Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:11]([C:12](O)=[O:13])=[C:10]([CH2:15][N:16]3[CH2:21][CH2:20][C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)[N:9]=[CH:8]2)=[CH:4][CH:3]=1.C1N=C[N:38](C(N2C=NC=C2)=O)C=1.N.C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([C:12]([NH2:38])=[O:13])=[C:10]([CH2:15][N:16]3[CH2:21][CH2:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:18][CH2:17]3)[N:9]=[CH:8]2)=[CH:34][CH:35]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1c(CN2CCC(c3ccccc3)(c3ccccc3)CC2)ncn1Cc1ccc(Cl)cc1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1c(CN2CCC(c3ccccc3)(c3ccccc3)CC2)ncn1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
The product of Example 19 (0.03 g) was dissolved in N,N-dimethylformamide (2 ml), N,N-carbonyldiimidazole (0.020 g) was added and the solution heated at 60° C. for 2 hours and cooled. Aqueous ammonia solution (1 ml) was added and the mixture stirred at room temperature for 16 hours. Brine and ethyl acetate were added, the organic phase was separated, dried and the solvent removed by evaporation to give a solid. Trituration under ether gave the product as a solid (0.014 g), m.p. 227-228° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:5]=[C:6]([C@H:9]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[N:16](COCC[Si](C)(C)C)[CH:15]=2)=[O:13])[CH3:10])[O:7][CH:8]=1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH2:3][C:4]1[N:5]=[C:6]([C@H:9]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[NH:16][CH:15]=2)=[O:13])[CH3:10])[O:7][CH:8]=1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1nc(CC#N)co1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1nc(CC#N)co1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyanomethyl-oxazol-2-yl)-ethyl]-amide (36 mg, 0.063 mmol) was dissolved in dichloromethane (0.4 ml) and trifluoroacetic acid (0.20 ml, 2.6 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.4 ml) and ethylenediamine (0.26 ml, 3.8 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resultant suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 18 mg (65%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyanomethyl-oxazol-2-yl)-ethyl]-amide as an off-white powder. MS: (M+Na)+=467; 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 12.93 (br. s., 1H), 9.12 (s, 1H), 8.66 (d, J=8.3 Hz, 1H), 8.50 (s, 1H), 8.46 (dd, J=8.9, 5.4 Hz, 1H), 8.06 (t, J=1.0 Hz, 1H), 7.69 (dd, J=9.7, 2.1 Hz, 1H), 7.12 (td, J=9.0, 2.3 Hz, 1H), 5.44-5.56 (m, 1H), 4.15 (s, 3H), 3.92 (d, J=1.3 Hz, 2H), 1.68 (d, J=7.0 Hz, 3H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(OC([N:33]1[CH:42]([CH2:43][N:44]([CH2:57][CH2:58][O:59][CH3:60])[CH:45]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=2)C([O-])=O)[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1)=O)(C)(C)C.[Li+]>>[ClH:56].[ClH:56].[ClH:56].[ClH:56].[Cl:56][C:53]1[CH:52]=[CH:51][C:50]([CH2:49][CH:45]([N:44]([CH2:57][CH2:58][O:59][CH3:60])[CH2:43][CH:42]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][NH:33]2)[C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:12][CH2:13]2)=[O:7])=[CH:55][CH:54]=1
Reactant: COCCN(CC1Cc2ccccc2CN1C(=O)OC(C)(C)C)C(Cc1ccc(Cl)cc1)C(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN2CCCC2)CC1
Agent: [Li+]
Product: COCCN(CC1Cc2ccccc2CN1)C(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2CN2CCCC2)CC1
Product: Cl

Procedure:
4-(2-Pyrrolidin-1-ylmethyl-phenyl)-piperazine-1-carboxylic acid t-butyl ester was deprotected and then the resulting amine hydrochloride (0.10 gm, 0.30 mmol) was coupled with lithium 2-[(2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-isoquinolin-3-ylmethyl)-(2-methoxy-ethyl)-amino]-3-(4-chloro-phenyl)-propionate (0.23 gm, 0.45 mmol). The mixture was chromatographed to obtain the crude coupled product [MS (m/z, ES+): 730.4], which was deprotected to give about 0.068 g of the final compound as brown solids. MS (m/z, ES+): 630.3
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]3[CH2:12][S:13][CH2:14][C:10]3=[C:9]([C:15]#[N:16])[CH:8]=2)[CH:2]=1.[OH-].[K+].C([OH:21])C.C>C(O)(C)(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]3[CH2:12][S:13][CH2:14][C:10]3=[C:9]([C:15]([NH2:16])=[O:21])[CH:8]=2)[CH:2]=1
Reactant: CCO
Reactant: N#Cc1cc(-c2cccnc2)n2c1CSC2
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: NC(=O)c1cc(-c2cccnc2)n2c1CSC2
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A suspension of 5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carbonitrile (11.35 g) and of potassium hydroxide powder (14 g) in tert-butyl alcohol (100 cc) is heated at 85° C. for 1 hour. After 16 hours' stirring at a temperature of about 20° C., the reaction mixture is poured into distilled water (2 liters). The suspension is stirred at a temperature of about 20° C. for 15 minutes and then the crystals which have appeared are separated off by filtration, washed 8 times with distilled water (1,200 cc in total) and then 3 times with ethanol (150 cc in total) and are dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. A crude product (10.5 g) is thus obtained which is combined with a product (3.9 g) prepared in the same manner in an earlier operation and dissolved in boiling ethanol (850 cc). The solution is treated with decolourising charcoal (0.5 g) and filtered hot. The filtrate is cooled at a temperature of about 4° C. for 3 days. The crystals which have appeared are separated off by filtration, washed 3 times with ethanol (30 cc in total) cooled to a temperature of about 4° C. and are dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. 5-(3-Pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (11.3 g) is thus obtained in the form of cream crystals melting at 215° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1OCCCC(O)=O)=[O:5])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O.[OH:53][C:54]1C2N=NNC=2[CH:57]=[CH:56][CH:55]=1.CN1CCOCC1.[NH:70]1[C:78]2[CH2:77][CH2:76][NH:75][CH2:74][C:73]=2[N:72]=[C:71]1[CH:79]([C:81]1[NH:82][C:83]2[CH:89]=[C:88]([NH:90][C:91]([NH2:93])=[NH:92])[CH:87]=[CH:86][C:84]=2[N:85]=1)[CH3:80]>CN(C)C=O>[NH:90]([C:88]1[CH:87]=[CH:86][C:84]2[NH:85][C:81]([CH:79]([C:71]3[NH:70][C:78]4[CH2:77][CH2:76][N:75]([C:54](=[O:53])[CH2:55][CH2:56][CH2:57][C:7]5[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=5[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:74][C:73]=4[N:72]=3)[CH3:80])=[N:82][C:83]=2[CH:89]=1)[C:91]([NH2:93])=[NH:92]
Reactant: CC(c1nc2c([nH]1)CCNC2)c1nc2ccc(NC(=N)N)cc2[nH]1
Reactant: CCOC(=O)c1ccccc1OCCCC(=O)O
Reactant: Oc1cccc2[nH]nnc12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccccc1CCCC(=O)N1CCc2[nH]c(C(C)c3nc4cc(NC(=N)N)ccc4[nH]3)nc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture comprising 4-(2-ethoxycarbonylphenoxy)butyric acid (155 mg, 0.61 mmol), PyBOP (360 mg, 0.69 mmol), hydroxybenztriazole hydrate (87 mg, 0.64 mmol), N-methylmorpholine (0.16 mL, 0.92 mmol) and dimethylformamide (2.5 mL) was stirred at room temperature for 10 minutes and then N-{2-[1-(4,5,6,7-tetrahydroimidazo[4,5-c]pyridin-2-yl)ethyl]-3H-benzimidazol-5-yl }guanidine (203 mg, 0.63 mmol) was added. The mixture was stirred for 3 hours at room temperature and concentrated in vacuo. The residue was dissolved in 5% aqueous acetonitrile and the product purified by preparative reverse phase HPLC. The combined pure fractions were then lyophillized to provide ethyl 2-(4-{2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl}-4-oxobutyl)benzoate; LRMS (BioIon): calculated for C29H34N8O4: 558.6; Found: 559.3.
Reaction SMILES: C(NC(C)C)(C)C.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[N:10]=1.[CH3:16][CH2:17][O:18][C:19]([C@H:21]1[CH2:25][CH2:24][C:23](=[O:26])[N:22]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:20].O>O1CCCC1.C([Li])CCC>[C:30]([O:29][C:27]([NH:22][C@H:21]([CH2:25][CH2:24][C:23]([C:14]1[C:9]([F:8])=[N:10][C:11]([F:15])=[CH:12][CH:13]=1)=[O:26])[C:19]([O:18][CH2:17][CH3:16])=[O:20])=[O:28])([CH3:31])([CH3:33])[CH3:32]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1cccc(F)n1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(F)nc1F)NC(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (0.653 mL) in tetrahydrofuran (30 mL), n-butyl lithium (1.57 M solution in hexane, 2.97 mL) was added at −78° C. over five minutes, and the reaction solution was stirred at the same temperature for 20 minutes. 2,6-Difluoropyridine (0.388 mL) was added dropwise to the solution at −78° C., and the reaction solution was stirred at −78° C. for three hours. A solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (1.0 g) in tetrahydrofuran (5.0 mL) was added dropwise to this solution at −78° C., and the reaction solution was stirred at 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 1.2 g of the title compound as a pale yellow oil. The property values of the compound are as follows.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1.Cl.ClC1C=CC(C[C@@H](C2C=CC=CC=2)[C@@H](N)C)=CC=1.[CH3:40][C:41]1([C:51](O)=[O:52])[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[O:43][CH2:42]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C@@H:9]([C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)[C@@H:10]([NH:12][C:51]([C:41]2([CH3:40])[CH2:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:43][CH2:42]2)=[O:52])[CH3:11])=[CH:15][CH:16]=1
Reactant: CC1(C(=O)O)COc2ccccc2C1
Reactant: CC(N)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: C[C@H](N)[C@@H](Cc1ccc(Cl)cc1)c1ccccc1
Agent: Cl
Product: C[C@H](NC(=O)C1(C)COc2ccccc2C1)[C@@H](Cc1ccc(Cl)cc1)c1ccccc1

Procedure:
The title compounds were prepared as a 1:1 mixture of diastereomers following the procedures described for Examples 5 and 6 substituting 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride salt (Reference Example 1) with N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-amine hydrochloride (Reference Example 3) and substituting 1,2,3,4-tetrahydro-2-naphthoic acid with 3-methylchromane-3-carboxylic acid (Reference Example 9). LC-MS: m/e 434 (M+H)+ (4.06 min).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
Oxalyl chloride (9.0 mL, 100 mmol) was added to a solution of DMSO (10.5 mL, 150 mmol) in 80 mL of CH2Cl2 at −78° C., under a nitrogen atmosphere. The solution was stirred for 20 min at −78° C., tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (9.9 g, 49 mmol) was added, and the resultant solution stirred at −78° C. for 20 min. Triethylamine (28 mL, 200 mmol) was added to the reaction solution, the dry ice-acetone bath was removed, and the resultant solution was allowed to stir for two hours, slowly warming to ambient temperature. The reaction solution was quenched with brine, the phases were separated, and the organic phase was washed with 1 M KH2PO4 and saturated NaHCO3. The organic solution was then dried over Na2SO4, filtered, and concentrated to an orange oil. This oil was then dissolved in heptane, filtered through a plug of silica gel eluting with heptane, and the filtrate was concentrated to yield tert-butyl (2R)-2-formylpyrrolidine-1-carboxylate (7.87 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].[F:11][C:12]([F:16])([F:15])CI.[F-].[Cs+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[O:10][C:12]([F:16])([F:15])[F:11]
Reactant: FC(F)(F)CI
Reactant: Oc1cc(F)c(F)cc1Br
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Product: Fc1cc(Br)c(OC(F)(F)F)cc1F
Temperature: 120 °C
Yield: 52.4 %

Procedure:
A mixture of 2-bromo-4,5-difluoro-phenol (1.0 g, 4.8 mmol), 1,1,1-trifluoro-2-iodo-ethane (706 mg, 7.2 mmol) and CsF (882 mg, 5.8 mmol) in DMSO (20 mL) was heated at 120° C. overnight. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographed using hexane/ethyl acetate (10:1) to give the title compound (697 mg, 50%). 1HNMR (500 MHz, CDCl3) δ ppm 4.36 (q, J=7.93 Hz, 2H) 6.85 (dd, J=10.98, 7.02 Hz, 1H) 7.43 (t, J=8.85 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][OH:13])=[CH:10][O:9][C:8]=2[Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>O1CCCC1>[C:28]([O:13][CH2:12][C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([Si:14]([CH2:17][CH3:18])([CH2:19][CH3:20])[CH2:15][CH3:16])[O:9][CH:10]=1)(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CC[Si](CC)(CC)c1occ(CO)c1-c1ccccc1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)OCc1coc([Si](CC)(CC)CC)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-phenyl-2-triethylsilyl-4-furanmethanol (345 mg, 1.20 mmol) and triethylamine (182 mg, 1.80 mmol) in tetrahydrofuran (15 ml) at 0 degrees under argon was added lauroyl chloride (786 mg, 3.60 mmol). This solution was allowed to warm gradually to room temperature. After stirring an additional 2 hours the white precipitate was filtered off. The filtrate was taken up into ethyl ether, washed with saturated ammonium chloride, saturated sodium bicarbonate, H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by flash chromatography on silica using 2% ethyl ether/hexanes to give the title compound.
Reaction SMILES: CC1C(=CC(=CC=1)N=C=O)[N:4]=[C:5]=[O:6].[CH2:14]([OH:17])[CH2:15]O>>[N-:4]=[C:5]=[O:6].[N-:4]=[C:5]=[O:6].[NH2:4][C:5]([O:17][CH2:14][CH3:15])=[O:6].[NH2:4][C:5]([O:17][CH2:14][CH3:15])=[O:6]
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: OCCO
Product: CCOC(N)=O
Product: [N-]=C=O

Procedure:
About 348 parts of toluene diisocyanate are mixed with 62 parts of ethylene glycol and reacted at room temperature (25° C.) to form a diurethane diisocyanate. About 260 parts of hydroxyethyl methacrylate are added to the resultant diurethane diisocyanate and the mixture heated to about 80° C. for about 3 hours.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]([CH2:21][C:22](O)=[O:23])[CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33].O>C(Cl)Cl.C(Cl)(=O)C(Cl)=O>[CH3:31][S:32]([NH:35][C:22](=[O:23])[CH2:21][C:18]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:20]=2[CH:19]=1)(=[O:34])=[O:33]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)Cc1ccc2c3ccccc3n(Cc3ccccc3)c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)Cc1ccc2c3ccccc3n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
0.055 ml (0.63 nmol) of oxalyl chloride was added, with ice-cooling, to a mixture of 100 mg (0.32 mmol) of (9-benzylcarbazol-2-yl)acetic acid (prepared as described in Example 42) in 3 ml of methylene chloride, and the whole was stirred for 30 minutes at room temperature. After this time, the solvent was removed by evaporation under reduced pressure. 5 ml of methylene chloride, 0.08 ml (0.99 mmol) of pyridine and 60 mg (0.63 mmol) of methanesulfonamide were added to the residue thus obtained, with ice-cooling. The reaction mixture was then stirred for 12 hours at room temperature. After the reaction had been allowed to go to completion, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic fraction was then washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, using 30 g of silica gel with a 50% v/v solution of methanol in ethyl acetate as eluent, to yield 46 mg of the title compound as an amorphous solid.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:19][C:20]1[S:21][CH:22]=[C:23]([C:25]([O:27]CC)=[O:26])[N:24]=1.O>CN(C)C=O>[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:19][C:20]3[S:21][CH:22]=[C:23]([C:25]([OH:27])=[O:26])[N:24]=3)[N:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1csc(CBr)n1
Reactant: c1ccc(-c2n[nH]c3ccccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1csc(Cn2nc(-c3ccccc3)c3ccccc32)n1
Reaction time: 0.08 h
Yield: 10.5 %

Procedure:
Sodium hydride (added with 40% mineral oil, 9 mg, manufactured by Kanto Chemical Co., Inc.) was added to a solution of 3-phenyl-1H-indazole (40 mg), which had been synthesized according to the literature (T. Edward, C., et al., Tetrahedron, 1991, 47, 9599-9620), in N,N-dimethylformamide (1 mL, manufactured by Kanto Chemical Co., Inc.) under ice cooling, and the mixture was stirred for 5 minutes at the same temperature. Subsequently, ethyl 2-bromomethylthiazole-4-carboxylate (51 mg) synthesized according to the method of the literature (K. Benno, et al., Leibigs. Ann. Chem., 1981, 4, 623-632) was added thereto, and the mixture was stirred overnight at room temperature. Water (1 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×2 mL), washed with brine (10 mL), and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by PTLC (hexane:ethyl acetate=2:1), to give 7.2 mg of the title compound. LC-MS: HPLC retention time 4.08 minutes, m/z 336 (M+H), condition A-1.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]#[CH:18])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:19](Cl)(=[O:21])[CH3:20].C(N(CC)CC)C.O>C1COCC1.[Cu]I>[N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]#[C:18][C:19](=[O:21])[CH3:20])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Reactant: CC(=O)Cl
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 28.8 %

Procedure:
To a solution of Compound 1c (52 mg; 0.213 mmol), acetyl chloride (46 mL, 0.647 mmol), bis(triphenyl)palladium(II)dichloride (4.49 mg, 0.0064 mmol) and copper (I) iodide (1.62 mg, 0.085 mmol) in anhydrous THF (5 mL), was added triethylamine (85 μL, 0.61 mmol) and the reaction mixture was stirred, in a closed vessel, at 60° C. for 5 h, cooled to r.t. poured into water and extracted with EtOAc. The combined extracts were washed with NaOH 0.1N, water, dried over Na2SO4 and evaporated to dryness in vacuo. Purification by flash chromatography (EtOAc—Petroleum Ether 25:75), afforded 17.5 mg of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.ClC(Cl)(O[C:18](=[O:24])[O:19][C:20](Cl)(Cl)Cl)Cl.[N-:26]=[C:27]=[O:28]>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:27]([NH:26][C:5]2[C:6]3[NH:7][C:18](=[O:24])[O:19][C:20]=3[CH:2]=[CH:3][CH:4]=2)=[O:28])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: [N-]=C=O
Reactant: NCc1ccc(Cl)cc1C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(Cl)cc1C(F)(F)F)Nc1cccc2oc(=O)[nH]c12
Temperature: 80 °C
Yield: 9.7 %

Procedure:
Commercially available 4-chloro-2-trifluoromethylbenzylamine (1 g, 4.77 mmol) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (1.41 g, 4.77 mmol) was added to the solution. The mixture was warmed at 80° C. for 4 hours then evaporated and the residue was dissolved in 5 ml of DMF. The solution of the isocyanate was added dropwise to a solution in DMF (5 ml) of compound 1b (475 mg, 3.2 mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt 4/petroleum ether 6). The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column gave 120 mg of a white solid. Yield=9.7% 1HNMR (DMSO, 200 MHz) δ 4.45 (2H, d, J=5.6 Hz), 6.99 (4H, m), 7.65 (1H, d), 7.73 (1H, d), 7.85 (1H, bs), 8.62 (1H, bs), 11.04 (1H, bs); [M+1] 386.6 (C16H11ClF3N3O3 requires 385.73).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>>[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH:27][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:21]
Reactant: NCc1ccccc1Cl
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccccc4Cl)cc3)c2)o1

Procedure:
N-(2-Chlorobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 2-chlorobenzylamine using method N. NMR; δH [2H6]—DMSO 9.15,(1H, t), 8.03,(2H, d), 7.90,(1H, dd), 7.77,(1H, d), 7.56-7.53,(3H, m), 7.47,(1H, m), 7.39,(1H, m), 7.35-7.28,(2H, m), 4.57,(2H, d), 2.56,(3H, s), LCMS; retention time 3.53 min, MH+ 418/420.