Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)C(Cl)=O>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(C)nc1Cl
Reaction time: 2 h

Procedure:
To the solution of 2-chloro-6-methylnicotinic acid (5 g, 29.1 mmol) in CH2Cl2 (40 mL) was added oxalyl dichloride (8.1 g, 63.8 mmol) at 0° C. and the reaction mixture was stirred for 2 h. The mixture was concentrated and 40 mL of methanol was then added at 0° C. and the reaction mixture was stirred at RT for 12 h. The mixture was then concentrated in vacuo and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide methyl 2-chloro-6-methylnicotinate that is used without further purification as a light yellow solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][C:24]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[NH2:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:44])=[C:39]([CH:43]=1)[C:40]([OH:42])=[O:41]>CN(C=O)C>[CH3:44][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][NH:33][C:30]([C:24]2([CH3:23])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:31])=[CH:43][C:39]=1[C:40]([OH:42])=[O:41]
Reactant: Cc1ccc(CN)cc1C(=O)O
Reactant: CC1(C(=O)O)CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(CNC(=O)C2(C)CCCCC2)cc1C(=O)O

Procedure:
TBTU (15 mmol; 4.9 g) was added to a mixture of 1-methylcyclohexylcarboxylic acid (15 mmol; 2.2 g), TEA (9.6 mL) and DMF (130 mL) at rt. After 10 min a mixture of 5-aminomethyl-2-methylbenzoic acid (6.3 g crude mixture with NaCl, see step (b) above) was added. After 3 h at rt the reaction mixture was concentrated, water was added and the formed precipitate was washed with water, dried and purified by preparative HPLC. Yield: 3.6 g (83%). MS [M+H]+=290; TLC: Rf=0.49 (silica gel, DCM:EtOH 9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:16]([O:18]C)=O)[C:8]([C:12]([O:14]C)=O)=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH2:23]([NH:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(O)C>[CH2:23]([N:30]1[C:16](=[O:18])[C:7]2[C:6](=[O:20])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:10]=3[NH:9][C:8]=2[C:12]([OH:14])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C

Procedure:
To a stirred suspension of dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (5.00 g, 16.90 mM) and benzyl hydrazine dihydrochloride (46.15 g, 236.50 mM) in ethanol (100 mL) was added triethylamine (75.8 mL, 541.0 mM). The mixture was heated to give a brown solution which was refluxed for 40 hours during which time a precipitate formed. The suspension was cooled to room temperature and filtered to give the benzyl hydrazine salt of the title compound as an impure yellow solid. Multiple crystallizations from ethanolic hydrogen chloride and methanol gave the title compound (0.370 g, 6%) as a white powder, mp=347°-350° C.; MS(CI): 354 (M+H). Analysis for C18H2ClN3O3 : Calculated: C, 61.10; H, 3.42; N, 11.90; Found: C, 60.68; H, 3.61; N, 11.80; NMR: 12.65 (br s, 1H, exchangeable), 11.93 (br s, 1H, exchangeable), 8.15 (d, J=8.67 Hz, 1H), 8.02 (d, J=1.83, 1H), 7.43 (d, J=8.55 Hz, 1H), 7.36-7.23 (m, 5H), 5.11 (s,2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:28]=[N:27][NH:26][C:5]2=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=[C:15]([Cl:17])[CH:16]=1)[O:8][C:7]2=[O:25].Cl.[C:30]1([NH2:36])([CH:33]2[CH2:35][CH2:34]2)[CH2:32][CH2:31]1.C(N(CC)CC)C>CN(C)C=O>[C:30]1([NH:36][C:7]([C:6]2[C:11]([NH:10][C:9]([C:12]3[N:13]([C:18]4[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=4)[N:14]=[C:15]([Cl:17])[CH:16]=3)=[O:8])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:5]=2[NH:26][N:27]=[CH:28]3)=[O:25])([CH:33]2[CH2:35][CH2:34]2)[CH2:32][CH2:31]1
Reactant: O=c1oc(-c2cc(Cl)nn2-c2ncccc2Cl)nc2c(Cl)cc3cn[nH]c3c12
Reactant: NC1(C2CC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1(C2CC2)CC1)c1c(NC(=O)c2cc(Cl)nn2-c2ncccc2Cl)c(Cl)cc2cn[nH]c12
Temperature: 50 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
To a solution of 400 mg (0.78 mmol) of the above 5-chloro-7-[5-chloro-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3-yl]-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 8 mL of N,N-dimethylformamide is added 262 mg (1.96 mmol) of bicyclopropyl-1-ylamine hydrochloride and 273 μL (1.96 mmol) of triethylamine. The reaction is stirred at 50° C. for 16 hours and then concentrated in vacuo. The residue is taken-up with water and tert-butylmethylether. The phases are separated and the aqueous layer is washed twice with tert-butylmethylether. The combined organic layers are washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexanes/ethyl acetate 1:1 to 1:2, gradient) affords 380 mg (91%) of the product as a white solid; LC/MS:530/532 (M+H)+, m.p.: 173-175° C.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[CH:30]=[CH:29][C:19]2[S:20][C:21]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)=[CH:22][C:18]=2[CH:17]=1.C(O)C>CS(C)=O>[Cl:15][C:16]1[CH:30]=[CH:29][C:19]2[S:20][C:21]([C:23]3[CH2:24][CH2:25][N:26]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:27][CH:28]=3)=[CH:22][C:18]=2[CH:17]=1
Reactant: Clc1ccc2sc(C3=CCNCC3)cc2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CCO
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2cc3cc(Cl)ccc3s2)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.075 g, 0.042 mmol), and 5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene (0.100 g, 0.042 mmol) using ethanol a s reaction solvent. Yield 0.103 g (58%) of an orange oil. FDMS m/e=438 (M+ of free base). α[D]589 =+7.3 (c=0.95, dimethylsulfoxide)
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8](=[O:16])[CH:7]=1.[BrH:17]>>[Br:17][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8](=[O:16])[CH:7]=1
Reactant: O=c1cc(CCCCO)c2ccccc2[nH]1
Reactant: Br
Product: O=c1cc(CCCCBr)c2ccccc2[nH]1
Yield: 61.3 %

Procedure:
4-(4-hydroxybutyl)-2(1H)-quinolinone (1 g, 4.60 mmol) was suspended in 47%hydrobromic acid solution (20 ml) and the mixture was refluxed for 16 hours. The reaction mixture was cooled in ice bath and the separated solid was filtered off by aspiration. The residue was washed with water and recrystallized with methanol (with treatment with activated carbon) to give the entitled compound (II-4) as white crystals (790 mg, yield 61.3%, mp 156°-158 ° C. (methanol)).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.CCOCC.Cl.O.[CH3:17][CH2:18][CH2:19][CH2:20][CH2:21]C>>[CH:1]1([C:7](=[O:9])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: CCCCCC
Reactant: O=C(O)C1CC=CCC1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CCCCCC(=O)C1CC=CCC1
Temperature: 25 °C

Procedure:
A 500 mL round bottom flask equipped with a mechanical stirrer was charged with 18.9 g (0.15 mol) 3-cyclohexene-1-carboxylic acid, and 300 mL of ether. 132 mL of hexylithium (2.5 M solution in hexane, 0.33 mol) was slowly added to above mixture in ice bath over 40 min. After the above mixture was reacted at 0° C. for 30 minutes, the reaction mixture was warmed to room temperature. The mixture is slowly added into a vigorously stirred mixture of 27 mL (0.32 mol) of concentrated HCl and 400 mL of water. The organic phase is separated, and aqueous phase is extracted with 3×150 mL of ether, the combined organic solution is dried over sodium sulfate, and the solution is evaporated and distilled to give pure product.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH:6]1([C:11]2[C:15]3[N:16]=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH3:29])[NH:18][C:19](=[O:20])[C:14]=3[O:13][N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1>ClCCl>[CH:6]1([C:11]2[C:15]3[N:16]=[C:17]([C:21]4[CH:26]=[C:25]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH3:29])[NH:18][C:19](=[O:20])[C:14]=3[O:13][N:12]=2)[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CCOc1ccccc1-c1nc2c(C3CCCC3)noc2c(=O)[nH]1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nc2c(C3CCCC3)noc2c(=O)[nH]1
Reaction time: 8 h

Procedure:
0.24 ml (3.6 mmol) of chlorosulfonic acid is introduced while cooling with ice. 130 mg (0.4 mmol) of 3-cyclopentyl-5-(2-ethoxyphenyl)-isoxazolo[4,5-d]pyrimidin-7(6H)-one (example VIII) are added in portions and the mixture is subsequently stirred overnight under reflux; after that, it is diluted with dichloromethane and poured onto ice water. The organic phase is separated off and extraction with dichloromethane takes place again; the organic phases are combined, dried and evaporated.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[C:3]1Cl.C([O-])([O-])=O.[K+].[K+].[SH:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[CH:11]=[C:21]([C:22]([O:24][CH3:25])=[O:23])[S:20][C:3]1=2
Reactant: Cn1c(Cl)c(C=O)c2ccccc21
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc2c3ccccc3n(C)c2s1

Procedure:
Prepared from (3) (9.6 g), K2CO3 (15 g) and methyl 2-mercaptoacetate (10 ml) yielding (6) (9.3 g), m.p. 133.5°-133.8° C.
Reaction SMILES: Cl[C:2]([N:4]1[CH2:7][CH:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH2:5]1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH3:25][NH:26][CH2:27][C:28]#[CH:29]>O1CCCC1>[CH3:25][N:26]([CH2:27][C:28]#[CH:29])[C:2]([N:4]1[CH2:7][CH:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH2:5]1)=[O:3]
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reactant: C#CCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C#CCN(C)C(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 73.7 %

Procedure:
A mixture of 5.6 g (0.02 mole) of 1-chlorocarbonyl-3-[3-(trifluoromethyl)phenoxy]azetidine and 3 g (0.022 mole) of potassium carbonate in 50 ml of tetrahydrofuran was treated while stirring with 1.52 g of N-methylpropargylamine. After stirring for 15 min, 10 g of ice was added and stirring continued for an additional 72 hr. The tetrahydrofuran was decanted from the salt paste and concentrated on a rotary evaporator to yield an amber oil, 5.9 g. This oil solidified when cooled to -70° C. and was recrystallized from hexane to yield 4.6 g (74.2%) of fine white crystals, m.p. 71°-73° C.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]([F:49])([F:48])[CH2:27][NH:28][C:29]([C:31]1([CH2:44][CH2:45][CH2:46]Br)[C:43]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:30]>CN(C=O)C.C(OCC)(=O)C>[F:25][C:26]([F:48])([F:49])[CH2:27][NH:28][C:29]([C:31]1([CH2:44][CH2:45][CH2:46][N:16]2[CH2:15][CH2:14][N:13]([C:10]3[CH:11]=[CH:12][C:2]([CH3:1])=[C:3]([CH:9]=3)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:18][CH2:17]2)[C:43]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:30]
Reactant: CCOC(=O)c1cc(N2CCNCC2)ccc1C
Reactant: O=C(NCC(F)(F)F)C1(CCCBr)c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N2CCN(CCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)ccc1C
Temperature: 75 °C
Reaction time: 7 h
Yield: 59.4 %

Procedure:
Ethyl 2-methyl-5-piperazinylbenzoate (1.8 g, 9.1 mmol) was dissolved in 20 ml of anhydrous DMF. Potassium carbonate (1.7 g) and 3-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]propyl bromide (2.5 g, 6.1 mmol) were added to the solution, and the mixture was stirred at 75° C. for 7 hr. The temperature of the reaction solution was returned to room temperature, and the reaction solution was then diluted with ethyl acetate. The dilution was washed twice with water and was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography (development system, n-hexane:ethyl acetate=2:1) to give 2.1 g (yield 59%) of ethyl 5-[4-[3-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]propyl]piperazinyl]-2-methylbenzoate as a pale yellow foam.
Reaction SMILES: I[C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: OB(O)c1ccco1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1-c1ccco1
Temperature: 105 °C
Yield: 15.6 %

Procedure:
5-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (400 mg, 1 mmol), furan 2-boronic acid (285 mg, 1.5 mmol) and Pd(Ph3)2Cl2 (50 mg) were taken up in 13 mL of degassed dioxane in a screw cap pressure flask. Sodium bicarbonate (2 mL of 2M aqueous solution) was added, and the reaction mixture was heated to 105° C. for 40 hours. The reaction mixture was cooled and partitioned between water and ethyl acetate. The organic phase was separated, dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (3% to 5% MeOH in methylene chloride with 1% ammonium hydroxide) to yield 53 mg of 5-(5-Furan-2-yl-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine. (M+H)=339. Mp=253.7-254.6° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:10][C:11]1[C:16](Br)=[N:15][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][N:12]=1>CN(C=O)C>[NH2:10][C:11]1[C:16]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:15][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][N:12]=1
Reactant: Nc1ncc(-c2ccccc2)nc1Br
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccccc2)nc1Oc1ccccc1
Temperature: 7.5 °C
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
To a cooled solution of phenol (0.07 mL, 0.80 mmol) in dry DMF (5 mL), sodium hydride (NaH) (0.02 g, 0.80 mmol) was added and the resulting mixture was cooled at 5-10° C. and stirred for 15 min. After this time 2-amino-3-bromo-5-phenylpyrazine 17b (0.25 g, 1.00 mmol) was added and the mixture refluxed for 20 h, cooled and extracted with EtOAc. The organic layer was washed with water, anidrified over Na2SO4, filtered and the solvent removed under reduced pressure to get a crude that was purified by flash chromatography using dichloromethane-EtOAc (70:30 v/v) as eluent, to obtain 0.13 g of the title compound 18q as a pink solid (mp 129-131° C., 62% yield). 1H-NMR (CDCh): 5.04 (br s, 2H), 7.28-7.43 (m, 8H), 7.69-7.73 (m, 2H), 8.18 (s, 1H). MS (ESI): m/z 264 (M+H+).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:9][C:10]1[N:15]=[C:14]([CH2:16]Cl)[CH:13]=[CH:12][CH:11]=1.[O-]CC.[Na+]>>[CH3:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:9][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:15]=1
Reactant: Sc1ccccc1
Reactant: Cc1cccc(CCl)n1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1cccc(CSc2ccccc2)n1

Procedure:
Following the method of Example 1A thiophenol is reacted with 6-methyl-2-picolyl chloride hydrochloride in the presence of sodium ethoxide to give 2-methyl-6-((phenylthio)methyl)pyridine.
Reaction SMILES: Cl[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:2]([CH:3]2[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]2)[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:11][CH:12]=1
Reactant: CN1CCC(C(Cl)c2ccc(F)cc2)CC1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN1CCC(C(c2ccc(F)cc2)N2CCNCC2)CC1
Yield: 62 %

Procedure:
A mixture of 4-(chloro(4-fluorophenyl)methyl)-1-methylpiperidine (1.2 g, 4.12 mmol) in butanone (10 ml), anhydrous piperazine (1.43 g, 16.48 mmol), anhydrous K2CO3 (0.54 g, 4.14 mmol) and KI (0.65 g, 4.14 mmol) was refluxed under nitrogen for 18 hours. The mixture was then cooled and filtered and the solvent removed in vacuo. The residue was dissolved in CH2Cl2 (50 ml) and washed with water (30 ml). Drying and removal of the solvent followed by chromatography (CH2Cl2: CH3OH:NH4OH 90:10:0.5) afforded desired product in 62% yield.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])([O-])=O.[Na+].[Na+].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1ccccc1Br
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1ccccc1-c1cccc(OC)c1
Temperature: 100 °C

Procedure:
To a stirred solution of ethyl 2-bromobenzoate (13.7 g, 59.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.46 g, 3.0 mmol) in 1,2-dimethoxyethane (600 mL) was added 2 M aq. Na2CO3 (60 mL, deoxygenated). 3-Methoxyphenylboronic acid (10.0 g, 65.8 mmol) was added in 1,2-dimethoxyethane (80 mL) and the mixture was heated to 100° C. for 36 hours, under argon atmosphere. The mixture was cooled, diluted with water (1 L) and extracted with EtOAc (2×800 mL). The combined organic extracts were washed with sat. aq. NaHCO3, then brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with a gradient of 0-10% EtOAc in hexane, to give the titled product as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]([C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Br:23])[CH:17]=1)[CH3:14].Cl>C1COCC1.[Li+].[OH-]>[Br:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[C:15]([N:13]([CH3:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][CH2:4][C:3]([OH:25])=[O:2])=[O:24]
Reactant: COC(=O)CCCc1ccccc1N(C)C(=O)c1ccc(Cl)c(Br)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1CCCC(=O)O
Reaction time: 2 h
Yield: 103 %

Procedure:
To a solution of 4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyric acid methyl ester (1.11 g, 2.6 mmol, Step 13D) in THF (8 mL), 2N LiOH (6.5 mL) was added and the mixture was stirred for 2 hours at it. 1N HCl was added to the reaction mixture to yield a pH ˜2 followed by extraction with EtOAc (2×). The combined organic layers were washed with water and brine, dried (Na2SO4) and concentrated in vacuo to afford 1.1 g of 4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyric acid as a white solid. MS [M+H]+: 411.7; tR=2.57 min, (method 1)
Reaction SMILES: [F:1][C:2]1[C:13]([I:14])=[CH:12][C:5]([CH2:6]OS(C)(=O)=O)=[C:4]([CH2:15]OS(C)(=O)=O)[CH:3]=1.C(N(CC)C(C)C)(C)C.[C:30]1([CH:36]([NH2:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[CH:36]([N:43]1[CH2:15][C:4]2[C:5](=[CH:12][C:13]([I:14])=[C:2]([F:1])[CH:3]=2)[CH2:6]1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)OCc1cc(F)c(I)cc1COS(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Fc1cc2c(cc1I)CN(C(c1ccccc1)c1ccccc1)C2
Temperature: 60 °C
Yield: 55 %

Procedure:
To a mixture of 5.93 mmol methanesulfonic acid 4-fluoro-5-iodo-2-methanesulfonyloxymethyl-benzyl ester and 14.8 mmol N,N-diisopropylethylamine in 7 ml DMF at 0° C. was added dropwise a solution of 6.53 mmol diphenylmethylamine in 5 ml DMF. The mixture was heated at 60° C. for 16 h and was then cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed sequentially with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: ethyl acetate/heptane) to afford the title compound as a light yellow solid (55% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.ON1C2C=CC=CC=2N=N1.[CH3:28][NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:28][NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([C:9]3[N:10]=[C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]4[CH:8]=3)=[CH:12][CH:13]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)cn2c1
Reactant: CNc1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNc1ccc(C(=O)Nc2ccc(-c3cn4cc(C)ccc4n3)cc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 33.2 %

Procedure:
To a stirred solution of 4-(6-methylimidazo[1,2-a]pyridin-2-yl)aniline (0.10 g, 0.448 mmol), 1-hydroxybenzotriazole (0.06 g, 0.448 mmol), 4-methylaminobenzoic acid (0.068 g, 0.448 mmol) and triethylamine (62 μl, 0.045 g, 0.448 mmol) in dry DMF (5 ml) at 0° C. was added 1-ethyl-3-[3-(dimethylaminopropyl]-carbodiimide hydrochloride (0.086 g, 0.448 mmol) under an atmosphere or argon. After 10 min the cooling bath was removed and the reaction mixture was stirred at room temperature for 4 d. The reaction mixture was then added to water (150 ml) with stirring and the precipitate was collected by filtration. Purification by flash chromatography (25:1 DCM/MeOH) gave the title compound (0.053 g, 33%) as an almost colourless solid.
Reaction SMILES: [C:1]([NH:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(SC)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[C:17]1(S)C=CC=CC=1.C(N(CC)CC)C>CO>[C:1]([NH:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH3:17])=[O:7])(=[O:3])[CH3:2]
Reactant: CSC(NC(C)=O)(C(=O)O)c1ccccc1
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C(NC(C)=O)c1ccccc1

Procedure:
173 Milligrams of a methanethiol ester of α-acetylamino-α-methylthiophenylacetic acid and 50 mg of thiophenol were dissolved in 10 ml of methanol. To the solution 1 ml of triethylamine was added, and the system was refluxed for 1.5 hours. Concentrating the reaction mixture under reduced pressure, the residue was parted by a column chromatography (silica gel and methylene chloride). Thus 127 mg of methyl α-acetylaminophenylacetate was obtained.