Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:46])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][C:24]([C:28](=[O:30])[NH2:29])=[CH:25][CH:26]=4)[O:21][C:20]4[CH:31]=[CH:32][CH:33]=[C:34]([N:35]5[CH2:40][CH2:39][CH:38]([C:41]([O:43]CC)=[O:42])[CH2:37][CH2:36]5)[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Li+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:46])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][C:24]([C:28](=[O:30])[NH2:29])=[CH:25][CH:26]=4)[O:21][C:20]4[CH:31]=[CH:32][CH:33]=[C:34]([N:35]5[CH2:40][CH2:39][CH:38]([C:41]([OH:43])=[O:42])[CH2:37][CH2:36]5)[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(c2cccc3c2CC(=CCCN2CCC(O)(c4ccc(Cl)cc4)CC2)c2ccc(C(N)=O)nc2O3)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1ccc2c(n1)Oc1cccc(N3CCC(C(=O)O)CC3)c1CC2=CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Reaction time: 3 h
Yield: 55.6 %

Procedure:
A solution of the compound of Example 420 (91 mg, 0.14 mmol) in MeOH (5 mL) was treated with a 0.4 M solution of lithium hydroxide (5 mL, 2 mmol) and stirred for 3 hours. After addition of 5 mL of 0.4 N HCl, the solvent was removed under reduced pressure to give the crude product. The residue was purified using silica gel chromatography eluting with a dichloromethane:methanol gradient (0 to 50% MeOH over 1 hour) to give the title compound (48 mg).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[O:13][N:12]=2)=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[2H][C:28]1([2H])[C:33]([2H])([2H])[C:32]([2H])([2H])[N:31]([2H])[C:30]([2H])([2H])[C:29]1([2H])[2H].C(#N)C>O>[F:20][C:18]1[CH:17]=[CH:16][C:15]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:31]4[CH2:32][CH2:33][CH2:28][CH2:29][CH2:30]4)=[CH:6][CH:7]=3)=[N:12][O:13][C:14]=2[CH:19]=1
Reactant: [2H]N1C([2H])([2H])C([2H])([2H])C([2H])([2H])C([2H])([2H])C1([2H])[2H]
Reactant: Fc1ccc2c(-c3ccc(OCCBr)cc3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Fc1ccc2c(-c3ccc(OCCN4CCCCC4)cc3)noc2c1
Temperature: 25 °C
Yield: 73.9 %

Procedure:
Combine 3-[4-(2-bromo-ethoxy)-phenyl]-6-fluoro-benzo[d]isoxazole (550 mg, 1.63 mmol), potassium carbonate (500 mg, 3.62 mmol), piperidine- d11 (630 mg, 6.55 mmol) and 5% aqueous acetonitrile. Under a nitrogen atmosphere, heat to reflux overnight. Cool to room temperature and pour the reaction mixture into water resulting in white solid precipitation. Collect the solid and dry in vacuo. Dissolve the solid in ethyl acetate and filter to remove the insoluble materials and concentrate in vacuo. Take the solid up in diethyl ether, filter and precipitate the hydrochloride salt out of solution by addition of hydrogen chloride in diethyl ether. Collect the desired salt and dry in vacuo to give the title compound as a solid (410 mg, 67% Yield).
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[C:1]([C:5]1[CH:22]=[CH:21][C:8]([C:9]2[O:15][C:14](=[O:16])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2nc3ccccc3c(=O)o2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.2 %

Procedure:
To a stirring mixture of the 2-(4-tert-butylbenzoyl-amino)benzoic acid (9.5 g, 32 mmol), CH2Cl2 (200 mL) and 2 drops of DMF was added 2 M oxalyl chloride in CH2Cl2 (19 mL). After stirring at ambient temperature for 45 minutes, the mixture was concentrated under vacuum to an oil, redissolved in 100 mL CH2Cl2 and cooled to 0° C. To this was added triethylamine (3.3 g, 33 mmol) at 0° C. for 1 hour. The solvent was removed in vacuo and the residue purified by flash chromatrography using hexanes/EtOAc to give 8.6 g (96%) of a white powder.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][C:33]=1[CH3:41]>>[CH2:21]([CH:18]([N:13]1[C:12]([C:35]2[CH:36]=[CH:37][C:32]([F:31])=[C:33]([CH3:41])[CH:34]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH2:19][CH3:20])[CH3:22]
Reactant: CCC(CC)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: Cc1cc(B(O)O)ccc1F
Product: CCC(CC)n1nc2c(c1-c1ccc(F)c(C)c1)CCNCC2
Yield: 87.3 %

Procedure:
The title compound (34 mg) was prepared according to Example 183 using 59 mg of 2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 183, Step A) and 19 mg of 4-fluoro-3-methylphenylboronic acid. MS (ESI): exact mass calculated for C19H26FN3, 315.21; found, m/z 316.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.27-7.18 (m, 3H), 4.69-4.65 (m, 1H), 3.93-3.89 (m, 1H), 3.50-3.27 (m, 5H), 3.00-2.80 (m, 2H), 2.35 (s, 3H), 1.95-1.87 (m, 2H), 1.83-1.76 (m, 2H), 0.81-0.68 (m, 6H).
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][C:16]1[CH:17]=[C:18]([N:23]2[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[C:24]2=[O:31])[CH:19]=[CH:20][C:21]=1[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[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:28]([CH:25]1[CH2:26][CH2:27][N:23]([C:18]2[CH:19]=[CH:20][C:21]([CH3:22])=[C:16]([CH3:15])[CH:17]=2)[C:24]1=[O:31])=[O:29]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: Cc1ccc(N2CCC(C(=O)O)C2=O)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1C
Yield: 51.8 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(3,4-dimethylphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.105 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.090 g (52%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(3,4-dimethylphenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: I[CH:2]([CH3:24])[CH2:3][O:4][C:5]1[C:10]2[C:11](=[O:20])[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:14][C:9]=2[C:8]([CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1.[O:25]1CCOCC1>Cl([O-])(=O)(=O)=O.[Ag+]>[OH:25][CH:2]([CH3:24])[CH2:3][O:4][C:5]1[C:10]2[C:11](=[O:20])[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:14][C:9]=2[C:8]([CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1
Reactant: C1COCCO1
Reactant: CCCc1ccc(OCC(C)I)c2c(=O)cc(C(=O)OCC)oc12
Agent: [Ag+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CCCc1ccc(OCC(C)O)c2c(=O)cc(C(=O)OCC)oc12

Procedure:
To a solution of ethyl 5-(2-iodopropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate (0.1 g) in 50% aqueous dioxan (15 ml) was added silver perchlorate (0.08 g). The solution was heated at reflux for 4 hours, filtered and evaporated to dryness. The brown, solid residue was crystallised from ethanol giving ethyl 5-(2-hydroxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate identical in all respects with authentic material.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:9]1[C:21]2[CH:20]=[CH:19][C:18]([C:22](O)=[O:23])=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([C:25](O)=[O:26])[CH:14]=2)[CH3:8].[H-].O>C1COCC1.ClCCl.[O-2].[O-2].[Mn+4]>[CH:25]([C:13]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:7][CH3:8])[C:21]3[C:16]([C:15]=2[CH:14]=1)=[CH:17][C:18]([CH:22]=[O:23])=[CH:19][CH:20]=3)=[O:26]
Reactant: CCn1c2ccc(C(=O)O)cc2c2cc(C(=O)O)ccc21
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCn1c2ccc(C=O)cc2c2cc(C=O)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
LiAlH4 (2.15 g, 56.3 mmol) is added portionwise to a suspension of N-ethylcarbazole-3,6-dicarboxylic acid (5.7 g, 20.12 mmol) in 160 ml of anhydrous THF cooled to 0° C. The suspension is stirred for 1 h 30 min at room temperature and then 1 hour under reflux. After cooling to 0° C., the excess hydride is hydrolyzed with a little water and the salts are filtered off. The filtrate is evaporated to dryness and dried under vacuum to give a yellow solid. The latter is suspended in dichloromethane in the presence of activated manganese dioxide (4 g, 15.16 mmol), and the mixture is stirred overnight at room temperature. 4 g of activated manganese dioxide are added and the mixture is stirred for a further 24 h. The suspension is filtered and the filtrate is evaporated under vacuum to give the expected product.
Reaction SMILES: [Na].S(N[N:13]=[CH:14][C:15]1[CH:20]=CC=C[C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)(C1C=CC(C)=CC=1)(=O)=O.[F:28][C:29]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:30]=1[C:31](N/C=C\C)=[O:32].O1CCOCC1.CCOC(C)=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2].O>[F:28][C:29]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:30]=1[C:31]([NH:13][C@@H:14]1[C@H:15]([CH3:20])[C@@H:16]1[C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)=[O:32]
Reactant: C/C=C\NC(=O)c1c(F)cccc1F
Reactant: Cc1ccc(S(=O)(=O)NN=Cc2ccccc2-c2ccc(F)cc2)cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1[C@@H](NC(=O)c2c(F)cccc2F)[C@H]1c1ccc(F)cc1
Temperature: 75 °C
Yield: 10 %

Procedure:
4-Fluorophenyl benzaldehyde-tosylhydrazone sodium salt from example P2b (261 mg, 0.832 mmol), 2,6-difluoro-N—[(Z)-prop-1-enyl]benzamide (164 mg, 832 mmol), benzyltriethylammonium chloride (18.6 mg, 0.083 mmol), and rhodium acetate dimer (3.6 mg, 0.0083 mmol) were stirred with dioxane (6 ml) to give a thick slurry. This was heated at 75° C. for 4 hours. The mixture was shaken between EtOAc and water. The organic phase was dried with MgSO4 and evaporated to yield 230 mg of a crude mixture. This was chromatographed on silica with EtOAc/cyclohexane to yield 26 mg (10%) of racemic 2,6-difluoro-N-[(1R,2R,3R)-2-(4-fluorophenyl)-3-methyl-cyclopropyl]benzamide. M.p. 90-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.CC(O)(C(C)(O)C)C.Br[C:29]1[S:33][C:32]([C:34]2([OH:38])[CH2:37][CH2:36][CH2:35]2)=[N:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:29]2[S:33][C:32]([C:34]3([OH:38])[CH2:37][CH2:36][CH2:35]3)=[N:31][CH:30]=2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC1(C)OB(c2cc(Cl)cc([N+](=O)[O-])c2)OC1(C)C
Reactant: OC1(c2ncc(Br)s2)CCC1
Agent: CC(C)(O)C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cc(-c2cnc(C3(O)CCC3)s2)c1
Yield: 54.8 %

Procedure:
The product of Step 1 (1.6 g, 3.98 mmol), Intermediate 1 (839 mg, 3.58 mmol), PdCl2 (dppf)-dichloromethane adduct (163 mg, 0.199 mmol), sodium carbonate (2M in water) (5.97 mL, 11.95 mmol), and DMF (39.8 mL) were heated at 100° C. for 2 hours under nitrogen. The reaction mixture was diluted with ethyl acetate and water, the solids were filtered and the organic fraction was washed with water, brine and dried over Na2SO4. Filtration and solvent evaporation gave a residue which was further purified by column chromatography on silica gel, eluting with ethyl acetate/hexane with a gradient 30-50% to afford 1-[5-(3-chloro-5-nitrophenyl)-1,3-thiazol-2-yl]cyclobutanol (610 mg, 49.3%).
Reaction SMILES: O.O.[Sn](Cl)Cl.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2C=C[C:17]([NH2:20])=[C:16]([N+:21]([O-])=O)[CH2:15]2)=[CH:10][CH:9]=1)#[N:7].[CH2:24](O)[CH3:25]>Cl.O>[NH2:21][C:16]1[CH:17]=[N:20][CH:24]=[CH:25][C:15]=1[NH:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]#[N:7])=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(N2C=CC(N)=C([N+](=O)[O-])C2)cc1
Reactant: CCO
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: N#Cc1ccc(Nc2ccncc2N)cc1
Temperature: 0 °C

Procedure:
According to a modification of the method of Pharm. Helv. Acta, 1975, 50, 188., tin dichloride dihydrate (56.4 g, 250 mmol) was added to a suspension of N-(4-cyanophenyl)-4-amino-3-nitropyridine (12.0 g, 50 mmol) in 2N aqueous hydrochloric acid (35 ml), water (150 ml) and ethanol (75 ml) and the resulting mixture was heated to reflux for 10 minutes under nitrogen. The mixture was cooled in ice, poured into ice-cold 2N aqueous sodium hydroxide (400 ml) and filtered. The creamy-coloured solid was washed with 2N aqueous sodium hydroxide and water, and then dried in a vacuum desiccator. The product, 3-amino-4-(4'-cyanophenyl)aminopyridine, 9.31 g, gradually turns reddish brown on exposure to light and air.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH:9]=[CH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:20](=[O:21])[N:19]([CH3:18])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:3][CH:4]=2)=[O:17])[CH:12]=1
Reactant: O=C(C=Cc1cccnc1)c1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(C(=O)C=Cc2cccnc2)cc1)c1ccccc1

Procedure:
The title product was prepared from 1-(4-hydroxy-phenyl)-3-pyridin-3-yl-prop-2-en-1-one and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (56%, off-white solid). HPLC-MS: m/z=359.0 (M+1); Rt: 3.27 min.
Reaction SMILES: C([O:4][CH:5](OC(=O)C)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][O:15]C(=O)C)=[CH:8][N:7]=1)(=O)C.Cl>O1CCOCC1>[OH:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[O:4])=[N:7][CH:8]=1
Reactant: CC(=O)OCCOc1ccc(C(OC(C)=O)OC(C)=O)nc1
Agent: Cl
Solvent: C1COCCO1
Product: O=Cc1ccc(OCCO)cn1
Reaction time: 1 h

Procedure:
100 mg of the crude product from example 27A are dissolved in 2 ml of dioxane, and 0.48 ml (1.93 mmol) of a 4 M solution of hydrogen chloride gas in dioxane is added. The mixture is stirred at +100° C. for 1 h. The reaction mixture is then concentrated on a rotary evaporator, and the residue is taken up in 2 ml of water. The mixture is neutralized using 0.7 ml of 1 N aqueous sodium hydroxide solution and extracted three times in total with in each case 4 ml of diethyl ether. The combined organic phases are dried over magnesium sulphate. After removal of the solvent, the crude product is used without further purification for the subsequent reaction.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:28])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH2:21][CH2:22][O:23]C(=O)C)=[CH:15][C:14]=2[CH3:27])=[CH:9][CH:8]=1.Cl>C(O)C>[OH:23][CH2:22][CH2:21][O:20][C:16]1[CH:17]=[C:18]([CH3:19])[C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:28])=[O:4])=[CH:8][CH:9]=2)=[C:14]([CH3:27])[CH:15]=1
Reactant: COC(=O)Cc1ccc(-c2c(C)cc(OCCOC(C)=O)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCCO)cc(C)c1-c1ccc(CC(=O)O)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 109 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (2 mL) was added to a solution of methyl[4′-(2-acetoxyethoxy)-2′,6′-dimethylbiphenyl-4-yl]acetate (0.318 g) in ethanol (10 mL), and the mixture was stirred at 40° C. for 1 hr. To the reaction mixture was added 2 mol/L hydrochloric acid (2 mL), and the solvent was evaporated under reduced pressure. Water and ethyl acetate were added to the residue. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (0.292 g).
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[CH3:10][N:11]1[CH:15]=[C:14]([Sn](CCCC)(CCCC)CCCC)[N:13]=[CH:12]1>>[CH3:10][N:11]1[CH:15]=[C:14]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[N+:7]([O-:9])=[O:8])[N:13]=[CH:12]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Reactant: O=[N+]([O-])c1ccsc1Cl
Product: Cn1cnc(-c2sccc2[N+](=O)[O-])c1
Temperature: 95 °C

Procedure:
The title compound was prepared from 2-chloro-3-nitrothiophene (2.57 g, 15.7 mmol) and 1-methyl-4-(tributylstannyl)-1H-imidazole (8.64 g, 23.3 mmol) using protocol E except the reaction was heated to 90° C. (rather than 95° C.) and was purified by flash chromatography (hexane:ethyl acetate). Method [1] Retention time 0.57 min by HPLC (MH+ 210).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([NH:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:4].[C:18]1([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC1C=CC=CC=1>[CH2:16]([O:15][CH2:14][CH2:13][NH:12][C:11]1[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:28]2[CH2:29][CH2:30][N:25]([CH2:24][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:26][CH2:27]2)=[N:7][CH:8]=[CH:9][CH:10]=1)[CH3:17]
Reactant: CCOCCNc1cccnc1NC(=O)CCl
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOCCNc1cccnc1NC(=O)CN1CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
A mixture of 3.62 parts of 2-chloro-N-[3-[(2-ethoxyethyl)amino]2-pyridinyl]acetamide, 10.6 parts of 1-(phenylmethyl)piperazine, 6.4 parts of sodium carbonate and 90 parts of methylbenzene was stirred for 20 hours at 80° C. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 7.9 parts (100%) of N-[3-[(2-ethoxyethyl)amino]-2-pyridinyl]-4-(phenylmethyl)-1-piperazineacetamide as a residue (int. 25).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.C1C(=O)N([Cl:23])C(=O)C1>CC#N>[Cl:23][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[C:10]([CH3:13])([CH3:14])[C:9](=[O:15])[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COc1cc2c(cc1Cl)CCC(=O)C2(C)C
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 3.37 g, 16.5 mmol) was dissolved in CH3CN (82 mL), added with NCS (2.42 g, 1.1 eq.) and stirred at 90° C. for 1.5 hours. The reaction solution was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed and the target compound was obtained after concentration under reduced pressure (yellow oily substance, 4.45 g).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10]C2)=[CH:4][CH:3]=1.N1CCC1>>[Br:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(CN2CCCC2)s1
Agent: C1CNC1
Product: Brc1ccc(CN2CCC2)s1

Procedure:
The above procedure to make 1-[(5-bromo-2-thienyl)methyl]pyrrolidine was repeated except using azetidine (86 mg, 1.5 mmol) as the amine. Following the purification with the SCX column as described -[(5-bromo-2-thienyl)methyl]pyrrolidine an additional purification step on a 40 g ISCO silica column was necessary to afford the title compound (166 mg) of acceptable purity for use in the next reaction.
Reaction SMILES: [CH2:1]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.C=O.[BH4-].[Na+].F[C:25](F)(F)C(O)=O.[OH-].[Na+].[Cl-].[Na+]>O.C1COCC1>[CH2:11]([N:10]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1)[CH3:25])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cccc(CNCc2cccc(OC)c2)c1
Agent: C=O
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(CN(C)Cc2cccc(OC)c2)c1
Temperature: 0 °C

Procedure:
10.0 g of N,N-Di(3-Anisyl)amine were dissolved 436 ml of anhydrous THF. 14.0 g of paraformaldehyde were added with stirring followed by 8.20 g of sodium borohydride. 190 ml of trifluoro acetic acid were added during 120 min and after completion of the addition the reaction mixture was stirred at room temperature over night. The reaction mixture was poured into 654 ml of an ice cubes containing 25.0%-weight solution of sodium hydroxide in water. After addition of 654 ml of a saturated aqueous solution of sodium chloride it was extracted three times with each 650 ml of dichloromethane and the combined organic extracts were dried with anhydrous sodium sulfate. After filtration the solvent was removed in vacuo and the crude product purified by fractionated distillation in vacuo. At a temperature of 125-135° C./0.04 mbar 8.60 g (80.4%) of DAMA are collected as yellow liquid.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11]([NH2:12])=[N:10][CH:9]=[C:8]([I:13])[N:7]=1)=[O:5].[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCOCC.O.ClCCl>[NH2:12][C:11]1[C:6]([C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:5])=[N:7][C:8]([I:13])=[CH:9][N:10]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)c1nc(I)cnc1N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1ncc(I)nc1C(=O)c1ccccc1
Temperature: 55 °C
Yield: 68 %

Procedure:
8.00 g (25.97 mmol) of 3-amino-6-iodo-pyrazine-2-carboxylic acid methoxy-methyl-amide was dissolved in 100 ml of anhydrous THF under nitrogen. The solution was cooled to 55° C. and 27 ml of a 3 M solution of phenylmagnesium bromide in ether was added. The mixture was allowed to warm to 10° C. and a solution of 10% citric acid in water was added. The mixture was diluted with dichloromethane and the phases were separated. The aqueous phase was extracted three times with dichloromethane and the combined organic phases were dried over sodium sulfate and evaporated. The resulting solid was crystallized from ethanol to afford 5.74 g (17.66 mmol; 68%) of (3-amino-6-iodo-pyrazin-2-yl)-phenyl-methanone as yellow-orange crystals. 1H-NMR (d6-DMSO) δ: 8.52 [1H] s, 7.94 [2H] s, br, 7.85 [2H] d, 7.62 [1H] t, 7.52 [2H] t. MS: m/z 326 [MH+].
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([NH:14][C:15]2[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)[CH:6]=[C:7]([C:9]2[S:13][CH:12]=[N:11][CH:10]=2)[CH:8]=1.[CH:25]1(B(O)O)C[CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2].O.C1(C)C=CC=CC=1>[CH:2]1([C:3]2[CH:4]=[C:5]([NH:14][C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=3)[CH:6]=[C:7]([C:9]3[S:13][CH:12]=[N:11][CH:10]=3)[CH:8]=2)[CH2:26][CH2:25]1
Reactant: FC(F)(F)c1ccnc(Nc2cc(CBr)cc(-c3cncs3)c2)n1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccnc(Nc2cc(-c3cncs3)cc(C3CC3)c2)n1
Temperature: 130 °C
Yield: 81.5 %

Procedure:
To a flask were added N-[3-(bromomethyl)-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)-pyrimidin-2-amine (523 mg, 1.30 mmol), cyclopropyl boronic acid (336 mg, 3.91 mmol), potassium phosphate (968 mg, 4.56 mmol), Pd(OAc)2 (15 mg, 0.07 mmol) and tricyclo-hexylphosphine (37 mg, 0.13 mmol). Degassed toluene (10 mL) and water (0.5 mL) were added and the solution was evacuated and then purged with argon 5 times. The mixture was then heated in the microwave at 130° C. for 30 minutes. The reaction was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield N-[3-cyclopropyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (384 mg, 1.06 mmol, 81% yield). MS ESI: [M+H]+ m/z 363. 1H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.06 (s, 1H), 8.83 (d, J=4.8, 1H), 8.23 (s, 1H), 7.92 (s, 1H), 7.41 (s, 1H), 7.28 (d, J=4.9, 1H), 7.12 (s, 1H), 2.03-1.80 (m, 1H), 1.05-0.92 (m, 2H), 0.78-0.61 (m, 2H).