Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br.Br[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH:20]=1
Reactant: BrCc1cccnc1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Agent: Br
Product: Cc1cc(C#Cc2cn(Cc3cccnc3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=288.9 (M+H30), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-(bromomethyl)pyridine hydrobromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]=2[C:20]([NH:22][CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)=[O:21])=[CH:5][CH:4]=1.Cl.C([S:53][CH2:54][CH2:55][NH2:56])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]=2[C:20]([NH:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH:56][CH2:55][CH2:54][SH:53])=[O:29])=[CH:31][CH:32]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(-c2cc(-c3ccccc3)[nH]c2C(=O)NCc2ccc(C(=O)O)cc2)cc1
Agent: Cl
Product: COc1ccc(-c2cc(-c3ccccc3)[nH]c2C(=O)NCc2ccc(C(=O)NCCS)cc2)cc1

Procedure:
This material was prepared using a method substantially similar to that of Example 22 from 4-[({[3-(4-methoxyphenyl)-5-phenyl-1H-pyrrol-2-yl]carbonyl}amino)methyl]benzoic acid and 2-(tritylsulfanyl)ethanamine hydrochloride, yielding the title compound 3-(4-methoxyphenyl)-5-phenyl-N-(4-{[(2-sulfanylethyl)amino]carbonyl}benzyl)-1H-pyrrole-2 carboxamide: Yield 70%; m.p. 131-132° C.; IR 3396, 3280, 1635, 1524, 1499, 1246 cm−1; 1H-NMR (500 MHz, δ ppm, CDCl3) 9.99 (s, 1H), 7.72 (d, J=8.1 Hz, 2H), 7.59 (d, J=7.6 Hz, 2H), 7.38 (t, J=7.7 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.28 (t, J=7.5 Hz, 1H); 7.17 (d, J=8.0 Hz, 2H), 7.03 (t, J=5.5 Hz, 1H), 6.89 (d, J=8.5 Hz, 2H), 6.47 (d, J=2.9 Hz, 1H), 6.17 (t, J=5.8 Hz, 1H), 4.45 (d, J=5.9 Hz, 2H), 3.85-3.73 (m, 5H), 2.97 (t, J=6.2 Hz, 2H), 1.62 (s, 1H); 13C-NMR (75 MHz, δ ppm, CDCl3) 167.7, 161.7, 159.6, 142.4, 134.6, 133.4, 131.6, 130.8, 129.6, 129.2, 128.7, 128.5, 128.3, 127.7, 127.6, 124.9, 122.3, 114.7, 109.8, 55.6, 43.1, 39.5, 38.4, 29.9.
Reaction SMILES: C([Li])CCC.[C:6]([NH-:10])([CH3:9])([CH3:8])[CH3:7].[CH3:11][C:12]1[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[O:14][N:13]=1.Cl.[O:21]1CCC[CH2:22]1>O.CN(C)C=O>[C:6]([NH-:10])([CH3:9])([CH3:8])[CH3:7].[CH:22]([C:16]1[C:12]([CH3:11])=[N:13][O:14][C:15]=1[C:17]([OH:19])=[O:18])=[O:21]
Reactant: Cc1cc(C(=O)O)on1
Reactant: C1CCOC1
Agent: CC(C)(C)[NH-]
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(C(=O)O)c1C=O
Reaction time: 1 h

Procedure:
56 ml of butyllithium (1.6 molar solution in n-hexane) are added dropwise, at -78° C., to 8 g of the tertbutylamide of 3-methylisoxazole-5-carboxylic acid in 150 ml of tetrahydrofuran. The mixture is stirred for 1 hour, after which 22 ml of dimethylformamide are slowly added dropwise. The mixture is allowed to reach room temperature overnight and is hydrolyzed with water, neutralized with concentrated hydrochloric acid and extracted with ether. The oil which remains after evaporation is chromatographed over silica gel sing cyclohexane/ethyl acetate. The tert-butylamide of 4-formyl-3-methylisoxazole-5-carboxylic acid is obtained as the first fraction, in the form of pale yellow crystals of melting point 36°-38° C. (compound No. 2).
Reaction SMILES: [Si:1]([CH:18]([OH:25])[C@H:19]1[O:23][C:22](=[O:24])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Si](Cl)(C)(C)C.[C:41]1([Se:47]Br)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1.CCOCC>[Si:1]([CH:18]([OH:25])[C@H:19]1[O:23][C:22](=[O:24])[C@H:21]([Se:47][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Se]c1ccccc1
Reactant: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)C(O)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)C(O)[C@@H]1C[C@@H]([Se]c2ccccc2)C(=O)O1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a solution of 4 (5 g, 14.1 mmol) in anhydrous THF (50 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1 M solution in THF, 15.8 mL, 15.8 mmol) over a period of 10 min. After stirring at −78° C. for 1 h, Me3SiCl (1.918 g, 17.65 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature. After being stirred at room temperature for 30 min, the mixture was cooled to −78° C., and a solution of PhSeBr (5 g, 21.19 mmol) in anhydrous THF (25 mL) was added rapidly. The mixture was diluted with ether (50 mL), washed with water until the color of organic layer changed from dark brown to light yellow, dried (Na2SO4), filtered, and evaporated. The resulting oily residue [containing 3R(α, 5) and 3S(β) isomers; TLC: hexane/EtOAc, 10:1; Rf=0.42 and 0.28, respectively] was purified by flash chromatography on silica gel eluting with hexane/EtOAc (99:1 to 95:5) to give the title compound 5 as a light yellow oil (4.22 g, 59%). 1H NMR (CDCl3) δ 7.69-7.60 (m, 6H, arom.), 7.46-7.30 (m, 9H, arom.), 4.37-4.34 (m, 1H, H-5), 4.12-4.08 (m, 1H, H-3), 3.86-3.82 (dd, J=3 & 11 Hz, 1H, CH2OH), 3.62-3.59 (dd, J=3 & 11 Hz, 1H, CH2OH), 2.73-2.67 (m, 1H, H-4), 2.32-2.28 (m, 1H, H-4), 1.02 (s, 9H, t-Bu).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[N:14]=[C:13]([CH2:15]I)[CH:12]=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[CH3:23])[N:10]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:8][C:9]1[N:10]=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[CH3:23])[CH:12]=[C:13]([CH2:15][S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[N:14]=1
Reactant: C[C@H]1COCCN1c1cc(CI)nc(Cl)n1
Reactant: Sc1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1COCCN1c1cc(CSc2ccncc2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 64.5 %

Procedure:
4-Mercaptopyridine (0.752 g, 6.77 mmol) was added to 2-chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (1.596 g, 4.51 mmol) in acetonitrile (100 mL) at RT under air. DBU (0.3 mL, 2.01 mmol) was then added and the resulting solution was stirred at RT for 2 minutes. The solvent was removed and DCM was added. The reaction mixture was washed sequentially with water, the organic layer dried (MgSO4), filtered and evaporated. The crude product was chromatographed on silica, eluting with 0-2% methanol in DCM. Impure fractions were further chromatographed on silica, eluting with 0-4.5% methanol in DCM and combined with the initial pure fractions to give the desired material as a yellow gum (0.980 g).
Reaction SMILES: [N+]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-])=O.C1(C2CCC3C(=CC=C(O)C=3)O2)C=CC=CC=1.Cl[C:45]1C=CC(C#N)=C[N:46]=1>>[C:21]1([CH:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([C:45]#[N:46])=[CH:9][N:8]=4)[CH:12]=3)[O:17]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: N#Cc1ccc(Cl)nc1
Agent: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Product: N#Cc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1

Procedure:
6-(2-Phenylchroman-6-yloxy)nicotinonitrile was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in example 1 (b) using 500 mg of 2-phenylchroman-6-ol and replacing 2-chloro-5-nitropyridine by 337 mg of 6-chloro-nicotinonitrile. The product was purified by column chromatography using heptane-ethyl acetate as an eluant and then crystallised from 2-propanol. 1H NMR (400 MHz, d6-DMSO) δ: 8.65 (d, 1H, J 2.4 Hz), 8.28 (dd, 1H, 8.8, 2.4 Hz), 7.47-7.34 (m, 5H), 7.17 (d, 1H, J 8.8 Hz) 6.96-6.87 (m, 3H), 5.14 (dd, 1H, J 10.1, 2.2 Hz), 2.99 (m, 1H), 2.73 (m, 1H), 2.18 (m, 1H), 2.00 (m, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]=[C:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH2:35]O)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>CN(C)C=O.C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[O:7]=[C:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:14]([O:16][CH2:35][C:27]2[CH:28]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:30]=[C:25]([C:24]([F:23])([F:37])[F:38])[CH:26]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: O=C1CCC(C(=O)O)(c2ccccc2)CC1
Reactant: OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C1CCC(C(=O)OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
Oxalyl chloride (4.8 mL, 55 mmol) was added to a solution of 4-oxo-1-phenylcyclohexanecarboxylic acid (Description 2, 6 g, 27 mmol) and dimethylformamide (1 drop) in toluene (150 mL) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and toluene was added. The solvent was evaporated under reduced pressure and the residue was dissolved in toluene (100 mL). 3,5-Bis(trifluoromethyl)benzenemethanol (6.25 g, 26 mmol) and 4-dimethylaminopyridine (3.62 g, 30 mmol) were added and the mixture was heated under reflux for 24 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and hydrochloric acid (2M, 100 mL). The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/CH2Cl2 (60:40 increasing to 50:50) to give the title compound (4.5 g, 40%). 1H NMR (360 MHz, CDCl3) δ 2.33-2.53 (6H, m), 2.72-2.77 (2H, m), 5.23 (2H, s), 7.28-7.41 (5H, m), 7.51 (2H, s), and 7.77 (1H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[C:4]([CH:17]=O)=[CH:5][C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1.[S:20]1[CH2:26][C:24](=[O:25])[N:23]([CH2:27][C:28]([OH:30])=[O:29])[C:21]1=[S:22]>>[CH3:1][N:2]([CH3:19])[C:3]1[C:4]([C:17]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH:5]=[C:4]([CH:17]=[C:26]2[S:20][C:21](=[S:22])[N:23]([CH2:27][C:28]([OH:30])=[O:29])[C:24]2=[O:25])[CH:3]=[CH:12]3)=[CH:5][C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CN(C)c1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Product: CN(C)c1cc2c(cc1-c1ccc3cc(C=C4SC(=S)N(CC(=O)O)C4=O)ccc3c1)C(C)(C)CCC2(C)C

Procedure:
{5-[6-(3-Dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-naphthalen-2-yl methylene]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid was prepared in a similar manner as described in Example 1 using 6-(3-dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-carboxaldehyde and rhodanine acetic acid, mp 194–196° C., 1H NMR (300 MHz; DMSO-d6) 1.25 (s, 6 H), 1.30 (s, 6 H), 1.66 (s, 4 H), 2.47 (s, 6 H), 4.76 (s, 2 H); 6.99 (s, 1 H), 7.21 (s, 1 H), 7.74 (dd, J1=1.5 Hz, J2=8.4 Hz, 1 H), 7.87 (dd, J1=1.5 Hz, J2=8.4 Hz, 1 H), 8.05 (brs, 2 H), 8.07 (d, J=8.1 Hz, 1 H), 8.10 (d, J=8.1 Hz, 1 H), 8.28 (s, 1 H).
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH2:30]([SH:33])[CH2:31][CH3:32].C(OCC)(=O)C>C(#N)CCC>[CH3:16][O:15][C:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:2]([S:33][CH2:30][CH2:31][CH3:32])=[C:3]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:4]=[N:5]2)=[CH:8][CH:9]=1)=[O:14]
Reactant: CCCS
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)OC(C)(C)C)c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC#N
Solvent: CCOC(C)=O
Product: CCCSc1c(C(=O)OC(C)(C)C)cnn1-c1ccc(C(=O)OC)cc1

Procedure:
tert-butyl 5-chloro-1-(4-methoxycarbonylphenyl)pyrazole-4-carboxylate (Intermediate #9) (2.016 g, 6.0 mmol) was dissolved in butyronitrile (30 mL), potassium carbonate (2.48 g, 18 mmol) and propanethiol (678 μL, 7.5 mmol) were added and the mixture heated to reflux for 5 h. Ethyl acetate (150 mL) was added and the mixture washed with water (4×25 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (120 g silica 0-25% EtOAc/isohexane) to give the title compound as a clear pale yellow oil that slowly crystallised on standing to a white solid. (2.01 g, 89%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:12]([CH3:13])=[CH:11][S:10][C:9]=2[CH:14]=1)=[O:4].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:12]([CH2:13][Br:15])=[CH:11][S:10][C:9]=2[CH:14]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(C)csc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(CBr)csc2c1
Yield: 56.2 %

Procedure:
A mixture of 3-methylbenzo[b]thiophene-6-carboxylic acid methyl ester (1.03 g), N-bromosuccinimide (0.89 g), azobisisobutyronitrile (0.2 g) and carbon tetrachloride (25 ml) was heated under reflux for 2 hours and then cooled. The mixture was diluted with a few ml. of chloroform, washed with water, dried (Na2SO4) and evaporated to give a solid which was crystallized from ethyl acetate/petrol (b.p. 60°-80° C. to give 3-bromomethylbenzo[b]thiophene-6-carboxylic acid methyl ester (0.80 g), m.p. 108°-110° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[C:34]([C:39]([OH:41])=O)=[CH:35][CH:36]=[CH:37][CH:38]=5)=[CH:29][CH:28]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.[CH3:42][NH:43][CH3:44].O1CCCC1>CN1CCCC1=O>[CH3:42][N:43]([CH3:44])[C:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:30]1[CH:29]=[CH:28][C:27]([C:25]([N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][N:20]3[C:11]([C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:10])=[CH:12][CH:13]=[C:14]3[CH2:15]2)=[O:26])=[CH:32][CH:31]=1)=[O:41]
Reactant: O=C(O)c1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CN(C)C(=O)c1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 4′-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1′-biphenyl-2-carboxylic acid of Example 65 (92 mg, 0.17 mmol) in 1-methyl-2-pyrrolidinone (4.5 mL) was added a 2.0 M solution of dimethylamine in tetrahydrofuran (0.42 mL, 0.848 mmol) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,tetramethyluronium hexafluorophosphate (71 mg, 0.187 mmol) and the reaction mixture stirred at room temperature under nitrogen for 2 hours. The reaction mixture was then partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was separated, washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a white foam. Purification by flash chromatography using a solvent gradient of 1 to 7% methanol in dichloromethane gave a colorless glass that was crystallized from ethyl acetate/hexane to afford the title compound 0.082 g, 85%) as a white solid, m.p. 206-207° C.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH2:5]([O:12][C:13](Cl)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1.CCOC(C)=O>[CH2:5]([O:12][C:13](=[O:14])[NH:4][CH2:1][C:2]#[CH:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C#CCNC(=O)OCc1ccccc1
Yield: 32.9 %

Procedure:
To a solution of propargylamine (6.4 g, 71.2 mmol) in pyridine (100 mL) was added benzylchloroformate (13.37 g, 78.2 mmol) in 100 mL CH2Cl2over 0.5 h. The reaction benzylchloroformate (13.37 g, 78.2 mmol) in 100 mL CH2Cl2over0.5 h. The reaction dissolved in EtOAc and the organic solution was washed with water (2×). The organic solution was washed with dilute aqueous HCl followed by saturated NaHCO3. The organic solution was dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound (4.43 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[S:13]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]1)(=[O:15])=[O:14].CS(O[CH2:35][C:36]1([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:38][CH2:37]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:35][C:36]1([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:37][CH2:38]1)[CH:6]=[C:5]2[S:13]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]1)(=[O:14])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2c[nH]c(=O)c3ccc(Br)cc23)CC1
Reactant: CC(C)(C)[Si](C)(C)OCC1(COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2cn(CC3(CO[Si](C)(C)C(C)(C)C)CC3)c(=O)c3ccc(Br)cc23)CC1
Temperature: 25 °C

Procedure:
tert-Butyl 4-[(6-bromo-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfonyl]-1,4-diazepane-1-carboxylate (Example 46b, 0.40 g), [1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl methanesulfonate (0.24 g) and cesium carbonate (0.536 g) were stirred together in DMF (20 mL) at 110° C. for 72 h under nitrogen, cooled to room temperature, diluted with water (100 mL) and extracted into ethyl acetate (3×20 mL). The combined organics were washed with saturated brine (3×20 mL), dried (MgSO4) filtered and evaporated, and the residue was purified (SiO2 chromatography, elution with 10% ethyl acetate in DCM) to give (tert-butyl 4-[(6-bromo-2-{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl}-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfonyl]-1,4-diazepane-1-carboxylate) as a solid. This was dissolved in DMF (10 mL), treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.089 g), potassium carbonate (0.077 g) and Pd-118 (0.006 g) and the resulting mixture was stirred at 70° C. under nitrogen for 1 h. After being cooled to room temperature, it was diluted with saturated brine and extracted into ethyl acetate (3×30 mL). The combined extracts were washed with brine (3×30 mL), dried (MgSO4) filtered and evaporated. The residue was dissolved in THF (20 mL), treated with 4 M HCl in dioxane (3 mL), stirred at room temperature for 3 h, evaporated and purified by preparative HPLC (Waters Xbridge column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent) to give the title compound (0.019 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]2[N:14]=[C:15]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=3)=[C:4]2[CH:3]=1.C(=O)(O)[O-:34].[Na+].ClC1C=C(C=CC=1)C(OO)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[N:5]2[N:14]=[C:15]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([S:23]([CH3:24])=[O:34])[N:18]=3)=[C:4]2[CH:3]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cc(Cl)cc3c2-c2ccnc(SC)n2)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nn3c(NC4CCCC4)cc(Cl)cc3c2-c2ccnc(S(C)=O)n2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
To a solution of N-{5-chloro-2-(4-methoxyphenyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-yl}-N-cyclopentylamine (133 mg, 0.28 mmol) in chloroform (10 mL) was added sodium bicarbonate (24 mg, 0.28 mmol). The reaction mixture was cooled to 0° C. m-Chloroperoxybenzoic acid (57˜86%, 86 mg, 0.50 mmol) was added. After stirring at 0° C. for 1.5 hours, the reaction mixture was quenched by addition of aqueous sodium bicarbonate and the resulting mixture extracted with dichloromethane. The organics were combined and washed with water, then dried over magnesium sulfate. Filtration and concentration followed by chromatography (19:1 dichloromethane/methanol) gave N-{5-chloro-2-(4-methoxyphenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-yl}-N-cyclopentylamine (121 mg, 88%) as a yellow solid. 1H NMR (CDCl3) δ 8.43 (d, 1H), 7.93 (d, 1H), 7.51 (d, 2H), 7.00 (d, 2H), 6.98 (d, 1H), 6.11 (d, 1H), 6.08 (d, 1H), 3.96 (m, 1H), 3.88 (s, 3H), 2.99 (s, 3H), 2.13 (m, 2H), 1.82–1.66 (m, 6H). MS m/z 482 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:13]=[CH:14][C:15]3[C:21](=[O:22])[NH:20][C:19]4[CH:23]=[C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:25]=[CH:26][C:18]=4[NH:17][C:16]=3[CH:32]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].O[NH:34][C:35](=[NH:37])[CH3:36].CC(C)N=C=NC(C)C>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:13]=[CH:14][C:15]3[C:21](=[O:22])[NH:20][C:19]4[CH:23]=[C:24]([CH2:27][CH2:28][C:29]([O:31][NH:37][C:35](=[NH:34])[CH3:36])=[O:30])[CH:25]=[CH:26][C:18]=4[NH:17][C:16]=3[CH:32]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(-c2ccc3c(c2)Nc2ccc(CCC(=O)O)cc2NC3=O)ccc1[N+](=O)[O-]
Reactant: CC(=N)NO
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(-c2ccc3c(c2)Nc2ccc(CCC(=O)ONC(C)=N)cc2NC3=O)ccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A mixture of Example 230 (65 mg, 0.15 mmol), N-hydroxy-acetamidine (14 mg, 0.18 mmol) in 1 mL of DMF was treated with DIC in 1 mL of CH2Cl2 at 0° C. The reaction mixture was stirred overnight and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 100:1 ethyl acetate/MeOH to provide the desired product. MS (DCI) m/e 490 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.01 (d, J=8.29 Hz, 1H), 7.94 (s, 1H), 7.79 (d, J=8.29 Hz, 1H), 7.52 (d, J=1.23 Hz, 1H), 7.33-7.34 (m, 2H), 7.29 (m, 1H), 6.93 (m, 1H), 6.83-6.85 (m, 2H), 6.27 (s, 2H), 4.03 (s, 3H), 2.73-2.76 (m, 2H), 2.58-2.62 (m, 2H), 1.72 (s, 3H).
Reaction SMILES: C(N[C:5](=[O:12])[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=O)(=O)C.[NH2:13][NH:14][C:15]([NH:17][NH2:18])=[S:16]>C(O)C.Cl>[NH2:13][N:14]1[C:5](=[O:12])[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[N:18][N:17]=[C:15]1[SH:16]
Reactant: CC(=O)NC(=O)C(=O)C(C)(C)C
Reactant: NNC(=S)NN
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1nnc(S)n(N)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.5 %

Procedure:
37.0 g (0.22 mol) of trimethylpyruvic acid N-acetylamide in 150 ml of ethanol were added dropwise to 23.2 g (0.22 mol) of thiocarbohydrazide in 400 ml of 1N HCl and the reaction mixture was subsequently stirred at room temperature for 5 hours. The product which had precipitated was filtered off, washed with water and dried. 41.2 g of the abovementioned product (VI) of melting point 210° C. were obtained, with a content, determined by gas chromatography, of >99% which corresponded to a yield of 95% of theory.