Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([NH2:19])=[N:16][C:17]=3[F:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:29]=O)[C:24]([O:27][CH3:28])=[N:25][CH:26]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([NH:19][CH2:29][C:23]4[C:24]([O:27][CH3:28])=[N:25][CH:26]=[C:21]([F:20])[CH:22]=4)=[N:16][C:17]=3[F:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ccc(Cc2c[nH]c3ncc(Br)cc23)c(F)n1
Reactant: COc1ncc(F)cc1C=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(F)cc1CNc1ccc(Cc2c[nH]c3ncc(Br)cc23)c(F)n1
Temperature: 80 °C

Procedure:
To 5-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-ylamine (173, 1 equivalent) and 5-fluoro-2-methoxy-pyridine-3-carbaldehyde (37, 1 equivalent), triethylsilane (4 equivalents) and trifluoroacetic acid (4 equivalents) are added. The reaction is stirred at 80° C. for several hours, then concentrated under vacuum. The resulting material is taken up in ethyl acetate and extracted with addition of aqueous potassium carbonate. The organic layer is concentrated under vacuum, then triturated with dichloromethane to provide the desired compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[CH3:18])[CH2:9]1)=O)(C)(C)C.[ClH:19]>O1CCOCC1>[ClH:19].[ClH:19].[CH3:18][C@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: C[C@H]1CCCN1[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CCCN1[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of (2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester (Intermediate (xiii)) (2.51 g, 9.87 mmol) in 1,4-dioxane (9 mL) was chilled to 0° C. and then added 4N HCl in dioxane (6 mL) and allowed to stir for 20 h at ambient temperature. Then the reaction mixture was concentrated to obtain an oil which was dried under high vacuum to afford 2.29 g of the title compound.
Reaction SMILES: [CH3:1][O:2][P:3]([O:13]C)([N:5]=[C:6]([S:10][CH2:11][CH3:12])[N:7]([CH3:9])[CH3:8])=[S:4].[CH3:15]I>CO>[CH3:1][O:2][P:3]([S:13][CH3:15])([N:5]=[C:6]([S:10][CH2:11][CH3:12])[N:7]([CH3:9])[CH3:8])=[O:4]
Reactant: CI
Reactant: CCSC(=NP(=S)(OC)OC)N(C)C
Solvent: CO
Product: CCSC(=NP(=O)(OC)SC)N(C)C
Reaction time: 6 h
Yield: 263.6 %

Procedure:
A mixture of 36.8 g of N'-(dimethoxyphosphinothioyl)-N,N-dimethylcarbamimidothioic acid, ethyl ester, 120 ml of methanol and 5.0 g of methyl iodide was heated under reflux for 18 hours, then another 5.0 g of methyl iodide was added and heating under reflux was continued for 6 hours. The mixture was concentrated under vacuum, the residue dissolved in methylene chloride, the methylene chloride solution washed once with water and dried over anhydrous magnesium sulfate. The solvent was removed in a rotary evaporator and the residual oil distilled in a Kugelrohr (bath temperature 140° C., pressure 0.3 mm) yielding 23.8 g (65% of theoretical) of N'-(methoxy(methylthio)phosphinyl)-N,N-dimethylcarbamimidothioic acid, ethyl ester. The IR and NMR spectra are in agreement with the assigned structure and identical to those obtained from the compound prepared by the method A.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.[CH:17]([O:20][CH2:21][CH2:22]O)([CH3:19])[CH3:18]>>[CH:17]([O:20][CH2:21][CH2:22][O:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)([CH3:19])[CH3:18]
Reactant: CC(C)OCCO
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Product: CC(C)OCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Yield: 11.8 %

Procedure:
Using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (609 mg, 2.76 mmol) and ethylene glycol monoisopropyl ether (432 mg, 4.15 mmol), the desired title compound (100 mg, yield 31%) was obtained by the same method as in Example 2 (2a).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:13]([NH:15][C@H:16]([C:21]([N:23]([C@@H:25]([CH:34]([CH3:36])[CH3:35])/[CH:26]=[CH:27]/[S:28]([O:31]CC)(=[O:30])=[O:29])[CH3:24])=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:14])[C:4]([CH3:12])([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][NH:2][C@H:3]([C:13]([NH:15][C@H:16]([C:21]([N:23]([C@@H:25]([CH:34]([CH3:36])[CH3:35])/[CH:26]=[CH:27]/[S:28]([OH:31])(=[O:30])=[O:29])[CH3:24])=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:14])[C:4]([CH3:11])([CH3:12])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOS(=O)(=O)/C=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)(C)c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC(C)=O
Product: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C/S(=O)(=O)O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
A solution of N,β,β-trimethyl-L-phenylalanyl-N1-[(1S,2E)-3-(ethoxysulfonyl)-1-isopropylprop-2-enyl]-N1,3-dimethyl-L-valinamide (30 mg, 0.057 mmol) from Example 63 in acetone (1 mL) is treated with tetrabutylammonium iodide (21 mg, 0.057 mmol). The reaction mixture is refluxed for 9 h, and then stirred at room temperature overnight. The solvent is removed. The residue is purified by reversal phase HPLC (mobile phase A: 0.1% TFA/5% acetonitrile/H2O, mobile phase B: 100% acetonitrile) to give 10 mg (28%) of the title compound as a white solid. HRMS (ESI) calcd for C25H41N3O5S [M+H] 496.2840, found 498.2840.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14](=[N+]=[N-])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)C1=Nc2ccccc2C1=[N+]=[N-]
Product: CCOC(=O)c1[nH]c2ccccc2c1OCc1ccccc1

Procedure:
React 3-diazo-3H-indole-2-carboxylic acid ethyl ester, 5, (305 mg, 1.4 mmol) with benzyl alcohol (5.0 equiv., 0.73 mL, 7.05 mmol) as described in General Synthetic Procedure VIII to afford 3-benzyloxy-1H-indole-2-carboxylic acid ethyl ester 6 (R1=benzyl) as a white solid [MS obs=296 (M+1)]. Hydrolyze the ester to the carboxylic acid 7 (R1=benzyl) using General Synthetic Procedure IX and then transform the carboxylic acid to the corresponding primary amide as described in General Synthetic Procedure V to afford the title compound Iu as a tan solid (115 mg), tlc (silica gel) Rf=0.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]([NH2:28])[CH3:27])=[C:16]([F:29])[CH:15]=1.C(N(CC)CC)C>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]([NH:28][S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH3:27])=[C:16]([F:29])[CH:15]=1
Reactant: CC(N)c1ccccc1-c1ccc(Cl)cc1F
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(Cl)cc2F)cc1

Procedure:
The title compound was prepared from 4-methoxybenzenesulfonyl chloride (331 mg, 1.6 mmol), 1-(4′chloro-2′-fluoro-1,1′-biphenyl-2-yl)ethylamine (400 mg, 1.6 mmol), and triethylamine (246 μL, 1.7 mmol) according to the procedure and in the same manner as described in Example 105, step c resulting in the isolation of 644 mg (96%) of a white solid;
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:33]([F:36])([F:35])[F:34])=[CH:8][C:9]=2[CH2:11][O:12][CH2:13][C:14]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[CH:4]=[N:3]1>FC(F)(F)C(O)=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:33]([F:36])([F:35])[F:34])=[CH:8][C:9]=2[CH2:11][O:12][CH2:13][C:14]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH:4]=[N:3]1
Reactant: Cn1ncc2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCNCC3)c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 4-(((1-methyl-5-(trifluoromethyl)-1H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (187 mg, 0.371 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 2 mL) and stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to 151 mg (quant.) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 7.97 (s, 1H), 7.92 (s, 1H), 7.31 (s, 1H), 7.21 (m, 4H), 7.14 (m, 1H), 4.64 (s, 2H), 3.90 (s, 3H), 3.46 (s, 2H), 2.82 (m, 2H), 2.69 (m, 2H), 2.09 (m, 2H), 1.79 (m, 2H), 1.60 (bs, 1H); 13C-NMR (CDCl3, 126 MHz) δ 144.2, 139.5, 133.8, 128.3, 127.1, 126.2, 124.8, 124.7 (q, J=272 Hz), 124.5, 122.5 (q, J=33 Hz), 121.3, 119.6 (q, J=4.8 Hz), 79.4, 70.6, 42.7, 41.7, 38.2, 33.8. Mass spec.: 404.14 (MH)+. Accurate mass spec.: m/z 404.1947 [MH]+, Δ=0.7 ppm.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([C:14]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([CH3:33])[CH:27]=1)([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[C:19]([CH3:25])[CH:18]=1)[CH2:15][CH3:16])[CH3:13].[CH3:34][C:35]([CH3:39])([CH3:38])[CH:36]=[O:37].[Cl-].[NH4+]>O1CCCC1>[CH2:12]([C:14]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([CH3:33])[CH:27]=1)([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH:36]([OH:37])[C:35]([CH3:39])([CH3:38])[CH3:34])=[C:19]([CH3:25])[CH:18]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: CC(C)(C)C=O
Reactant: C#Cc1ccc(C(CC)(CC)c2ccc(O)c(C)c2)cc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC(O)C(C)(C)C)c(C)c1
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
A 2.44 M solution of n-butyllithium in hexane (42.8 mL, 104.5 mmol) was added to a solution of 4-[1-ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-phenol (Example 1-(3); 12.22 g, 41.8 mmol) in tetrahydrofuran (300 mL) at 0° C., and the mixture was stirred at the same temperature for 30 minutes. Trimethylacetaldehyde (13.79 mL, 125.4 mmol) was added at 0° C., and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane/ethyl acetate=9/1 to 3/1) to give the title compound (13.08 g, 83%).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CS(O)(=O)=O.[N-:21]=[N+]=[N-].[Na+].[OH-].[Na+]>ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:15])[NH:21][CH2:10][CH2:11][O:12][C:13]=2[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1ccc2c(c1)OCCC2=O
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)OCCNC2=O
Temperature: 0 °C

Procedure:
7-tert-Butyl-chroman-4-one (1.3 g, 6.36 mmol) was taken up in dichloromethane (11.25 mL) and methane sulfonic acid (7.5 mL) and cooled to 0° C. With stirring at 0° C. was added sodium azide (827 mg, 2 eq) portion-wise. The resulting mixture was stirred at 0° C. for 3 hours and by TLC analysis there was no more starting material remaining, so the reaction mixture was poured into a 20% solution of NaOH(aq) (25 mL) at 0° C. This solution was stirred for 10 minutes and then it was extracted with dichloromethane (3×50 mL) and the combined dichloromethane layers were washed with brine (1×50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography on silica gel eluting with a gradient of 5% ethyl acetate in hexanes to 100% ethyl acetate afforded the title compound as a white solid (1.304 ) (M+H)+=220.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]#[CH:33]>CC#N>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:33][C:32]#[CH:31])[CH2:20][C:19]1=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)n1c(CN2CCNCC2=O)cc2cnccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCN1CCN(Cc2cc3cnccc3n2C(=O)OC(C)(C)C)C(=O)C1
Temperature: 25 °C
Yield: 70.6 %

Procedure:
A solution containing 2-(2-oxo-piperazin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (4.3 g, 13.0 mmol), EXAMPLE 69, in CH3CN (250 mL) is cooled to 0° C. Potassium carbonate (1.98 g, 14.3 mmol) is added to the reaction mixture followed by propargyl bromide (1.55 g, 13.0 mmol). The mixture is slowly warmed to ambient temperature and maintained until complete consumption of starting material is observed by TLC (approx. 8 h). The mixture is concentrated to dryness and then partitioned between aqueous NaHCO3 (200 mL) and CH2Cl2 (200 mL) and the layers are separated. The aqueous phase is extracted twice with CH2Cl2 (100 mL) and the combined organic phase is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue is purified by flash silica gel chromatography (CH2Cl2 to 5% MeOH/CH2Cl2) to provide 3.38 g (70%) of the title compound as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ1.69 (s, 9H), 2.34 (t, J=2.4 Hz, 1H), 2.89 (m, 2H), 3.42 (s, 2H), 3.45 (d, J=2.4 Hz, 2H), 3.52 (m, 2H), 4.95 (d, J=1.4 Hz, 2H), 6.42 (br s, 1H), 7.88 (dd, J=5.8, 0.8 Hz, 1H), 8.41 (d, J=5.8 Hz, 1H), 8.78 (d, J=0.8 Hz, 1H) ppm; MS (EI): m/z 368 (M+).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.[NH2:9][C@H:10]([CH3:26])[CH2:11][N:12]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[CH:18]=2)=[N:13]1>>[Cl:25][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@H:10]([NH:9][C:6]([C:4]3[N:3]=[CH:2][O:1][CH:5]=3)=[O:8])[CH3:26])[N:13]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cocn1
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cocn1
Yield: 45.5 %

Procedure:
(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 4-oxazolecarboxylic acid (0.202 g, 1.749 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g, 1.457 mmol). The product was triturated using diethyl ether. Yield 45.5%. 1H-NMR (400 MHz; DMSO-d6): δ 1.11 (d, 3H), 4.31 (dd, 1H), 4.38 (dd, 1H), 4.41-4.48 (m, 1H), 6.95 (d, 1H), 7.84 (d, 1H), 7.96-8.01 (m, 2H), 8.15 (dd, 1H), 8.50 (d, 1H), 8.54 (d, 1H), 8.58 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[CH3:15])=[O:5].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=2[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH3:15])=[O:5])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Cc1nccn1CCCNC(=O)c1ccccc1N
Solvent: c1ccncc1
Product: Cc1nccn1CCCNC(=O)c1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Amino-N-[3-(2-methylimidazol-1-yl)propyl]benzamide (10.5 g) was dissolved in pyridine (50 ml) and 4-chlorobenzenesulphonyl chloride (12.35 g) was added in portions during five minutes. The temperature of the reaction mixture rose to 45° C. The solution was stirred at room temperature for 4 hours and the pyridine was evaporated in vacuo to give a brown oil. The oil was chromatographed on silica gel, eluting with a mixture of chloroform and methanol (19:1) to give 2-(4-chlorobenzenesulphonamido)-N-[3-(2-methylimidazol-1-yl)propyl]benzamide in the form of a white solid (7 g), m.p. 122°-123° C.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]3[CH:23]=[CH:24][S:25][C:15]=23)[CH2:9][CH2:8]1)(=[O:5])=[O:4]>[Pd].CO>[NH2:20][C:19]1[C:14]([NH:13][C@H:10]2[CH2:9][CH2:8][C@H:7]([CH2:6][S:3]([NH:2][CH3:1])(=[O:5])=[O:4])[CH2:12][CH2:11]2)=[C:15]2[S:25][CH:24]=[CH:23][C:16]2=[N:17][CH:18]=1
Reactant: CNS(=O)(=O)C[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Agent: [Pd]
Solvent: CO
Product: CNS(=O)(=O)C[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Reaction time: 10 h

Procedure:
A mixture of N-methyl-1-{trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methanesulfonamide (35 mg, 0.091 mmol) and 10% palladium on carbon (10 mg) in methanol (1.0 mL) was stirred under an atmosphere of H2 for 10 h. The mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give the desired product (32 mg). LCMS calculated for C15H23N4O2S2 (M+H)+: m/z=355.1. Found: 355.1.
Reaction SMILES: [CH2:1]([NH:7][NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:9][S:10]([C:12]1[S:16][C:15]([N:17]=[C:18]=[O:19])=[N:14][N:13]=1)=[O:11].NN>C(Cl)Cl>[CH2:1]([N:7]([C:18]([NH:17][C:15]1[S:16][C:12]([S:10]([CH3:9])=[O:11])=[N:13][N:14]=1)=[O:19])[NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNN
Reactant: CS(=O)c1nnc(N=C=O)s1
Agent: NN
Solvent: ClCCl
Product: CCCCCCN(N)C(=O)Nc1nnc(S(C)=O)s1
Temperature: 25 °C

Procedure:
A solution of n-hexylhydrazine (0.3 mole) in methylene chloride (150 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 5-Methylsulfinyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.1 mole) is then added, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is stripped of solvent and excess hydrazine to yield the desired product 2-n-hexyl-4-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)semicarbazide as the residue.
Reaction SMILES: [O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][CH2:2]1)[C:11](O)=[N:10][CH:9]=[CH:8]3.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:11]1[C:12]2[C:7](=[C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]3=[CH:14][CH:13]=2)[CH:8]=[CH:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nccc2c3c(ccc12)OCCO3
Product: Clc1nccc2c3c(ccc12)OCCO3

Procedure:
A solution of 2,3-dihydro-[1,4]dioxino[2,3-f]isoquinolin-7-ol (5 g, 24.61 mmol) in POCl3 (50 mL) was refluxed for 14 h. After Concentration, the residue was taken into the mixture of DCM and 4N NaOH solution. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 20% EtOAc/Hexanes as eluent to give 4 g of the desired product 7-chloro-2,3-dihydro-[1,4]dioxino[2,3-f]isoquinoline as a solid. 1H NMR (400 Hz, CDCl3) δ ppm 4.42 (m, 4H), 7.24 (d, J=9.05 Hz, 1H), 7.77 (d, J=5.87 Hz, 1H), 7.84 (d, J=9.05 Hz, 1H), 8.18 (d, J=5.87 Hz, 1H); MS: (M+H)+ 222.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>[F:1][C:2]([F:11])([F:10])[CH:3]1[CH2:8][CH2:7][C:6]([C:15]2[CH:16]=[CH:17][C:12]([OH:18])=[CH:13][CH:14]=2)([C:15]2[CH:16]=[CH:17][C:12]([OH:18])=[CH:13][CH:14]=2)[CH2:5][CH2:4]1
Reactant: O=C1CCC(C(F)(F)F)CC1
Reactant: Oc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Oc1ccc(C2(c3ccc(O)cc3)CCC(C(F)(F)F)CC2)cc1

Procedure:
A solution of 4-(trifluoromethyl)cyclohexanone (1.13 g, 6.8 mmol) and phenol (2.01 g, 21.4 mmol) in 3 mL of concentrated HCl (aq) was stirred at 40° C. for 18 h. The reaction mixture was diluted with EtOAc and saturated aqueous NaHCO3 was slowly added. The organic layer was collected and the aqueous layer was extracted twice with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0% to 40% EtOAc/hexanes over 10 column volumes, then 40% to 100% EtOAc/hexanes over 5 column volumes, affording the title compound as a white solid.
Reaction SMILES: [NH4+:1].[OH-].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](Cl)=[O:11])[CH:5]=1.CC(OC)(C)C>CCOC(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([NH2:1])=[O:11])[CH:5]=1
Reactant: [NH4+]
Reactant: O=C(Cl)c1cc(Cl)ccn1
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aqueous NH4OH (40%, 250 mL) was added dropwise at 0° C. to a suspension of 4-chloro-pyridine-2-carbonyl chloride (75 g, 533 mmol) in EtOAc. Upon addition, the temperature rose to 30° C. The mixture was stirred for 2 h at RT then kept at RT for 12 h without stirring. MTBE (250 mL) was added to the mixture and the resulting emulsion was filtered. The solid was washed with EtOAc. The MTBE/EtOAc layer was washed twice with water and once with 5% Na2CO3, then dried over MgSO4 and concentrated under vacuum. The resulting solid was suspended in EtOAc several times and filtered out to give the desired compound.
Reaction SMILES: Cl[S:2]([C:5]1[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:14]([NH:18][S:2]([C:5]1[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)o1
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)NC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 5-(chlorosulfonyl)-2-furoate (3.0 g) in DCM (100 mL) was added tert-butylamine (3.6 mL). After stirring at room temperature for 2 days the mixture was filtered through a pad of celite, washing with DCM (2×10 mL). The filtrate was evaporated to dryness in vacuo. The resulting crude residue was purified by column chromatography using EtOAc/isohexane (2:8) as eluent to give the subtitle compound as a foam Yield: 2.75 g.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[N:6][C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 43.5 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-1-pyridin-3-yl-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (24 mg, 0.062 mmol), β-alanine (552 mg, 6.2 mmol) and NaOMe solution (10 mL, 5.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between water and EtOAc. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined and concentrated to dryness. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 12 mg of the title compound as a light yellow solid. MS: (+) m/z 445.39 (M+1).