Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:30]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>CN(C)C(=O)C.C(OCC)(=O)C>[CH:31]1([C:34]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=5)[CH:14]=[CH:15][CH:16]=4)=[CH:6][N:5]3[CH:30]=2)=[O:35])[CH2:33][CH2:32]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cn2cc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (300 mg, 0.727 mmol) in N,N-dimethylacetamide (3.0 mL) was added cyclopropanecarbonyl chloride (69 μL, 0.763 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (200 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=60/40→0/100), and fractions containing the desired product were concentrated under reduced pressure. The residue was triturated with ethyl acetate, diisopropyl ether and hexane to give the title compound (145 mg, 42%) as a colorless solid.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C>>[F:13][C:12]1[C:7]([F:6])=[C:8]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:9]=[CH:10][C:11]=1[B:22]([OH:27])[OH:23]
Reactant: CCCCCCCOc1cccc(F)c1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: CCCCCCCOc1ccc(B(O)O)c(F)c1F

Procedure:
Quantities: n-butyllithium (20 cm3, 10.0M in hexanes, 0.2 mol), compound from Example 40 (45.5 g, 0.2 mol) and triisopropyl borate (74.4 g, 0.4 mol). The experimental procedure was as described in Example 28.
Reaction SMILES: BrCCCCC[OH:7].CCN(CC)CC.[CH3:15][C:16]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])[CH3:17].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:19]([OH:7])([C:16]([CH3:18])([CH3:17])[CH3:15])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCCCCBr
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](O)(c1ccccc1)c1ccccc1
Yield: 155.3 %

Procedure:
A solution of 5-bromo-pentanol (0.9889 g, 5.9 mmol, 1 eq) in anhydrous CH2Cl2 (20 mL) under N2 at 25° C. was treated with anhydrous Et3N (1.0 mL, 7.2 mmol, 1.2 eq), TBDPSCl (1.7 mL, 6.5 mmol, 1.1 eq) and DMAP (0.23 g, 1.9 mmol, 0.3 eq). The reaction mixture was stirred for 2 h before an aqueous solution of saturated NH4Cl (100 mL) was added. The aqueous layer was extracted with EtOAc (3×100 mL) and the organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was chromatographed (SiO2, 5×20 cm, 0-20% EtOAc/hexanes, gradient elution) to afford TBDPSOH (2.35 g, 98%) as a clear oil; 1H NMR (CDCl3, 400 MHz) δ 7.66-7.60 (m, 4H), 7.44-7.33 (m, 6H), 3.64 (t, 2H, J=6.1 Hz), 3.37 (t, 2H, J=6.9 Hz), 1.82 (p, 2H, J=7.3 Hz), 1.59-1.45 (m, 4H), 1.03 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 135.6, 129.6, 127.6, 127.5, 63.5, 33.9, 32.5, 31.6, 26.8, 24.5, 19.2; IR (film) υmax 3069, 2930, 2856, 2359, 1470, 1427, 1389, 1106, 822, 738, 700 cm−1; FABHRMS (NBA-CsI) m/z 537.0235 (C21)H29OSiBr+Cs+ requires 537.0225).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:31]([O:35][C:36]([N:38]1[CH2:39][CH:40]=[C:41]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:17])([CH3:16])[C:10]=3[CH:18]=2)[CH2:42][CH2:43]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To trifluoro-methane sulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 7.80 g, 18.0 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (6.11 g, 19.8 mmol, 1.1 eq.), Pd(PPh3)2Cl2 (630 mg, 0.898 mmol, 0.05 eq.), and sodium carbonate (5.71 g, 53.9 mmol, 3.0 eq.), DME (125 ml) and water (25 ml) were added. The mixture was subjected to reduced pressure under ultrasonication treatment, followed by filling with nitrogen. This procedure was repeated five times to remove air. After further stirring at 80° C. for 2 hours under nitrogen atmosphere, the mixture was cooled to room temperature, added with water (250 ml), and further stirred for 30 minutes. The precipitates were filtered and washed with water (50 ml). They were further washed with CH3CN (50 ml) to obtain the target compound as a crude product (gray powder, 7.54 g, 90%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[N:33][CH:32]=[CH:31][N:30]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cnccn3)c1)=N2

Procedure:
The title compound was prepared from {5-methyl-2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M80) (0.34 g, 0.66 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (211 mg, 81%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:7]([CH:11]=1)[C:8]([OH:10])=O.[F:18][C:19]1[CH:20]=[C:21]([C:31](=[O:33])[CH3:32])[CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[F:18][C:19]1[CH:20]=[C:21]([C:31](=[O:33])[CH3:32])[CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][N:28]([C:8](=[O:10])[C:7]2[CH:11]=[C:3]([S:2][CH3:1])[CH:4]=[CH:5][C:6]=2[N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:27][CH2:26]1
Reactant: CSc1ccc(N2CCOCC2)c(C(=O)O)c1
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Product: CSc1ccc(N2CCOCC2)c(C(=O)N2CCN(c3ccc(C(C)=O)cc3F)CC2)c1

Procedure:
The title compound was prepared according to the procedure described for example K step 2 from 5-Methylsulfanyl-2-morpholin-4-yl-benzoic acid and 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone (8%, white solid), MS (m/e): 458.2 (M+, 100%)
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].S(Cl)(Cl)=O.[CH3:17]O>>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1/[CH:4]=[CH:5]/[C:6]([O:8][CH3:17])=[O:7]
Reactant: CO
Reactant: Cc1ccccc1C=CC(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)/C=C/c1ccccc1C
Temperature: 60 °C
Reaction time: 10 h

Procedure:
To 2-Methylcinnamic acid (5.68 g, 35 mmol) in MeOH (175 ml) was added thionyl chloride (2.55 ml, 35.0 mmol) dropwise. The resulting solution was stirred for 10 hours at 60° C. The solution was cooled to room temperature and concentrated. The crude ester was dissolved in CH2Cl2 and washed twice with saturated NaHCO3. The organics were combined, dried, and concentrated affording 6.45 g of methyl(2E)-3-(2-methylphenyl)acrylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23](O)=[O:24])=[CH:13][C:12]=2[N:11]=1.C(Cl)(=O)C(Cl)=O.[F:32][C:33]1([F:40])[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([NH:39][CH:36]3[CH2:37][CH2:38][C:33]([F:40])([F:32])[CH2:34][CH2:35]3)=[O:24])=[CH:13][C:12]=2[N:11]=1
Reactant: NC1CCC(F)(F)CC1
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(o1)c(C(=O)NC1CCC(F)(F)CC1)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Yield: 11.5 %

Procedure:
The title compound was prepared following the procedure described for Example-177 using 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-55, 0.100 g, 0.265 mmol), oxalyl chloride (0.2 mL), 4,4-difluorocyclohexanamine (0.069 g, 0.397 mmol), THF (5.0 mL), DIPEA (0.103 g, 0.795 mmol) and TEA (0.2 mL). The obtained crude product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.66-1.68 (m, 2H), 1.90-2.15 (m, 6H), 2.60 (s, 3H), 4.01 (s, 1H), 7.36 (m, 1H), 7.50 (s, 1H), 7.58 (d, J=7.2 Hz, 2H), 7.89 (s, 1H), 9.38 (s, 1H), 11.46 (s, 1H); MS [M+H]+: 494.41.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[C:7]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.Cl.[N:18]1([C:23](N)=[NH:24])C=CC=N1.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>CN(C=O)C>[C:23]([N:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:2]1)(=[NH:18])[NH2:24]
Reactant: CS(=O)(=O)Nc1cccc2c1CCNC2
Reactant: N=C(N)n1cccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1cccc2c1CCN(C(=N)N)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A suspension of N-(1,2,3,4-tetrahydro-5-isoquinolyl)methanesulfonamide hydrochloride obtainable by the method of Example 19(b) of WO 98/30560 (15 g, 69 mmol), 1H-pyrazole-1-carboxamidine hydrochloride (10.0 g, 0.57 mol) and diisopropylethylamine (16.2 g, 125 mmol) in DMF (119 ml) was stirred overnight at room temperature. After this time 2N aqueous sodium hydroxide-was added to adjust to pH 12. The resulting white suspension was stirred for three hours, filtered and the solid dried in vacuo overnight at 45° C. to give 14.5 g of the title product (95%).
Reaction SMILES: [CH2:1]([NH:6][C:7]([NH:9][CH2:10][CH2:11][Cl:12])=[O:8])[C:2]([CH3:5])([CH3:4])[CH3:3].C(O)C.[N:16]([O-])=[O:17].[Na+]>Cl.O>[CH2:1]([NH:6][C:7]([N:9]([CH2:10][CH2:11][Cl:12])[N:16]=[O:17])=[O:8])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=N[O-]
Reactant: CC(C)(C)CNC(=O)NCCCl
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)CNC(=O)N(CCCl)N=O
Reaction time: 2 h

Procedure:
The entire yield of 1-neopentyl-3-(2-chloroethyl) urea (0.08 mol) was dissolved in 120 ml of concentrated HCl:ethanol, 2:1 at 5° C. in a 500 ml round bottom flask equipped with magnetic stirring. Sodium nitrite (5.5 g, 0.08 mol) was dissolved in 30 ml of water and added to the solution over a ten-minute period. Stirring continued for 2 hrs, and the yellow, crystalline precipitate was filtered and washed with five 100 ml portions of chilled distilled water. The product was dried in vacuo for 18 hrs. giving 15 g (84%) which melted with decomposition at 52°-3° C. IR analysis showed peaks at 1730/cm (C=O) and 1520/cm (C--N--H). NMR showed a singlet (9H) at 1 ppm, a doublet (2H, J=6.5 HZ) at 3.3 ppm, a triplet (2H, J=6.5 Hz) at 3.6 ppm, and a triplet (2H, J=6.5 Hz) at 4.2 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:21]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:21][C:13]3[NH:12][C:20]4[C:15]([CH:14]=3)=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1cc2ccccc2[nH]1
Temperature: 95 °C
Yield: 86 %

Procedure:
A mixture of 6-chloro-2-oxindole (41 mg) (commercially available), indole-2-carbaldehyde (42 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (1 drop) in ethanol (3 mL) was heated in a sealed tube at 95° C. for 3 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in vacuum oven for overnight to give 62 mg (87% yield) of 6-chloro-3-(1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one as a shiny orange solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: BrCCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCCOc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 55.4 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with (3-bromopropoxy)benzene (1.3 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 3:1) and crystallized from dichloromethane-hexane to provide 0.7 g of alpha-oxo-4-[[(3-phenoxy) propyl]oxy]benzeneacetic acid methyl ester, mp 61°-62° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][CH2:6][C@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:12][CH:13]=2)[O:8]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:33]1COCC1>>[C:20]1([S:17]([C:11]2[CH:10]=[C:9]3[C:14]([CH2:15][CH2:16][C@H:7]([CH2:6][N:5]([CH3:33])[CH2:4][CH2:3][OH:2])[O:8]3)=[CH:13][CH:12]=2)(=[O:18])=[O:19])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)CNC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN(CCO)C[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Reaction time: 1 h

Procedure:
(R)-[(7-benzenesulfonyl-chroman-2-ylmethyl)-amino]-acetic acid methyl ester (40 mg, 1 mmol) was dissolved in 2 mL dry THF under Ar atmosphere. LAH (0.25 mL of 1M solution in THF) was added dropwise, and the reaction mixture was stirred for one hour. The reaction was quenched by addition of aqueous sodium sulfate solution. The mixture was extracted with methylene chloride and the combined organic layers were washed with water and brine, dried (Na2SO4), filtered and contrated under reduced pressure. The residue was recrystallized from diethyl ether and 1 M HCl in EtOH to give 32.2 mg of (R)-2-[(7-Benzenesulfonyl-chroman-2-ylmethyl)-methyl-amino]-ethanol as a hydrochloride, MS (M+H)=362.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[Se](=O)=[O:15]>>[CH3:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=[C:2]([CH:1]=[O:15])[CH:11]=1
Reactant: O=[Se]=O
Reactant: Cc1ccc2nc(C)cc(C)c2c1
Product: Cc1ccc2nc(C=O)cc(C)c2c1
Yield: 61 %

Procedure:
The title compound was prepared from 2,4,6-trimethylquinoline (6a) and selenium dioxide using methods as described in the literature for similar compounds (Mathes et al., 1957) in 61% yield. 1H NMR (DMSO-d6, HMDSO), δ: 2.58 (3H, s); 2.72 (3H, s); 7.72 (1H, dd, J=1.8 Hz and J=8.6 Hz); 7.76 (1H, s); 7.92 (1H, unresolved d); 8.09 (1H, d, J=8.6 Hz), 10.05 (1H, s).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH2:16]([O:18][C:19]([C:21]1[C:25]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:24]([CH:35]=O)[NH:23][C:22]=1[CH3:37])=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[C:25]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:24]([CH:35]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([S:3](=[O:5])(=[O:4])[NH:2][CH3:1])[CH:7]=3)[NH:11][C:10]2=[O:15])[NH:23][C:22]=1[CH3:37])=[O:20])[CH3:17]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCOCC1
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)NC)cc32)c1CCCN1CCOCC1

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide was stirred with 5-formyl-2-methyl-4-(3-morpholin-4-ylpropyl)-1H-pyrrole-3-carboxylic acid ethyl ester overnight at room temperature to give the title compound.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:21])[C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])[CH:7]=[CH:6][N:5]=1)=[N+]=[N-].O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:21])[C:12]2[C:13]([Cl:20])=[CH:14][C:15]([Cl:19])=[CH:16][C:17]=2[Cl:18])[CH:7]=[CH:6][N:5]=1
Reactant: [N-]=[N+]=Nc1cc(NC(=O)c2c(Cl)cc(Cl)cc2Cl)ccn1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(NC(=O)c2c(Cl)cc(Cl)cc2Cl)ccn1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a solution of N-(2-azidopyridin-4-yl)-2,4,6-trichlorobenzamide (90 mg, 0.26 mmol) in ethanol (5 mL) was added SnCl2.2H2O (300 mg, 1.31 mmol). The mixture was heated at reflux for 1 hour and then cooled to room temperature. The reaction was concentrated under reduced pressure and the residue was diluted with water (10 mL). The mixture was extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to give N-(2-aminopyridin-4-yl)-2,4,6-trichlorobenzamide (82 mg, yield: 100%). LCMS (ESI) m/z: 316.0 [M+H+].
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].C(N(CC)CC)C.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1.Cl.C(N(CC)CC)C>CCOCC>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][S:3]([NH:2][CH3:1])(=[O:5])=[O:4])=[CH:16][CH:17]=1)(=[O:23])[CH3:22]
Reactant: CNS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CNS(=O)(=O)Nc1ccc(C(C)=O)cc1
Temperature: -50 °C

Procedure:
Methylsulfamoyl chloride (42.5 g., 0.33 mole) is added dropwise to a mixture of triethylamine (33.4 g., 0.33 mole) and p-aminoacetophenone (40.5 g., 0.30 mole )in ether (1.5 1.) at -50° C. The mixture is stirred at -50° C. and then allowed to warm to -10° C. The mixture is filtered to give a mixture of product and triethylamine hydrochloride. Washing with water and recrystallization from isopropanol furnishes 30.6 g. (40%) of the above pure intermediate, m.p. 159°-159.5° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C4C=CC([N+]([O-])=O)=CC=4)[CH2:16][CH2:15]3)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:44][C:45]([F:54])([F:53])[CH:46]([C:48]1[N:49]=[CH:50][S:51][CH:52]=1)[OH:47]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:24])[O:47][CH:46]([C:48]4[N:49]=[CH:50][S:51][CH:52]=4)[C:45]([F:44])([F:53])[F:54])[CH2:16][CH2:15]3)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: OC(c1cscn1)C(F)(F)F
Reactant: O=C(NCCC1CCN(c2cccc(-c3ccc(F)cc3)n2)CC1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCC1CCN(c2cccc(-c3ccc(F)cc3)n2)CC1)OC(c1cscn1)C(F)(F)F
Yield: 47.2 %

Procedure:
The procedure described in Example 4 (step 4.6.) is followed. Starting from 0.183 g (1 mmol) of 4-nitrophenyl 2-[6′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]ethylcarbamate, described in Example 4 (step 4.4.), 0.19 g (1.5 mmol) of N,N-diisopropylethylamine, 0.006 g (0.05 mmol) of N,N-dimethylaminopyridine and 0.51 g (1.1 mmol) of 2,2,2-trifluoro-1-thiazol-4-ylethanol, obtained in step 5.1., and after chromatography on silica gel, eluting with a 40/60 mixture of ethyl acetate and cyclohexane, followed by recrystallization from a mixture of diethyl ether and hexane, gives 0.240 g of pure product in the form of a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:24][CH2:23][CH2:22][N:12]2[C:13]=1[C:14]1[N:15]=[N:16][C:17]([NH:20][NH2:21])=[CH:18][CH:19]=1.[N:25]([CH2:28][CH3:29])=[C:26]=S>CN(C1C=CN=CC=1)C.CCO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:24][CH2:23][CH2:22][N:12]2[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]2[N:16]([C:26]([NH:25][CH2:28][CH3:29])=[N:21][N:20]=2)[N:15]=1
Reactant: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3n2CCC3)nn1
Reactant: CCN=C=S
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: CCNc1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn12
Temperature: 75 °C
Yield: 17.2 %

Procedure:
2-(2,4-Difluorophenyl)-3-(6-hydrazinylpyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (0.200 g, 0.609 mmol, Example #35, Step E) and isothiocyanatoethane (0.085 g, 0.975 mmol) were added to EtOH (3 mL). The suspension was heated to about 75° C. for about 3 h. DMAP (0.138 g, 0.670 mmol) was added and the solution was heated in a CEM® microwave at about 150° C. for about 10 min (250 psi maximum pressure, 10 min ramp, 300 max watts). Solvent was removed in vacuo and the material was purified by flash chromatography using MeOH/DCM (0-6% gradient) and then further purified by RP-HPLC (Table 1, Method m). The ACN was removed and the resulting precipitate was collected to afford the title compound (0.040 g, 17%): LC/MS (Table 1, Method g) Rt=1.77 min; MS m/z: 382.2 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[S:16][C:17]([C:20]([CH2:23][O:24][C:25](=[O:31])[CH2:26][O:27][C:28](=[O:30])[CH3:29])([CH3:22])[CH3:21])=[N:18][N:19]=1>C1(C)C=CC=CC=1.CCCCC>[C:28]([O:27][CH2:26][C:25]([O:24][CH2:23][C:20]([C:17]1[S:16][C:15]([NH:14][C:5](=[O:6])[C:4]2[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:8]=2[O:12][CH3:13])=[N:19][N:18]=1)([CH3:22])[CH3:21])=[O:31])(=[O:30])[CH3:29]
Reactant: CC(=O)OCC(=O)OCC(C)(C)c1nnc(N)s1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: COc1cccc(OC)c1C(=O)Nc1nnc(C(C)(C)COC(=O)COC(C)=O)s1
Temperature: 25 °C
Yield: 3 %

Procedure:
A solution of 300 mg of 2,6-dimethoxybenzoyl chloride in 20 ml of toluene containing 300 mg of 2-amino-5-[(2-acetoxy-1-acetoxymethyl)-1-methylethyl]-1,3,4-thiadiazole was heated at reflux for eighteen hours. The reaction mixture was cooled to room temperature and diluted with pentane. A solid precipitate which formed was collected by filtration and air dried to give N-[5-((2-acetoxy-1-acetoxymethyl)-1-methylethyl)-1,3,4-thiadiazol-2-yl]-2,6-dimethoxybenzamide in 3% yield.