 mL, 27.2 mmol). The reaction mixture was stirred for 2 hours at room temperature then diluted with dichloromethane (50 mL). The solution was washed with saturated sodium bicarbonate (3×25 mL) then the combined aqueous washes were extracted with dichloromethane (50 mL). The combined dichloromethane extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The pale yellow oil was filtered through a pad of silica (100% DCM) to afford (6Z,15Z)-henicosa-6,15-dien-11-yl methanesulfonate 5 as a crude colorless oil (7.6 g). Rf 0.8 (100% CH2Cl2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([C:11]1C=CC=C2[C:12]=1[CH2:13][CH2:14]C2=O)(O)=[O:9].Cl.CNC>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:8](=[O:9])[CH2:11][CH2:12][C:13]#[CH:14]
Reactant: O=C(O)c1cccc2c1CCC2=O
Reactant: Nc1ccccn1
Agent: CNC
Agent: Cl
Product: C#CCCC(=O)Nc1ccccn1

Procedure:
The desired product was prepared by substituting 4-pentynoic acid and 2-aminopyridine for 4-carboxy-1-indanone and dimethylamine hydrochloride, respectively, in Example 40. MS (APCI(+)) m/e 175.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH:43]1([C:46]2[O:50][N:49]=[CH:48][C:47]=2[C:51](O)=[O:52])[CH2:45][CH2:44]1>CN(C=O)C>[CH:43]1([C:46]2[O:50][N:49]=[CH:48][C:47]=2[C:51]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)[CH2:2]2)=[O:52])[CH2:45][CH2:44]1
Reactant: c1cncc(C2CCNC2)c1
Reactant: O=C(O)c1cnoc1C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnoc1C1CC1)N1CCC(c2cccnc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
A solution of 3-pyrrolidin-3-yl-pyridine (15 mg, 0.1 mmol), TBTU (48 mg, 0.15 mmol, 1.5 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.1 mmol) in DMF (0.6 mL) was added to 5-cyclopropylisoxazole-4-carboxylic acid (15 mg, 0.1 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound (12 mg). MS (ESI, pos. ion) m/z calcd for C16H17N3O2: 283.1321, found 283.1316.