Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.[C:20](O)(=[O:24])[CH2:21][C:22]#[CH:23].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:20](=[O:24])[CH:21]=[C:22]=[CH2:23])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C#CCC(=O)O
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: C=C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Yield: 64.8 %

Procedure:
To a solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (316 mg, 1.0 mmol), and 3-butynoic acid (173 mg, 2.06 mmol) in DMF (5 mL) stirred under nitrogen at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (384 mg, 2.0 mmol). After 1.5 hours the reaction was quenched with 0.1 M HCl solution (10 mL). The yellow precipitate was collected by Buchner filtration and washed with water followed by acetone. The solid was taken up into acetone with the addition of triethylamine. The formed solution was filtered through a 2-inch silica gel eluting with 50% acetone/CH2Cl2. The filtrate was collected and concentrated under reduced pressure to give the title compound as a yellow solid (247 mg, 56%), mp 268-270° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:29])[CH2:27][NH2:28]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:28][CH2:27][CH2:26][NH2:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCCN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and ethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 397, 1H NMR (400 MHz, CD3OD) δ ppm 7.86 (m, 2 H), 7.65-7.50 (m, 2 H), 7.42-7.30 (m, 2 H), 7.28-7.16 (m, 1 H), 6.10-5.95 (m, 1 H), 5.09 (brs, 2 H), 3.64-3.42 (m, 2 H), 3.15-2.98 (m, 2 H), 2.84 (s, 2 H), 2.35 (s, 3 H), 1.20 (s, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]2[CH:22]=[N:23][N:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH:25]=2)[N:14]=1>CN(C=O)C.CCN(CC)CC.[Pd]>[CH3:1][O:2][C:3](=[O:39])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]2[CH:22]=[N:23][N:24]([CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:30][CH2:31]3)[CH:25]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1C
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 10% Pd/C (53% water; 0.020 g) and tert-butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (A125) (0.092 g, 0.17 mmol) in DMF (5 mL) and Et3N (0.5 mL) was stirred at room temperature for 18 hours under a hydrogen atmosphere. The resulting mixture was filtered through Celite, and the filter cake washed with EtOAc (250 mL). The combined filtrates were washed with water (3×100 mL) and brine (3×100 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in hexanes) to give the title compound A126 as a pale brown oil (80 mg, 86%); 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.89 (s, 1H), 7.51 (d, J=0.4 Hz, 1H), 7.25-7.15 (m, 4H), 6.92 (s, 1H), 4.31-4.15 (m, 3H), 3.70 (s, 2H), 3.66 (s, 3H), 3.08 (dd, J=9.4, 6.3 Hz, 2H), 2.90 (dd, J=9.5, 6.3 Hz, 4H), 2.15-2.07 (m, 2H), 2.05 (s, 3H), 2.00-1.85 (m, 2H), 1.46 (s, 9H). LCMS-A: rt 6.195 min; m/z 535.3 [M+H]+.
Reaction SMILES: [CH3:1]I.[CH3:3][O:4][CH:5]([O:10][CH3:11])[CH2:6][C:7](=[O:9])[CH3:8]>CCOCC>[CH3:3][O:4][CH:5]([O:10][CH3:11])[CH2:6][C:7]([OH:9])([CH3:1])[CH3:8]
Reactant: CI
Reactant: COC(CC(C)=O)OC
Solvent: CCOCC
Product: COC(CC(C)(C)O)OC
Temperature: 25 °C

Procedure:
CH3I (18.5 mL, 297 mmol) in 50 mL of ether was added slowly, to maintain reflux, to a suspension of Mg (6.0 g, 250 mmol) in 50 mL of ether. The solution was vigorously stirred during the addition. After the magnesium was consumed, the solution was chilled with an ice bath to ≃5° C. Acetylacetaldehyde dimethyl acetal (16.5 mL, 124 mmol) in 50 mL of ether was added very slowly, over a period of 2 h. After the addition was complete, the reaction was stirred for an additional hour while warming to room temperature. The reaction was quenched with 1 mL of saturated (NH4)2SO4 (aq) and filtered. The residue was washed with ether (2×50 mL). The combined filtrates were dried over Na2SO4, and the solvent was removed under water aspirator vacuum. Distillation of the residue yielded 9.9 g of 3-hydroxy-3-methylbutanal dimethyl acetal, bp4.2 53°-56° C. (67 mmol bp10 60°-65° C., bp14 72°-79° C. in agreement with Malik, O. P.; Kapil, R. S., Anand, N., Ind. J. Chem. 14B (1976) 449); 1H-NMR (200 MHz, CDCl3) δ 1.24 (s, 6H, CH3), 1.80 (d, J=5.9 Hz, 2 H, CH2), 3.36 (s, 6H, CH3O), 3.41 (s, 1 H, OH), 4.66 (t, J=5.9 Hz, 1 H, CH), 13C-NMR (50 MHz, CDCl3) δ 29.46 (CH3), 43.85 (CH2), 52.61 (CH3O), 68.63 (COH), 102.51 (CH).
Reaction SMILES: [CH2:1]([S:5]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)=[O:6])[CH2:2][CH2:3][CH3:4].[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16](Cl)=[O:17])[CH:13]=[CH2:14].O1CCCC1>C(N(CC)CC)C>[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[O:6])=[N:8]1)=[O:17])[CH:13]=[CH2:14]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCCCS(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)CCCC)n1
Temperature: 100 °C

Procedure:
A mixture of 5.2 g. 3-butylsulphinyl-1,2,4-triazole, 6.0 g. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 7.5 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate distilled under reduced pressure to remove solvent. Finally the residue was maintained at 100° C./0.5 mm. for 30 minutes in order to remove all traces of volatile material from the product. The product, 1-diallylcarbamoyl-3-n-butylsulphinyl-1,2,4-triazole, was obtained as an oil, nD26 1.5277. Elemental analysis satisfactory.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[Cl:8][C:9]1[NH:14][C:13]([N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26]([C:28]3[NH:29][C:30]([CH3:35])=[C:31]([Cl:34])[C:32]=3[Cl:33])=[O:27])[CH2:21][CH2:20]2)(C(OC)=O)[CH:12]=[CH:11][N:10]=1.CN([CH:39]=[O:40])C>>[Cl:8][C:9]1[N:10]=[C:11]([C:39]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:40])[CH:12]=[C:13]([N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26]([C:28]3[NH:29][C:30]([CH3:35])=[C:31]([Cl:34])[C:32]=3[Cl:33])=[O:27])[CH2:21][CH2:20]2)[N:14]=1
Reactant: CS(N)(=O)=O
Reactant: CN(C)C=O
Reactant: COC(=O)C1(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)C=CN=C(Cl)N1
Agent: [H-]
Agent: [Na+]
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)NS(C)(=O)=O)nc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of methanesulfonamide (40 mg, 0.44 mmol) and DMF (0.5 ml) was added to a suspension of sodium hydride (95%) (11 mg, 0.44 mmol) and DMF (0.5 ml) under nitrogen. The mixture was stirred for 20 minutes at room temperature. A solution of methyl 2-chloro-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)pyrimidine-4-carboxylate (Example 6, 47 mg, 0.11 mmol) in DMF (1 ml) was added dropwise to the mixture over 5 minutes. The mixture was stirred for 1 h at room temperature and for 3 h at 60° C. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by preparative reversed-phase HPLC (water/acetonitrile gradient, 10-90%) to afford the title compound (14 mg).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:18]=[C:19]3[C:27]4[C:26](Cl)=[N:25][CH:24]=[N:23][C:22]=4[NH:21][C:20]3=[O:29])=[C:15]([CH3:17])[CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:30]([C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])#[CH:31].Cl>>[N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:18]=[C:19]3[C:27]4[C:26]([NH:35][C:34]5[CH:36]=[CH:37][CH:38]=[C:32]([C:30]#[CH:31])[CH:33]=5)=[N:25][CH:24]=[N:23][C:22]=4[NH:21][C:20]3=[O:29])=[C:15]([CH3:17])[CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Reactant: C#Cc1cccc(N)c1
Agent: Cl
Product: C#Cc1cccc(Nc2ncnc3c2C(=Cc2[nH]c(C(=O)NCCN4CCOCC4)cc2C)C(=O)N3)c1
Yield: 15 %

Procedure:
The title compound (15% yield) was prepared from 5-(4-chloro-6-oxo-6,7-dihydro-pyrrolo[2,3-d]pyrimidin-5-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide and 3-ethynylaniline according to the procedure described for Example 12 without the conversion to HCl salt. MS 498.2 [M++1].
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:12]([O:14][C:15](=[O:21])[CH2:16][C:17](=[O:20])[CH2:18][CH3:19])[CH3:13].Br[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([NH:30][CH:31]2[CH2:34][CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[Cl:37]>O1CCCC1.O>[CH2:12]([O:14][C:15](=[O:21])[CH:16]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28](=[O:29])[NH:30][CH:31]2[CH2:34][CH2:33][CH2:32]2)=[CH:26][C:25]=1[Cl:37])[C:17](=[O:20])[CH2:18][CH3:19])[CH3:13]
Reactant: O=C(NC1CCC1)c1ccc(CBr)c(Cl)c1
Reactant: CCOC(=O)CC(=O)CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(=O)NC2CCC2)cc1Cl)C(=O)CC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of potassium tert-butoxide (0.34 g) in anhydrous tetrahydrofuran (15 mL) at 0° C. was treated with a mixture of tert-butanol (1.0 mL) and 3-oxopentanoic acid ethyl ester (038 mL). The mixture was stirred at 0° C. for 45 minutes and then a solution of 4-bromomethyl-3-chloro-N-cyclobutylbenzamide (0.67 g) in tetrahydrofuran (5.0 mL) was added and the resulting mixture heated at 70° C. for 24 hours. The mixture was cooled to room temperature, diluted with water and the tetrahydrofuran removed under reduced pressure. The residue was extracted with ethyl acetate and the combined extracts washed With saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:5 by volume) to afford title compound, 0.44 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([C:28]([O:30]CC)=[O:29])=[O:27])[CH2:22][CH2:21]2)=[O:19])=[CH:12][C:11]=1[N+:33]([O-:35])=[O:34].[Li+].[OH-].O.Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([C:28]([OH:30])=[O:29])=[O:27])[CH2:22][CH2:21]2)=[O:19])=[CH:12][C:11]=1[N+:33]([O-:35])=[O:34]
Reactant: CCOC(=O)C(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc(Cl)cc3Cl)c([N+](=O)[O-])c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc(Cl)cc3Cl)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a stirred solution of the ethyl ester (40 mg, 0.074 mmol) from Example 43A in 2 mL of ethanol was added saturated LiOH (0.25 mL). The mixture was then stirred at room temperature for 2 hours. Water (2 mL) was then added to the reaction mixture, which was then acidified to pH=2 with concentrated HCl. The precipitates were collected through filtration, washed with cold water, dried under vacuum to give the title compound (30 mg, 79%) as a light yellow solid. 1H NMR (d6-DMSO, 300 MHz) δ 3.52 (br m, 4H), 3.62 (br m, 2H), 3.76 (br m, 2H), 6.84 (d, J=9.0 Hz, 1H), 7.46 (d, J=15.3 Hz,1H), 7.56 (d, J=15.3 Hz, 1H), 7.63 (dd, J=2.7, 8.7 Hz, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H), 8.70 (br d, 1H). MS (APCI) (M-COO)+ at m/z 466, 468, 470.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:15][C@@:14]3([CH2:20][CH2:19][CH2:18][C@@:17]([CH2:22][N:23]4[C:27]5[CH:28]=[C:29]([C:32]#[N:33])[CH:30]=[CH:31][C:26]=5[N:25]=[CH:24]4)([CH3:21])[CH2:16]3)[O:13][C:12]2=[O:34])=[N:9][CH:10]=1)([CH3:4])[CH3:3].[H-].[Na+].[CH3:37]I>CN(C)C=O>[CH3:37][O:1][C:2]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:15][C@@:14]3([CH2:20][CH2:19][CH2:18][C@@:17]([CH2:22][N:23]4[C:27]5[CH:28]=[C:29]([C:32]#[N:33])[CH:30]=[CH:31][C:26]=5[N:25]=[CH:24]4)([CH3:21])[CH2:16]3)[O:13][C:12]2=[O:34])=[N:9][CH:10]=1)([CH3:3])[CH3:4]
Reactant: CC(C)(O)c1cnc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)(C)c1cnc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Reaction time: 0.17 h
Yield: 58.2 %

Procedure:
To a solution of 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (75 mg, 0.163 mmol) in N,N-Dimethylformamide (DMF) (1 mL) was added sodium hydride (9.77 mg, 0.244 mmol) at RT. After 10 minutes, MeI (0.020 mL, 0.326 mmol) was added. The mixture stirred for an hour and was purified by reverse phase HPLC (Waters Sunfire 30×150 mm Acetonitrile:Water 0.1% TFA 30-70%, 50 mL/min, 15 min). The product was free based with PL-HCO3 resin SPE to yield 1-(((5S,7S)-3-(5-(2-methoxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as a white powder (45 mg, 58%). 1H NMR (400 MHz, DMSO-d6) δ 9.25 (d, J=1.51 Hz, 1H), 8.47-8.53 (m, 2H), 8.39 (d, J=1.00 Hz, 1H), 7.84 (d, J=8.78 Hz, 1H), 7.60 (dd, J=8.53, 1.51 Hz, 1H), 4.17 (s, 2H), 3.88 (dd, J=23.09, 10.29 Hz, 2H), 3.09 (s, 3H), 2.00 (d, J=14.05 Hz, 1H), 1.89 (d, J=14.56 Hz, 1H), 1.59-1.78 (m, 3H), 1.30-1.56 (m, 9H), 1.08 (s, 3H). MS (m/z) 443.2 (M-OMe).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:9][CH:10]([C:12]1[S:16][C:15]([NH2:17])=[N:14][N:13]=1)[CH3:11]>C(OC(=O)C)C>[Cl:5][C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:9][CH:10]([C:12]1[S:16][C:15]([N:17]=[C:1]=[O:2])=[N:14][N:13]=1)[CH3:11]
Reactant: CC(Oc1ccc(Cl)c(Cl)c1)c1nnc(N)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(Oc1ccc(Cl)c(Cl)c1)c1nnc(N=C=O)s1
Reaction time: 17 h

Procedure:
A 500 milliliter, neck flask equipped with a magnetic stirrer, thermometer, dry ice condenser/drying tube and inlet from a phosgene (COCl2) tank via a calibrated rotometer was charged with 50 milliliters of ethylacetate saturated with phosgene at 20° C. (approximately 0.5 mole of phosgene). An additional 50 milliliters of ethylacetate was added and 8.0 grams of 5-[1-(3,4-dichlorophenoxy)ethyl]-2-amino-1,3,4-thiadiazole, (prepared above) was added. The resulting solution was stirred for 17 hours with formation of an emulsion, and then purged with nitrogen until no COCl2 was detected. The solution was filtered, and topped at 70° C. in a roto-vac to form 9.0 grams of a viscous yellow oil of 5-[1-(3,4-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](Br)=[CH:5][CH:4]=1.[C:14]([O:18][C:19]([N:21]1[CH2:27][C@H:26]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:25][C@H:22]1[CH:23]=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>O1CCCC1>[C:14]([O:18][C:19]([N:21]1[CH2:27][C@H:26]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:25][C@H:22]1[CH:23]([OH:24])[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: OCc1ccc(Br)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1ccc(CO)c2ccccc12
Temperature: -72 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
A solution of 4-hydroxymethyl-1-bromonaphthalene (3 g, 12.7 mmol) in tetrahydrofuran (50 ml) was added dropwise to a solution of 1.6M butyl lithium-hexane solution (20.6 ml, 32.9 mmol) in tetrahydrofuran (100 ml) at -72° C. in a nitrogen stream over 30 minutes. The resulting reaction solution was stirred at -72° C. for 30 minutes and a solution of (2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (4.17 g, 12.7 mmol) in tetrahydrofuran (50 ml) was added dropwise over 10 minutes. Then, the reaction solution was stirred at -63° C. for 10 minutes. After addition of saturated aqueous ammonium chloride, the reaction solution was concentrated in vacuo. The resulting residue was poured into a liquid mixture of ethyl acetate with water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting oily residue was subjected to silica gel column chromatography (Wakogel™ C-300 heptane-ethyl acetate 3:1→2:1) to give (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-[hydroxy(4-hydroxymethyl-1-naphthyl)methyl]pyrrolidine (2.71 g, yield: 44.0%) as a colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[CH:24]=1>>[CH3:28][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:6][CH:7]=2)[O:27][N:26]=1
Reactant: Cc1cc(CCCCCBr)on1
Reactant: Oc1ccc(-c2nc3ccccc3s2)cc1
Product: Cc1cc(CCCCCOc2ccc(-c3nc4ccccc4s3)cc2)on1

Procedure:
2-{4-[[5-(3-Methyl-5-isoxazolyl)pentyl]oxy]phenyl}-benzothiazole [II; R1 and R2 =H, Het=benzothiazol-2-yl] was prepared from 5 g 2-(4-hydroxyphenyl)benzothiazole and 5.1 g 5-(5-bromopentyl)-3-methylisoxazole according to the procedure of Example 4: yield 6.9 g, m.p. 120-121° C. when recrystallized from triethylamine and then from isopropyl acetate.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH3:21])(=[O:10])=[O:9])[CH2:3]1.[N:22]1[N:26]2[CH:27]=[CH:28][CH:29]=[N:30][C:25]2=[C:24]([C:31](O)=[O:32])[CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][C@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:12]=2[CH3:21])(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:31]([C:24]1[CH:23]=[N:22][N:26]2[CH:27]=[CH:28][CH:29]=[N:30][C:25]=12)=[O:32]
Reactant: O=C(O)c1cnn2cccnc12
Reactant: Cc1cc(C(F)(F)F)ccc1S(=O)(=O)N1CCN[C@@H](C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(F)(F)F)ccc1S(=O)(=O)N1CCN(C(=O)c2cnn3cccnc23)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.5 %

Procedure:
To a solution of (3S)-3-methyl-1-{[2-methyl-4-(trifluoromethyl)phenyl]sulfonyl}piperazine (100 mg, 0.310 mmol) (may be prepared as described in Description 27), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (55.7 mg, 0.341 mmol), HOBt (52.3 mg, 0.341 mmol) and DIPEA (0.081 ml, 0.465 mmol) in dry DMF (5 ml) at rt was added HBTU (129 mg, 0.341 mmol) and the resulting orange solution stirred at rt for 45 min. Concentration under vacuum left an orange oil. Purification by MDAP and concentration of the desired fractions gave the title compound (108 mg) as a clear film that became a white solid on trituration with ether.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(O)(=O)[CH:12]([CH2:14][C:15](O)=O)[OH:13].S(=O)(=O)(O)O>[2H]C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]2[C:6]([CH:15]=[CH:14][C:12](=[O:13])[O:9]2)=[CH:7][CH:8]=1
Reactant: O=C(O)CC(O)C(=O)O
Reactant: CN(C)c1cccc(O)c1
Agent: O=S(=O)(O)O
Agent: [2H]C(Cl)(Cl)Cl
Product: CN(C)c1ccc2ccc(=O)oc2c1
Temperature: 0 °C

Procedure:
m-Dimethylaminophenol 6.0g, malic acid 6.0g and 85% sulfuric acid 12.0ml were heated in an oil bath at 120° for an hour. The mixture was cooled, diluted with crushed ice 50g, filtered, made alkaline with sodium carbonate and extracted with chloroform, which was separated, washed and dried over sodium sulfate. Evaporation of the chloroform produced a deep red gum which could not be induced to crystallize. The material was separated down an alumina column using dichloromethane, and the strong blue fluorescent ring was cut out, eluted with methanol and evaporated to dryness. Crystallization from i-propanol gave light brown needles, which on resrystallization became light yellow and lustrous, 0.65g (8%), m.p. 161°-161.5found C 69.95, 69.80; H 5.74, 5.79; N 7.36, 7.37; C11H11NO2 requires C 69.8; H 5.82; N 7.41%. The nuclear magnetic resonance spectrum (A-60) in deuterochloroform showed the methyl singlet 3.02 and the aromatic protons as follows: H4 and H3 centered at 6.00 and 7.54 respectively split by 9 cycles to give an AB quartet, H8 singlet at 6.47, H6 and H5 centered at 6.51 and 7.27 respectively split by 9 cycles to give another AB quartet and the H6 was further split by interaction with H8. Integrated intensities were in accord with the proposed structure.
Reaction SMILES: FC1C=CC=CC=1CN1C=C(C2C3C(=NC=C(C4C=C(NS(C)(=O)=O)C=CC=4)C=3)NC=2)C=N1.Br[C:35]1[CH:36]=[C:37]2[C:43]([C:44]3[C:45]([CH3:58])=[N:46][N:47]([CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[CH:52]=4)[C:48]=3[CH3:49])=[CH:42][N:41]([S:59]([C:62]3[CH:68]=[CH:67][C:65]([CH3:66])=[CH:64][CH:63]=3)(=[O:61])=[O:60])[C:38]2=[N:39][CH:40]=1.[CH3:69][N:70]([CH3:95])[CH2:71][CH2:72][CH2:73][O:74][C:75]1[CH:80]=[CH:79][C:78](B2OC(C)(C)C(C)(C)O2)=[CH:77][C:76]=1[NH:90][S:91]([CH3:94])(=[O:93])=[O:92].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:95][N:70]([CH3:69])[CH2:71][CH2:72][CH2:73][O:74][C:75]1[CH:80]=[CH:79][C:78]([C:35]2[CH:36]=[C:37]3[C:43]([C:44]4[C:45]([CH3:58])=[N:46][N:47]([CH2:50][C:51]5[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[CH:52]=5)[C:48]=4[CH3:49])=[CH:42][N:41]([S:59]([C:62]4[CH:63]=[CH:64][C:65]([CH3:66])=[CH:67][CH:68]=4)(=[O:60])=[O:61])[C:38]3=[N:39][CH:40]=2)=[CH:77][C:76]=1[NH:90][S:91]([CH3:94])(=[O:93])=[O:92]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(Br)cnc32)cc1
Reactant: CN(C)CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Agent: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5ccccc5F)c4)c3c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(OCCCN(C)C)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 13.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example 1, 5-bromo-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step-i of example-14) (250 mg, 0.4 mmol) was coupled with N-(2-(3-(dimethylamino)propoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (intermediate-30) (200 mg, 0.5 mmol) in sodium carbonate (154 mg, 1.4 mmol) PdCl2(dppf) (18 mg, 0.05 mmol), 1,2-dimethoxyethane/water (2/2 mL) to afford 40 mg (12% yield) of the titled compound after purification by preparative TLC (SiO2)-eluted by 30% ethyl acetate in hexane.