Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18]C)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+]>CO.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([OH:18])=[O:17])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
A solution of methyl 1-(4-nitrophenyl)piperidine-4-carboxylate (3.84 g, 14.53 mmol) and NaOH (0.87 g, 21.79 mmol) in 15 mL of MeOH and 5 mL of water was stirred at room temperature for 3 hours. The volatiles were removed in vacuo to give 1-(4-nitrophenyl)piperidine-4-carboxylic acid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11].CON(C)[C:15]([C:17]1[S:24][C:23]([CH3:25])=[C:22]2[C:18]=1[CH2:19][C@H:20]1[C:26]([CH3:28])([CH3:27])[C@H:21]12)=[O:16]>C1COCC1>[CH3:11][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][C:15]([C:17]1[S:24][C:23]([CH3:25])=[C:22]2[C:18]=1[CH2:19][C@H:20]1[C:26]([CH3:28])([CH3:27])[C@H:21]12)=[O:16]
Reactant: COc1ccccc1CCBr
Reactant: CON(C)C(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Solvent: C1CCOC1
Product: COc1ccccc1CCC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
At rt, a solution of 1-(2-bromo-ethyl)-2-methoxy-benzene (1.0 g, 4.15 mmol) in abs. THF (5 mL) is added to Mg turnings (0.13 g, 5.35 mmol) suspended in abs. THF (5 mL) over a period of 20 min. The thus obtained Grignard reagent is then added at to an ice-cold solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid methoxy-methyl-amide (400 mg, 1.5 mmol) in THF (5 mL). The reaction mixture is stirred at rt for 1 h, quenched by adding sat. aq. NH4Cl (10 mL), diluted with water (100 mL) and extracted twice with DCM (100 mL). The combined organic extracts are dried over Na2SO4, filtered and evaporated. The resulting residue is purified by prep. HPLC to afford 3-(2-methoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]penta-len-4-yl)-propan-1-one (390 mg) as a colourless oil. LC-MS: tR=1.15 min, [M+1]+=341.21; 1H NMR (CDCl3): δ 7.22-7.14 (m, 2H), 6.90-6.81 (m, 2H), 3.82 (s, 3H), 3.20-2.90 (m, 5H), 2.79 (d, J=18.8 Hz, 1H), 2.38 (s, 3H), 1.88 (d, J=2.9 Hz, 2H), 1.12 (s, 3H), 0.72 (s, 3H).
Reaction SMILES: Br[C:2]1[C:8]([CH3:9])=[C:7]([CH3:10])[CH:6]=[C:4]([CH3:5])[C:3]=1[CH3:11].C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C.C1([Li])C(C)=C(C)C=C(C)C=1C>C1COCC1.CCOCC>[C:2]1([B:17]([OH:20])[OH:18])[C:8]([CH3:9])=[C:7]([CH3:10])[CH:6]=[C:4]([CH3:5])[C:3]=1[CH3:11]
Reactant: Cc1cc(C)c(C)c(Br)c1C
Reactant: COB(OC)OC
Agent: [Li]CCCC
Agent: [Li]c1c(C)c(C)cc(C)c1C
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C)c(C)c(B(O)O)c1C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
0.2 mol of 3-bromodurene is reacted in 800 ml of absolute THF by means of 0.25 mol of butyllithium under inert conditions at −78° C. On completion of the BuLi addition, the reaction mixture is stirred at −78° C. for another 1 h and then allowed to thaw. A 2 l flask is then initially charged with 500 ml of absolute ether and 0.3 mol of trimethyl borate at −78° C. and the duryllithium prepared beforehand is added dropwise within a period of 30 min. The mixture is then allowed to thaw and the reaction mixture is stirred for another 12 h. Finally, the reaction mixture is poured onto 2 N HCl-ice mixture and hydrolyzed for 12 h, the organic phase is extracted and concentrated, and the residue is admixed with pentane to precipitate out the product. The product is filtered off with suction and dried under reduced pressure mp: 101-3° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:24][C:23]4[CH:25]=[C:26]([Br:29])[CH:27]=[CH:28][C:22]=4[N:21]=3)=[CH:16][C:15]=2[NH2:30])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([C:35]1[C:36]([N:42]=[CH:43][N:44]([CH3:46])C)=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=1)#N>>[CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:24][C:23]4[CH:25]=[C:26]([Br:29])[CH:27]=[CH:28][C:22]=4[N:21]=3)=[CH:16][C:15]=2[NH:30][C:46]2[C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[N:37][C:36]=3[N:42]=[CH:43][N:44]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: Nc1cc(-c2nc3ccc(Br)cc3[nH]2)ccc1Oc1ccc(OCc2ccccc2)cc1
Product: Cc1ccc2c(Nc3cc(-c4nc5ccc(Br)cc5[nH]4)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1

Procedure:
The product from Example 147C was reacted with the product from Example 10B using the procedure described in Example 147D substituting the product from Example 10B for the product from Example 36E to provide [2-(4-Benzyloxy-phenoxy)-5-(6-bromo-1H-benzoimidazol-2-yl)-phenyl]-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine which was debenzylated according to the procedure described in Example 147E to provide the crude product which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.74 (s, 3H), 6.77 (d, J=9.19 Hz, 2H), 6.95 (d, J=8.82 Hz, 2H), 7.01 (d, J=8.82 Hz, 1H), 7.35 (dd, J=8.46, 1.84 Hz, 1H), 7.54 (d, J=8.82 Hz, 1H), 7.74-7.85 (m, 2H), 8.10 (dd, J=8.82, 2.21 Hz, 1H), 8.36 (d, J=2.21 Hz, 1H), 8.90 (s, 1H), 8.95 (d, J=8.46 Hz, 1H), 9.45 (bs, 1H), 11.35 (bs, 1H); MS (ESI+) m/z 539/541 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].C([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][C:27]=1[C:34]([F:37])([F:36])[F:35])C1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[CH3:17][O:16][C:14](=[O:15])[C:13]([O:12][CH3:11])=[CH:30][C:29]1[CH:32]=[CH:33][C:26]([OH:25])=[C:27]([C:34]([F:35])([F:36])[F:37])[CH:28]=1
Reactant: COCC(=O)OC
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)C(=Cc1ccc(O)c(C(F)(F)F)c1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a solution of sodium bis(trimethylsilyl)amide 1N (0.8 mL, 0.8 mmol) in THF (4 mL), was added dropwise methyl methoxyacetate (0.066 mL, 0.66 mmol) at −78° C. After allowing the mixture to stir for 1 hour, 4-Benzyloxy-3-trifluoromethyl-benzaldehyde (185 mL, 0.66 mmol) was added dropwise. When the addition was finished the mixture was warmed to room temperature and stirred for 3 additional hours. Trifluoroacetic anhydride (0.28 mL, 1.98 mmol) was added and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated and the residue dissolved in ethyl acetate (50 mL). 10% palladium on carbon (200 mg) was added to the solution and the mixture stirred under hydrogen pressure (5 atm) for 16 hours, filtered through a pad of celite and concentrated under vacuum. The residue was chromatographed (silica gel, hexanes/ethyl acetate 4:1) to produce 3-(4 hydroxy-3-trifluoromethyl-phenyl)-2-methoxy-acrylic acid methyl ester as a white solid (72 mg, 40%). 1H-NMR ((CD3)2CO, 200.15 MHz): δ 9.65 (b, 1H), 8.02 (d, 1H, J=1.8), 7.87 (dd, 1H, J=8.4, 1.8), 7.08 (d, 1H, J=8.4), 6.90 (s, 1H), 3.77 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[C:7]([CH:9]=1)[OH:8])[OH:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24].O>CN(C=O)C>[OH:4][C:3]1[CH:5]=[CH:6][C:7]([O:8][CH2:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:9][C:2]=1[C:1]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc(O)ccc1O
Reactant: C[Si](C)(C)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCCC[Si](C)(C)C)ccc1O
Temperature: 90 °C

Procedure:
To a mixture of methyl gentisate (16.8 g, 0.1 mol) and potassium carbonate (15.2 g, 0.11 mol) in 80 ml of DMF, under a nitrogen atmosphere at 80° C., was added chloropropyltrimethylsilane (16.6 g, 0.11 mol) dropwise over 20 minutes. The mixture was heated at 90° C. for 8 hours. It was cooled and poured into 200 ml of water. The mixture was extracted with diisopropyl ether. The organic phase was washed with water, dried over sodium sulphate and then concentrated. After chromatography on silica of the yellow oil obtained (eluent: 90/10 heptane/CH2 Cl2), 3.3 g of a clean fraction of methyl 2-hydroxy-5-(3-trimethylsilanylpropyloxy)benzoate were recovered.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[NH2:30][C:31]1[N:36]=[C:35]([CH:37]([CH3:39])[CH3:38])[C:34]([C:40]([O:42][CH3:43])=[O:41])=[C:33]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)[C:32]=1[CH:51]=O>O1CCCC1.C(OCC)(=O)C>[NH2:30][C:31]1[C:32]([CH:51]=[CH:2][O:3][CH3:4])=[C:33]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)[C:34]([C:40]([O:42][CH3:43])=[O:41])=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=1
Reactant: COC(=O)c1c(C(C)C)nc(N)c(C=O)c1-c1ccc(F)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC=Cc1c(N)nc(C(C)C)c(C(=O)OC)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of (methoxymethyl)triphenyl-phosphonium chloride (260 mg, 0.75 mmol) in tetrahydrofuran (0.3 mL) was added, dropwise, a solution of potassium tert-butoxide (0.75 mL, 1.0 M in tetrahydrofuran). After 15 min, a solution of methyl 6-amino-4-(4-fluorophenyl)-5-formyl-2-(1-methylethyl)-3-pyridinecarboxylate (95 mg, 0.3 mmol) in tetrahydrofuran (0.3 mL) was added to the above mixture. The resulting mixture was stirred at room temperature for 2.5 h, diluted with ethyl acetate (15 mL) and washed with brine, dried (Na2SO4) and evaporated. The residue was purified by a silica gel chromatography (45 g column), eluting with 15% to 20% of ethyl acetate in hexanes to provide methyl 6-amino-4-(4-fluorophenyl)-2-(1-methylethyl)-5-(2-methoxyethenyl)nicotinate as a E/Z mixture (80 mg, 77%): LCMS (ESI, pos. ion spectrum) m/z 345 (M+H); HPLC (method 3) tR=2.4 min.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]([CH3:22])=[CH2:21].CN(C=O)C>C1(C)C=CC=CC=1>[CH2:1]([N:5]([CH2:21][C:20]([CH3:22])=[CH2:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccccc1
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=C(C)CN(CCCC)c1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of N-butylaniline (12.35 parts), anhydrous potassium carbonate (17.1 parts), 3-chloro-2-methylpropene (11.24 parts) and DMF (20 parts) was stirred at 90° C. for 8 hours. The cooled mixture was poured into toluene, washed with water (×2), 1N hydrochloric acid (30 parts) and water (×2). The dried organic phase was evaporated to leave N-butyl-N-(2-methylprop-2-eneyl)aniline (14.3 parts).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[CH3:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:23][C:22]1[CH:24]=[CH:25][C:19]([CH3:18])=[CH:20][CH:21]=1)=[O:9]
Reactant: Cc1ccc(N)cc1
Reactant: O=C(Cl)c1cccnc1Oc1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2cccnc2Oc2cccc(Cl)c2)cc1

Procedure:
In the same manner as in Example 1(b), 1.1 grams (0.01 mole) 2(3-chlorophenoxy) nicotinoyl chloride, 1.0 grams (0.01 mole) 4-methylaniline, 1.0 grams (0.01 mole) triethylamine and 125 milliliters toluene were combined to yield 2.4 grams (70.9% of theoretical yield) of the desired product, m.p. 140°-143° C. The structure was confirmed by mass spectrometry.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:8]1([C:5]2[O:4][C:3]([CH2:2][N:23]3[CH2:24][CH2:25][N:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:21][CH2:22]3)=[N:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: ClCc1ncc(-c2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(-c2cnc(CN3CCN(c4ccccc4)CC3)o2)cc1

Procedure:
A solution of 2-choromethyl-5-phenyloxazole (3.87 g; 0.02 mole) and N-phenylpiperazine (3.25 g; 0.02 mole) in absolute ethanol (60 ml) was boiled and stirred with finely powdered anhydrous sodium carbonate (5 g) for 6 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].N1C=CC=CC=1.[CH2:16]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](Cl)=[O:39])=[CH:33][CH:32]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([NH:1][C:38](=[O:39])[CH2:37][C:34]2[CH:35]=[CH:36][C:31]([O:30][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:32][CH:33]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1
Reactant: Nc1cccc(CO)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(CO)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of 15.5 g of m-aminobenzyl alcohol and 36.21 g of pyridine in 250 ml of tetrahydrofuran, cooled to 0° C. is added over 40 minutes a solution of 42 g of p-tetradecyloxyphenylacetyl chloride in 250 ml of tetrahydrofuran. The mixture is stirred overnight at room temperature and the solvent is evaporated. The residue is partitioned between water and chloroform with some heating to afford a complete solution. The hot chloroform solution is washed with warm water and warm dilute hydrochloric acid. The organic layer is dried and evaporated to a residue which is crystallized from carbon tetrachloride to give 40 g of the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:9])=[N:4][CH:5]=[N:6][C:7]=1I.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[NH2:14].O>CN1CCCC1=O>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:7]2[C:2]([NH2:1])=[C:3]([I:9])[N:4]=[CH:5][N:6]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: Nc1c(I)ncnc1I
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1c(I)ncnc1Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Yield: 81 %

Procedure:
A solution of 5-amino-4,6-diiodopyrimidine (3.83 g) and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (2.78 g) in 1-methyl-2-pyrrolidone (30 mL) was stirred at 70° C. for 14 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (eluent, ethyl acetate:hexane=1:4→2:3→1:1) to give the title compound (4.21 g) as brown powder crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:5]=[C:4]([OH:15])[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:5]=[C:4]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][S:23][C:20]2[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][CH:21]=2)[CH:3]=1
Reactant: CC1(C)OC(=O)Nc2c(Cl)cc(O)cc21
Reactant: ClCCCCSc1ccc(Cl)cc1
Product: CC1(C)OC(=O)Nc2c(Cl)cc(OCCCCSc3ccc(Cl)cc3)cc21

Procedure:
Prepared analogously to Example 4 from 8-chloro-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(4-chloro-phenylmercapto)-butylchloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[C:5](I)=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[C:18]([N:25]1[CH2:28][C:27](=[O:29])[CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[C:21]([O:20][C:18]([N:25]1[CH2:28][C:27]([C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][C:6]=2[CH2:8][OH:9])([OH:29])[CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: OCc1cc(Cl)ncc1I
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2cnc(Cl)cc2CO)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.2 %

Procedure:
To a stirred solution of (2-chloro-5-iodo-pyridin-4-yl)-methanol (2 g, 7.44 mmol, 1 eq) in dry THF (20 mL) was added i-PrMgCl.LiCl complex (1.3M in THF, 13.7 mL, 17.8 mmol, 2.4 eq) at −20° C. in drop wise manner over period of 10 minutes. Pre-dissolved solution of N-boc-3-azetidinone (1.53 g, 8.9 mmol, 1.2 eq) in dry THF (10 mL) was added at −20° C. to above reaction mixture. Resulting reaction mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. After maximum consumption of starting material, reaction mixture was cooled to 0° C., quenched with 10% citric acid solution (20 mL) and extracted with ethyl acetate (3×50 mL). Combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get brown oil (2.2 g, crude). Crude compound was purified by column chromatography by using silica gel (100-200 mesh). Desired compound was eluted at 20% ethyl acetate in hexane to afford title compound as yellow solid (0.45 g, 19%). 1H NMR (400 MHz, CDCl3) δ: 1.38 (s, 9H), 3.96 (d, J=8.8 Hz, 2H), 4.38 (d, J=9.32 Hz, 2H), 4.53 (d, J=5.64 Hz, 2H), 5.53 (t, J=5.32 Hz, 1H), 6.40 (s, 1H), 7.57 (s, 1H), 8.33 (s, 1H). LC-MS (m/z): 314.9 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][NH:13][CH3:14]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]=[S:9]([CH3:11])([N:13]([CH3:14])[CH3:12])=[O:10])=[CH:4][N:3]=1
Reactant: CS(=O)Nc1cnc(Cl)nc1
Reactant: CNC
Product: CN(C)S(C)(=O)=Nc1cnc(Cl)nc1

Procedure:
The title compound is prepared from N-(2-chloropyrimidin-5-yl)methanesulfinamide and dimethylamine following a procedure analogous to that described for Intermediate 3 (Step 2). LC (method 1): tR=0.72 min; Mass spectrum (ESI+): m/z=235 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]Cl)=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.[C:11]([O-:14])(=[O:13])[CH3:12].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:7]([CH2:8][O:14][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: ClCc1ccc(Cl)nc1Cl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc(Cl)nc1Cl

Procedure:
840 g (4.28 mols) of 2,6-dichloro-3-chloromethylpyridine, 700 g (8.5mols) of sodium acetate and 1,600 ml of anhydrous acetic acid are heated together for 4 hours under reflux. The reaction product is then freed from solvent by distilling the latter off, is made alkaline (pH 8-10) with aqueous sodium hydroxide solution and is suspended in water. The reaction product is extracted with diethyl ether and the organic phase is dried over magnesium sulphate and evaporated. After distilling the crude product, colourless 2,6-dichloro-3-acetoxymethylpyridine is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[Cl:9].[Cu][C:11]#[N:12].C(OCC)(=O)C>CN(C)C=O>[Cl:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[C:11]#[N:12]
Reactant: N#C[Cu]
Reactant: Cc1ccc(Br)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)c(Cl)c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
25.0 g 4-bromo-3-chlorotoluene and 21.8 g copper (I) cyanide were dissolved in 200 ml dimethylformamide and stirred at 150° C. for three hours. The cooled reaction mixture was diluted by addition of 300 ml ethyl acetate and washed three times with portions of 150 ml saturated NH4Cl solution. The precipitates were filtered off and the filtrate dried over MgSO4 and then reduced in vacuo to obtain 17.3 g 2-Chloro-4-methyl-benzonitrile. This material was used without purification in the next step.
Reaction SMILES: [C:1]([CH2:5][S:6](Cl)(=[O:8])=[O:7])([F:4])([F:3])[F:2].[NH4+:10].[OH-]>C(Cl)Cl.O>[C:1]([CH2:5][S:6]([NH2:10])(=[O:8])=[O:7])([F:4])([F:3])[F:2]
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)CC(F)(F)F
Temperature: 25 °C

Procedure:
The CF3CH2SO2NH2 was prepared by cooling a solution of commercially available CF3CH2SO2Cl (0.6 ml, 1 eq) in CH2Cl2 to 0° C. NH4OH (0.75 ml, 14.8 N, 2 eq) was then added dropwise. The mixture was allowed to warm to room temperature overnight. The reaction was diluted with water and extracted three times with CH2Cl2. The combined organic layers were dried with Na2SO4 and concentrated. The sulfonamide was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[N:13]1([C:19]2[CH:20]=[CH:21][C:22]3[N:23]([C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][N:27]=3)[N:24]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[F:31][C:28]([F:29])([F:30])[C:25]1[N:23]2[C:22]([CH:21]=[CH:20][C:19]([N:13]3[CH2:18][CH2:17][N:16]([S:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)(=[O:11])=[O:10])[CH2:15][CH2:14]3)=[N:24]2)=[N:27][N:26]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: N#Cc1ccc(S(=O)(=O)N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Yield: 32 %

Procedure:
Obtained in 32% yield by an analogous procedure to Example 394, starting from 4-cyanobenzenesulfonyl chloride and 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH:11]1[CH2:16][CH:15]=[C:14]([CH2:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1.[CH3:23][C:24]1([CH3:40])[C:33](=[O:34])[NH:32][C:31]2[N:30]=[CH:29][C:28](/[CH:35]=[CH:36]/[C:37](O)=[O:38])=[CH:27][C:26]=2[CH2:25]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:23][C:24]1([CH3:40])[CH2:25][C:26]2[C:31](=[N:30][CH:29]=[C:28](/[CH:35]=[CH:36]/[C:37](=[O:38])[N:11]3[CH2:12][CH2:13][C:14]([CH2:17][C:18]4[S:19][CH:20]=[CH:21][N:22]=4)=[CH:15][CH2:16]3)[CH:27]=2)[NH:32][C:33]1=[O:34]
Reactant: CC1(C)Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Reactant: C1=C(Cc2nccs2)CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(/C=C/C(=O)N3CC=C(Cc4nccs4)CC3)cnc2NC1=O
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
DIPEA (0.33 mL, 1.83 mmol) was added to a stirred solution of 2-((1,2,3,6-tetrahydro-pyridin-4-yl)methyl)thiazole hydrochloride (Intermediate-2) (158 mg, 0.73 mmol), (E)-3-(6,6-dimethyl-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid (Intermediate-22) (150 mg, 0.61 mmol), HOBt (98 mg, 0.73 mmol) and EDC.HCl (232 mg, 1.22 mmol) in dry DMF (2 mL) at 20-35° C. and the reaction mixture was allowed to stir at 20-35° C. for 16 h. Then the reaction mixture was poured into ice water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 4% methanol/dichloromethane as an eluent to get the desired compound as an off-white solid (160 mg, 51%); 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.71 (d, J=2.9 Hz, 1H), 7.61 (d, J=3.0 Hz, 1H), 7.45 (d, J=15.2 Hz, 1H), 7.30-7.14 (m, 1H), 5.68-5.65 (m, 1H), 4.28-4.20 (m, 1H), 4.08-4.02 (m, 1H), 3.80-3.72 (m, 3H), 3.68-3.60 (m, 1H), 2.79 (s, 2H), 2.18-2.04 (m, 2H), 1.08 (s, 6H); LC-MS: 409.2 (M+1)+.