Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.O.C(COC)OC>[C:9]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH:10]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ccc(-c2cccc(-c3ccccc3)c2)nc1
Yield: 72.7 %

Procedure:
To a 1000 mL, 3-necked flask equipped with a stir bar, nitrogen inlet, and a reflux condenser were added 2,5-dibromopyridine (39.9 g, 84.2 mmol), 3-biphenylboronic acid (20.0 g, 101 mmol), palladium(H) acetate (0.47 g, 2.1 mmol), triphenylphosphine (2.2 g, 8.4 mmol), sodium carbonate (24.1 g, 227 mmol), dimethoxyethane (170 mL), and water (114 mL). The reaction mixture was heated at reflux for 16 h, after which ethyl acetate (200 mL) was added. The organic layer was then dried over magnesium sulfate and evaporated to dryness. Purification of the resulting solid on a silica gel column with ethyl acetate/hexane as the eluent yielded 19.0 g (73%) of 2-(biphenyl-3-yl)-5-bromopyridine as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:7]=[C:6]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[N:5]=1)([CH3:3])=[CH2:2].[N+](=[CH2:27])=[N-]>C(OCC)C.C(O)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:2][C:1]1([C:4]2[CH:9]=[C:8]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)(=[O:11])=[O:12])[CH:7]=[C:6]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:5]=2)[CH2:27][CH2:3]1
Reactant: C=C(C)c1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC1(c2cc(S(=O)(=O)c3ccc(N)cc3)cc(N3CCCC3)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
0.164 g (0.00048 Mol) 4-(2-Isopropenyl-6-pyrrolidin-1-yl-pyridine-4-sulfonyl)-phenylamine were dissolved in ethyl ether (100 ml) and cooled to 0° C. A solution of diazomethane in ethyl ether (30 ml) was carefully added. Upon addition of a catalytic amount of Pd(OAc)2 gas evolution started. The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min. After addition of a few drops of acetic acid the solvent was evaporated and the residue chromatographed on SiO2 with ethyl acetate hexane 1:2. It was obtained 0.136 g (71%) of 4-[2-(1-Methyl-cyclopropyl)-6-pyrrolidin-1-yl-pyridine-4-sulfonyl]-phenylamine as pale yellow cristals; mp.: 235-236° C. (dec.).
Reaction SMILES: [I:1][C:2]1[C:3]([O:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[N:33]([C:37]([NH:39][CH3:40])=[O:38])[CH:32]=[CH:31]3)=[N:4][C:5](N(C(OC2C=CC=CC=2)=O)C(=O)OC2C=CC=CC=2)=[N:6][CH:7]=1.CO.C[NH2:44].O.[CH3:46][N:47](C)[CH:48]=[O:49]>>[CH3:40][NH:39][C:37]([N:33]1[C:34]2[C:30](=[CH:29][C:28]([O:27][C:3]3[C:2]([I:1])=[CH:7][N:6]=[C:5]([NH:44][C:48]([NH:47][CH3:46])=[O:49])[N:4]=3)=[CH:36][CH:35]=2)[CH:31]=[CH:32]1)=[O:38]
Reactant: CN(C)C=O
Reactant: CN
Reactant: CNC(=O)n1ccc2cc(Oc3nc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)ncc3I)ccc21
Solvent: CO
Solvent: O
Product: CNC(=O)Nc1ncc(I)c(Oc2ccc3c(ccn3C(=O)NC)c2)n1
Temperature: 0 °C
Yield: 86 %

Procedure:
Phenyl N-(5-iodo-4-(1-methylaminocarbonyl-1H-indol-5-yloxy)pyrimidin-2-yl)-N-(phenoxycarbonyl)carbamate (597 mg, 0.919 mmol) was dissolved in dimethylformamide (3.0 ml); a 40% methanol solution of methylamine (1.0 ml) was added while stirring at 0° C.; and the reaction mixture was further stirred for 30 minutes keeping the temperature. Water (10 ml) was added to the reaction mixture after the completion of the reaction; the precipitated crystals were filtered off, washed with water, methanol and diethyl ether, and dried under warm aeration to yield the title compound as white crystals (367 mg, 0.787 mmol, 86%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[S:7][C:6]([C:8]#[N:9])=[N:5][CH:4]=1.C[O-].[Na+].[Cl-:15].[NH4+:16]>>[ClH:15].[F:11][C:2]([F:1])([F:10])[C:3]1[S:7][C:6]([C:8](=[NH:16])[NH2:9])=[N:5][CH:4]=1
Reactant: N#Cc1ncc(C(F)(F)F)s1
Reactant: [NH4+]
Reactant: [Cl-]
Agent: C[O-]
Agent: [Na+]
Product: Cl
Product: N=C(N)c1ncc(C(F)(F)F)s1

Procedure:
5-(trifluoromethyl)thiazole-2-carbonitrile (1.25 g, 7 mmol) was reacted with sodium methoxide (0.38 g, 7 mmol) and ammonium chloride (0.76 g, 14 mmol) according to the procedure as described in Example 61, Step B to give the title compound as an offwhite solid (1.3 g, 80%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C-:1]#[N:2].[Na+].[O:4]=[CH:5][C:6]1[CH:14]=[CH:13][C:11]([OH:12])=[C:8]([O:9][CH3:10])[CH:7]=1.C(O)C.Cl>O>[OH:4][CH:5]([C:6]1[CH:14]=[CH:13][C:11]([OH:12])=[C:8]([O:9][CH3:10])[CH:7]=1)[C:1]#[N:2]
Reactant: COc1cc(C=O)ccc1O
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(C(O)C#N)ccc1O
Temperature: 0 °C

Procedure:
Sodium cyanide (10.2 g) is dissolved in water (40 ml) and cooled to 0° C. A second solution comprising vanillin (15.5 g) and ethanol (30 ml) is added at 0° C. Now, concentrated hydrochloric acid (28.5 g 32%) is added to the mixture at 0 to +5° C. within 30 to 45 minutes and the dropping funnel is rinsed with water (10 ml). After confirming that the conversion has proceeded to a satisfactory level by HPLC, the mixture is worked up by extracting repeatedly with t-butyl methyl ether (3×50 ml). The collected organic phases are washed twice with 10% aqueous bisulfite (50 ml) and once with water (40 ml). Finally, the product solution is dried and the solvent is evaporated in vacuum to yield the crude product as a yellow oil, which crystallized on standing (mp 80-81° C.). If the already pure product needs further purification, it can be crystallized from ether/hexane (m.p82-83° C.).
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([NH:13][C:14]2[N:19]3[N:20]=[C:21]([NH2:23])[N:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl.Cl[CH2:26][C:27]1[N:32]=[CH:31][C:30]([C:33](Cl)=[O:34])=[CH:29][CH:28]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(Cl)Cl.C1COCC1>[CH:7]1([NH:13][C:14]2[N:19]3[N:20]=[C:21]([NH:23][C:33](=[O:34])[C:30]4[CH:29]=[CH:28][C:27]([CH2:26][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[N:32][CH:31]=4)[N:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: C1COCCN1
Reactant: Nc1nc2cccc(NC3CCCCC3)n2n1
Reactant: O=C(Cl)c1ccc(CCl)nc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1nc2cccc(NC3CCCCC3)n2n1)c1ccc(CN2CCOCC2)nc1
Temperature: 60 °C
Reaction time: 0.2 h
Yield: 9.2 %

Procedure:
Pyridine (198 mg; 2.5 mmol; 5.0 eq.) was added to a solution of N5-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A9), 116 mg; 0.50 mmol; 1.0 eq.) in DCM (2.0 mL). 6-(chloromethyl)pyridine-3-carbonyl chloride hydrochloride (190 mg; 1.0 mmol; 2.0 eq.) was added and the resulting black solution was stirred under reflux for 14 h. The solvents were evaporated to yield a black oil. Morpholine (218 mg; 2.5 mmol; 5.0 eq.) and THF (0.5 mL) were added to this residue, and the mixture was then stirred and heated at 60° C. for 12 h. Purification by RP-HPLC (Waters Sunfire™ Prep C18 OBD™ 5 μM, 100×49 mm) following a gradient starting with 20/80 (0.1% formic acid in CH3CN/0.1% formic acid in H2O) up to 95/5 in 12 min. The fractions were collected and lyophilized to give the title compound as a white powder (20 mg, 9%). HPLC, Rt: 2.11 min. (purity 100%). LC/MS, M+(ESI): 436.3.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[NH2:16]>C1(C)C=CC=CC=1.C1COCC1>[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[N:16]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[N:5]=1)[CH3:11]
Reactant: Nc1c(F)cccc1F
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc(C(C)=Nc2c(F)cccc2F)n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 19.9 %

Procedure:
2,6-Diacetylpyridine (4.04 g, 24.7 mmol) and 2,6-difluoroaniline (3.2 g, 24.7 mmol) were dissolved in 50 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 5 days at room temperature, the mixture was filtered. The solvent was removed in vacuo. From the resulting mixture of 2,6-diacetylpyridine, monoimine, and diimine. Most of the 2,6-diacetylpyridine was removed by sublimation in vacuo at 80-90° C. The residue contained based on 1H-NMR data 0.35 mmol 2,6-diacetylpyridine , 1.28 mmol diimine and 5.46 mmol monoimine. This mixture was reacted with 162 mg (1.28 mmol) FeCl2 in 10 ml THF to remove the diimine. After stirring for 16 h at room temperature, the solvent was removed in vacuo. Toluene (50 ml) was added to the resulting mixture. The precipitated complex was filtered off over a small layer of silica, yielding a yellow solution. The solvent was removed in vacuo. Crystallisation from ethanol yielded 1.35 g of 2-[1-(2,6-difluorophenylimino)ethyl]-6-acetylpyridine (18) (19.8%).
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=O.[C:6]1(=[O:12])C[CH2:10][CH2:9][CH:8]=[CH:7]1.[C:13]1(N=C=O)C=CC=CC=1>CCOCC.C(N(CC)CC)C>[CH3:13][C:4]1[CH:5]2[C:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH:10]2[O:3][N:1]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC[N+](=O)[O-]
Reactant: O=C1C=CCCC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC1=NOC2CCCC(=O)C12
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.8 %

Procedure:
Under an inert atmosphere a solution of nitroethane (5.36 g, 5.1 ml, 71.4 mmol) in ether (20 ml) was treated at room temperature with a solution of cyclohex-2-enone (6.73 g, 6.78 ml, 70 mmol) in ether (120 ml) followed by the addition of triethylamine (70.8 mg, 97.6 μl, 700 μmol) and the dropwise addition (appr. 1 minute) of phenyl isocyanate (17.0 g, 15.6 ml, 143 mmol). The clear solution was stirred at 25° C. for 48 hours while solid started to precipitate after 2 hours. For the workup, the solid material was filtered and washed three times with ether. The yellow filtrate was evaporated, then the yellow crude product was suspended in dichloromethane (30 ml), the solid was filtered off and washed three times with dichloromethane. After evaporation of the filtrate the crude product was purified by flash chromatography on silica gel using a gradient of heptane and ethyl acetate=5:1 to 4:1 to 1:1 as the eluent. The rac-(3aR,7aR)-3-methyl-5,6,7,7a-tetrahydrobenzo[d]isoxazol-4(3aH)-one (7.27 g, 68% yield) was obtained as an orange liquid. MS: m/z=154.1 [M+H]+. In addition, the rac-(3aR,7aS)-3-methyl-3a,5,6,7a-tetrahydro-4H-benzo[d]isoxazol-7-one (0.52 g, 4.9% yield) was obtained as a light brown solid. MS: m/z=154.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:33]1[C:35]2([CH2:40][NH:39][CH2:38][CH2:37][N:36]2C(OC(C)(C)C)=O)[CH2:34]1>>[NH:26]1[C:22]([C:21]2[C:2]([N:39]3[CH2:40][C:35]4([CH2:33][CH2:34]4)[NH:36][CH2:37][CH2:38]3)=[N:3][CH:4]=[C:5]([CH:20]=2)[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:18])([F:19])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:23][CH:24]=[N:25]1
Reactant: CC(C)(C)OC(=O)N1CCNCC12CC2
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCNC3(CC3)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 32.1) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate to afford an amorphous white powder. HPLC (Condition 4) tR=4.17 min, UPLC-MS (Condition 3) tR=0.78 min, m/z=459.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.46-0.85 (m, 4H) 3.04 (br. s, 2H) 3.16-3.37 (m, 5H) 6.67 (br. s, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.86 (d, J=9.38 Hz, 3H) 8.34 (br. s, 1H) 8.75 (s, 1H) 10.43 (s, 1H) 12.96-13.19 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N:15]([CH2:20][CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:22]=[C:23]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:24]([C:25](O)=[O:26])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[CH2:36][N:37]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN>ClCCl.O>[CH2:1]([O:8][C:9]1[C:14]([N:15]([CH2:20][CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:22]=[C:23]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:24]([C:25]([NH:37][CH3:36])=[O:26])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)O)c2cc1OCc1ccccc1)S(C)(=O)=O
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1OCc1ccccc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(Benzyloxy)-6-(N-ethyl methylsulfonamido)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.11 g, 0.22 mmol, 1 eq), EDCI.HCl (0.048 g, 0.25 mmol, 1.1 eq), HOBT (0.036 g, 0.27 mmol, 1.2 eq), DIPEA (0.12 ml, 0.68 mmol, 3 eq) were dissolved in dichloromethane and the reaction was stirred at room temperature for 10 minutes. Then Methylamine (1 M in THF, 0.6 ml, 5 eq) was added to the above solution and the reaction was stirred at room temperature for 14 h. Finally, the mixture was diluted with water and the product was extracted with dichloromethane. The organic layer was washed with water, dried and concentrated. Yield: 0.1 g (90%). 1HNMR (400 MHz, DMSO-d6): δ 1.06 (t, J=7.12 Hz, 3H), 2.77 (s, 3H), 3.00 (s, 3H), 3.62 (br m, 2H), 5.30 (s, 2H), 7307.32 (m, 3H), 7.33 (d, J=5.8 Hz, 1H), 7.40-7.43 (m, 21-1), 7.53-7.55 (m, 2H), 7.81 (t, J=3.52 Hz, 1H), 7.95 (s, 2H), 8.88 (s, 1H). LCMS: (ES+) m/z=497.0 (M+H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH2:8][OH:9])[S:6][CH:7]=1.[CH2:12]([C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[C:21]([N:24]3[CH:29]=[CH:28][C:27](O)=[CH:26][C:25]3=[O:31])[CH:22]=[CH:23][C:16]=2[N:15]=1)[CH3:13].N(C(OCCOC)=O)=NC(OCCOC)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[CH2:12]([C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[C:21]([N:24]3[CH:29]=[CH:28][C:27]([O:9][CH2:8][C:5]4[S:6][CH:7]=[C:3]([C:2]([F:10])([F:1])[F:11])[CH:4]=4)=[CH:26][C:25]3=[O:31])[CH:22]=[CH:23][C:16]=2[N:15]=1)[CH3:13]
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Reactant: OCc1cc(C(F)(F)F)cs1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2ccc(-n3ccc(OCc4cc(C(F)(F)F)cs4)cc3=O)cc2n1C
Reaction time: 3 h
Yield: 8.6 %

Procedure:
To a solution of (4-(trifluoromethyl)thiophen-2-yl)methanol (50 mg) in THF (3 ml) were added 1-(2-ethyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (73.9 mg), bis(2-methoxyethyl) azodicarboxylate (129 mg) and PPh3 (144 mg) at room temperature, and the mixture was stirred for 3 h. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO3 solution and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/MeOH) to give the title compound (10.2 mg) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.ClS(O)(=O)=O.ClC1C=CC(Cl)=CC=1[SH:22].Cl[CH2:24][C:25]([OH:27])=[O:26]>[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:24]([SH:22])[C:25]([OH:27])=[O:26]
Reactant: Clc1ccc(Cl)cc1
Reactant: Sc1cc(Cl)ccc1Cl
Reactant: O=C(O)CCl
Agent: O=S(=O)(O)Cl
Agent: [Zn]
Product: O=C(O)C(S)c1cc(Cl)ccc1Cl

Procedure:
the method in which 1,4-dichlorobenzene is sulfochlorinated with chlorosulfonic acid and then reduced to 2,5-dichlorothiophenol with zinc powder under acidic conditions, followed by reaction with monochloroacetic acid to yield 2,5-dichlorophenylthioglycolic acid (U.S. Pat. No. 3440288),
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].ClC1C2C(=CC=CC=2)C(CNC(O)C(C)CO)=C2C=1C=CC=C2.[Cl:29][C:30]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[C:36]2[C:31]=1[CH:32]=[CH:33][CH:34]=[C:35]2[CH:44]=O.[NH2:46][C:47]([CH3:52])([CH2:50][OH:51])[CH2:48]O>>[CH3:1][S:2]([O:5][CH2:48][C:47]([NH:46][CH2:44][C:35]1[C:36]2[C:31](=[C:30]([Cl:29])[C:43]3[C:38]([CH:37]=2)=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:32]=[CH:33][CH:34]=1)([CH3:52])[CH2:50][OH:51])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)O
Reactant: CC(N)(CO)CO
Reactant: O=Cc1cccc2c(Cl)c3ccccc3cc12
Agent: CC(CO)C(O)NCc1c2ccccc2c(Cl)c2ccccc12
Product: CC(CO)(COS(C)(=O)=O)NCc1cccc2c(Cl)c3ccccc3cc12

Procedure:
Using the reductive amination procedure described in 2B, 10-chloroanthracene-1-carbaldehyde (37D) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-(((10-chloro-1-anthracenyl)methyl)amino)-2-methyl-1,3-propanediol methanesulfonate.9/20H2O mp 230°-231° (dec), (EtOH/Et2O), (C, H, Cl, N, S).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([C:16]([N:18]2[CH2:27][CH2:26][C:25]3[N:24]=[CH:23][C:22]([C:28]([F:31])([F:30])[F:29])=[CH:21][C:20]=3[CH2:19]2)=[O:17])[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[CH3:1][O:2][CH2:3][C:4]1([C:16]([N:18]2[CH2:27][CH2:26][C:25]3[N:24]=[CH:23][C:22]([C:28]([F:30])([F:29])[F:31])=[CH:21][C:20]=3[CH2:19]2)=[O:17])[CH2:8][CH2:7][NH:6][CH2:5]1
Reactant: COCC1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)CCNC1
Reaction time: 17 h

Procedure:
The title compound was prepared according to general procedure D described in connection with Scheme 2. tert-Butyl 3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidine-1-carboxylate (1.7 g, 3.84 mmole) was dissolved in 50 mL CH2Cl2 and 16 mL TFA was added at RT. The reaction mixture was stirred for 17 h and the solvents evaporated. The residue was dissolved in CH2Cl2 and the organic layer was washed twice with 50 mL of saturated NaHCO3 and then dried over Na2SO4. The solvent was evaporated to give product (1.3 g, quantitative yield) of the desired product. 1H NMR (400 MHz, CDCl3): δ 8.71 (s, 1H), 7.70 (s, 1H), 4.81 (s, 2H), 4.13-3.89 (m, 2H), 3.52-3.43 (m, 3H), 3.29 (s, 3H), 3.12-2.97 (m, 5H), 2.22-2.18 (m, 1H), 2.04-1.97 (m, 1H); MS (ESI) m/z: Calculated for C16H20F3N3O2(free base): 343.2. found: 344 (M+H)+.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[C:13]([NH2:21])(=[S:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CC(C)=O>[Cl:11][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3([OH:12])[N:21]=[C:13]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[S:20][CH:2]3[CH2:10][C:9]=2[CH:8]=1
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Reactant: NC(=S)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: OC12N=C(c3ccncc3)SC1Cc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.98 g of 2-bromo-5-chloroindan-1-one and 0.55 g of thioisonicotinamide are dissolved in 40 ml of dry acetone at room temperature and treated with 0.55 ml of triethylamine. The mixture is stirred at room temperature for 2 days. The reaction mixture is concentrated, and the residue is taken up with ethyl acetate and washed twice with water and then twice with satd sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated, and the residue is chromatographed on silica gel using ethyl acetate/n-heptane 10/1. 6-Chloro-2-pyridin-4-yl-8,8a-dihydro-indeno[1,2-d]thiazol-3a-ol of melting point 155-160° C. (dec.) is obtained.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[Br:9][C:10]1[CH:11]=[C:12]([C:16](=[O:18])[CH3:17])[CH:13]=[N:14][CH:15]=1>>[Br:9][C:10]1[CH:11]=[C:12]([C:16](=[O:18])[CH:17]=[CH:3][N:4]([CH3:5])[CH3:6])[CH:13]=[N:14][CH:15]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cncc(Br)c1
Product: CN(C)C=CC(=O)c1cncc(Br)c1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
An N,N-dimethylformamide dimethylacetal (2 ml) solution containing 1-(5-bromopyridin-3-yl)ethanone (100 mg) (WO2009/87224 A1) was stirred at 100° C. for 5 hours. The solvent was distilled away under reduced pressure, and a yellow solid of 1-(5-bromopyridin-3-yl)-3-(dimethylamino)prop-2-ene-1-one was thus obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:18])=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: COS(=O)(=O)OC
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91 %

Procedure:
A suspension of 4-formylcinnamic acid (10.0 g), dimethyl sulfate (5.9 ml) and potassium carbonate (11.8 g) in 100 ml dimethylformamide was stirred at room temperature for 17 hours. After removal of inorganic salts by filtration, saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, and dried over sodium sulfate. The drying agent was filtered off and the filtrate was evaporated and dried under reduced pressure to give methyl 4-formylcinnamate (9.78 g, 91%) as a pale yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][N:16]1[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[N:17]1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:18]1[CH:19]=[CH:20][N:16]([CH3:15])[N:17]=1)=[O:22]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: Cn1ccc(C(=O)Cl)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)n1
Yield: 64.5 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0443 g, 0.188 mmol), 1-methyl-1H-pyrazole-3-carbonyl chloride (0.028 g; 0.188 mmol), and triethylamine (0.066 mL; 0.470 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 16% of ethyl acetate in dichloromethane gave 0.0367 g (65%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-methyl-1H-pyrazole-3-carboxamide as a solid.
Reaction SMILES: [CH3:1]/[C:2](=[CH:12]\[S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.S(Cl)(Cl)=O.CN(C=O)C>C1(C)C=CC=CC=1>[CH3:1][C:2](=[CH:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C/C(=C\Sc1ccccc1)C(=O)Nc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCCCCSC(=Nc1ccccc1)C(C)=CSc1ccccc1
Reaction time: 0.08 h
Yield: 12 %

Procedure:
A suspension of 1.0 g (3.71 mmol) of (E)-2-methyl-N-phenyl-3-(phenylthio)-2-propenamide, 0.81 ml of thionyl chloride, and 10 mg of DMF in 10 ml of toluene was refluxed for 1 hour and then concentrated under vacuum. The residue was dissolved in 5 ml of DMF and cooled in ice bath. To a solution of 241 mg of n-hexylthiol in 5 ml of DMF was added 90 mg of sodium hydride (60% in oil) under ice cooling and stirred for 5 minutes. The mixture was added portionwise to the above-described DMF solution of the residue under ice cooling and then stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with tert-butyl methyl ether (three times). The combined organic layer was washed sequentially with water and a saturated NaCl solution, dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain 82 mg of n-hexyl 2-methyl-N-phenyl-3-(phenylthio)-2-propenimidothioate (hereinafter referred to as the present compound 47) and 114 mg of n-hexyl 3-(hexylthio)-2-methyl-N-phenyl-2-propenimidothioate (hereinafter referred to as the present compound 48).