Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][NH:8][C:7]2=[O:13])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[C:20](#[N:23])[CH:21]=[CH2:22]>O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:22][CH2:21][C:20]#[N:23])[NH:8][C:7]2=[O:13])([O-:3])=[O:2]
Reactant: O=c1[nH][nH]c2ccc([N+](=O)[O-])cc12
Reactant: C=CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#CCCn1[nH]c(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
5-Nitro-1,2-dihydro-indazol-3-one (prepared according to Org. Synth. 1949, 29, 54 or Chem Ber. 1942, 75, 1104) (0.6 g) was suspended in water (8 mL) and 2N K2CO3 (aq.) (1.8 g) was added to the flask and the mixture was heated to 50° C. for 10 minutes. Acrylonitrile (0.24 mL) was then added dropwise. The reaction was stirred overnight and was quenched with 2 N HCl (aq.) solution while cooling in an ice bath. The aqueous phase was extracted with EtOAc and the combined phases were washed with brine, dried over sodium sulfate, filtered and reduced in vacuo. Flash column chromatography over silica gel (eluting with EtOAc, nheptane, 3% AcOH) afforded pure desired 3-(5-Nitro-3-oxo-2,3-dihydro-indazol-1-yl)-propionitrile as a white solid. MS (ESI+: 233.3[M+H]+).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].CN(C)C1C=CC=CC=1.S(=O)(=O)(O)O.[C:21]([OH:25])([CH3:24])([CH3:23])[CH3:22]>C(Cl)(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:4]
Reactant: CC(C)(C)O
Reactant: CC(Br)C(=O)Br
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CC(Br)C(=O)OC(C)(C)C
Yield: 86.7 %

Procedure:
A solution of 2-bromopropionyl bromide (25 g.) in dry chloroform (50 ml.) was dropwise added with stirring and ice-cooling to a solution of N,N-dimethylaniline (24 g.) in t-butanol (11 g.) and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was poured into 6N sulfuric acid (150 ml.) and extracted with ether. The extract was in turn washed with 6N sulfuric acid, water, a 10% potassium carbonate aqueous solution and water and dried over magnesium sulfate. The solvent was distilled off to give oil of t-butyl 2-bromopropionate (21 g.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:12][O:13][NH:14][CH3:15].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:14]([O:13][CH3:12])[CH3:15])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccnc(Cl)n1
Reactant: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccnc(Cl)n1
Reaction time: 4 h
Yield: 65.7 %

Procedure:
To a solution of 2-chloropyrimidine-4-carboxylic acid (3.95 g, 24.9 mmol) and N-methoxymethanamine hydrogen chloride salt (2.43 g, 24.9 mmol) in dichloromethane (15 mL) were added triethylamine (6.95 mL, 50 mmol) and (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (13 g, 24.91 mmol) and stirred for 4 hr. The solution was diluted with EtOAc, washed with brine, dried with MgSO4, filtered, and concentrated to dryness. Purification on silica gel by flash chromatography (0-100% EtOAc/hexanes) afforded 2-chloro-N-methoxy-N-methylpyrimidine-4-carboxamide (3.30 g, 16.37 mmol, 66% yield). MS ESI: [M+H]+ m/z 202.0. 1H NMR (500 MHz, CDCl3) δ 8.75 (d, J=4.6, 1H), 7.48 (d, J=4.6, 1H), 3.77 (s, 3H), 3.35 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].C(N(CC)CC)C.C(O)=O>C(#N)C.[Pd]>[N+:14]([C:3]1[CH:4]=[C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:7][CH:2]=1)([O-:16])=[O:15]
Reactant: CC(C)(C(=O)O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O=CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C(=O)O)c1cccc([N+](=O)[O-])c1
Yield: 92.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 6.3 g of 2-(4-chloro-3-nitrophenyl) -2-methylpropionic acid, 7.62 ml of triethylamine, 0.6 g of 5% palladium-on-charcoal and 1.46 ml of formic acid in 100 ml of acetonitrile. 5.0 g of 2-(3-nitrophenyl)-2-methylpropionic acid are thus obtained in the form of an orange oil [NMR spectrum (DMSO-d6, 200 MHz): 1.57 (s, 6H); 7.65 (t, J=7 Hz, 1H); 7.9 (d, J=7 Hz, 1H); 8.13 (d, J=7 Hz, 1H); 8.15 (s, 1H); 12.5 (broad s, acidic OH)].
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:14])[CH2:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1.C(OCC)(=O)C>C(Cl)Cl>[Br:1][CH2:2][CH:3]([O:14][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][O:32]1)[CH2:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6]
Reactant: C1=COCCC1
Reactant: CCOC(=O)CNC(=O)CC(O)CBr
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)CC(CBr)OC1CCCCO1
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of 1 g ethyl 2-(4-bromo-3-hydroxybutanamido)acetate in 30 ml methylene chloride are added 100 mg pyridinium p-toluenesulphonate and 1 ml dihydropyran. Stirring is continued for 3 h at ambient temperature, the solvent is evaporated in vacuo and the residue chromatographed on silica, eluting with ether. A pale straw-coloured oil is obtained in 91% yield, Rf 0.5 (silica gel plates, thickness 0.25 mm eluent ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:16][C@H:17]3[C@H:21]([OH:22])[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl>O1CCOCC1.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][C@H:17]3[C@H:21]([OH:22])[CH2:20][NH:19][CH2:18]3)=[O:15])=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](NC(=O)c2ccc(-c3cccc(F)c3)nc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(N[C@@H]1CNC[C@H]1O)c1ccc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.4 %

Procedure:
To a solution of trans-tert-butyl 3-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)-4-hydroxypyrrolidine-1-carboxylate (500 mg, 1.24 mmol) in dioxane was added 4N HCl in dioxane (10 mL). The reaction was stirred at room temperature for ˜4 hrs and then diluted with ether to give a white solid, which was filtered and collected to give the desired product as the hydrochloride salt, trans-6-(3-fluorophenyl)-N-[4-hydroxypyrrolidin-3-yl]nicotinamide (390 mg, 92% ). LC/MS (M+H)=301.9 observed, 302.13 expected.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:15]([C:16]3[CH:17]=[N:18][CH:19]=[N:20][CH:21]=3)=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[CH2:3]1.[C:22]([O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([C:16]3[CH:17]=[N:18][CH:19]=[N:20][CH:21]=3)[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]3)=[N:8][CH:9]=2)=[CH:32][CH:33]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(O)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1
Reactant: CC(C)(C)Oc1ccc(N)cc1
Product: CC(C)(C)Oc1ccc(NC(=O)c2cnc(N3CC[C@@H](O)C3)c(-c3cncnc3)c2)cc1

Procedure:
The title compound was prepared in an analogous fashion to that described infashion to that described in Example 170 using (R)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinic acid (Stage 170.1) and 4-tert-butoxyaniline to afford an off-white foam. HPLC (Condition 4) tR=4.31 min, UPLC-MS (Condition 3) tR=0.84 min, m/z=434.4 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.26 (s, 9H) 1.67-1.77 (m, 1H) 1.79-1.91 (m, 1H) 2.88 (d, J=3.91 Hz, 1H) 3.14-3.25 (m, 2H) 3.30-3.45 (m, 1H) 4.14-4.24 (m, 1H) 4.86 (d, J=3.52 Hz, 1H) 6.88-7.00 (m, 2H) 7.56-7.66 (m, 2H) 8.07 (d, J=2.35 Hz, 1H) 8.76 (d, J=2.35 Hz, 1H) 8.87 (d, J=0.78 Hz, 2H) 9.17 (s, 1H) 9.92 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][C:7]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:6]1)=[O:4].CO.[BH4-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]([C@H:5]1[C@H:10]([OH:11])[CH2:9][CH2:8][C:7]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:6]1)=[O:4].[CH3:1][O:2][C:3]([C@H:5]1[C@@H:10]([OH:11])[CH2:9][CH2:8][C:7]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC2(CCCCC2)CCC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@H]1CC2(CCCCC2)CC[C@@H]1O
Product: COC(=O)[C@@H]1CC2(CCCCC2)CC[C@H]1O

Procedure:
To a solution of 3-oxo-spiro[5.5]undecane-2-carboxylic acid methyl ester (29.6 g) obtained in Step 3 in a mixed solvent of methanol (200 mL)-tetrahydrofuran (50 mL), sodium borohydride (4.67 g) was added in three portions under ice-cooling, followed by stirring the reaction mixture under ice-cooling for 1 hour. Then, after addition of 1N aqueous hydrochloric acid solution to the reaction mixture, the resulting insolubles were filtered off. Methanol in the filtrate was evaporated off in vacuo, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:10 to 1:3) to give trans-3-hydroxy-spiro[5.5]undecane-2-carboxylic acid methyl ester (4.15 g) and cis-3-hydroxy-spiro[5.5]undecane-2-carboxylic acid methyl ester (4.9 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].Br[C:11]1[S:12][CH:13]=[CH:14][N:15]=1.CC([O-])(C)C.[K+].CCOC(C)=O>CC(N(C)C)=O>[F:9][C:3]1[CH:4]=[C:5]([O:8][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(O)cc1F
Reactant: Brc1nccs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2nccs2)cc1F
Temperature: 150 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A mixture of 427A (0.814 g, 6.41 mmol), 2-bromothiazole (1.0 g, 6.10 mmol) and t-BuOK (0.821 g, 7.32 mmol) in DMA (25 ml) was stirred at 150° C. under argon for 1 h, then cooled to rt. Treated with EtOAc (150 ml), the mixture was washed with H2O (50 ml), 3N NaOH (2×50 ml), H2O (50 ml), dried with Na2SO4. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (10%-25% EtOAc-hexanes) gave 427B (1.02 g, 80%) as a colorless oil. It has a retention time of 4.02 min (standard LC1 method, 8 min run). MS Found: (M+H)+=211.1
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:31][C:25]1[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[S:21]([N:18]1[CH2:19][CH2:20][CH:15]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[CH:14]=2)[CH2:16][CH2:17]1)(=[O:23])=[O:22]
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccc(Cl)cc3Cl)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(C2CCN(S(=O)(=O)c3ccc(Cl)cc3Cl)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.6 %

Procedure:
To a stirred solution of {4-[1-(2,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (115 mg, 0.23 mmol) in THF (6 mL) was added a solution of lithium hydroxide monohydrate (50 mg, 1.2 mmol) in water (1.5 mL) and the reaction mixture was stirred for 24 h at RT. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give {4-[1-(2,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid (100 mg, 89%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.35 (br s, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.96-8.00 (m, 2H), 7.87-7.95 (m, 1H), 7.68-7.73 (m, 2H), 7.34-7.44 (m, 2H), 3.87 (d, J=12.2 Hz, 2H), 3.72 (s, 2H), 3.04 (t, J=11.5 Hz, 2H), 1.89-1.96 (m, 2H), 1.67-1.78 (m, 2H); MS cald. for C23H19Cl2FNO4S [(M−H)−]: 494, obsd. 494.3.
Reaction SMILES: C(O)(=O)C.[CH:5](N)=[NH:6].[Cl:8][C:9]1[C:14]([NH:15][C:16](=[NH:26])[C:17]2[C:22](F)=[CH:21][C:20]([F:24])=[CH:19][C:18]=2[F:25])=[C:13]2[O:27][CH2:28][O:29][C:12]2=[CH:11][CH:10]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:8][C:9]1[C:14]([NH:15][C:16]2[C:17]3[C:22](=[CH:21][C:20]([F:24])=[CH:19][C:18]=3[F:25])[N:6]=[CH:5][N:26]=2)=[C:13]2[O:27][CH2:28][O:29][C:12]2=[CH:11][CH:10]=1
Reactant: N=C(Nc1c(Cl)ccc2c1OCO2)c1c(F)cc(F)cc1F
Reactant: N=CN
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Fc1cc(F)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Temperature: 25 °C

Procedure:
Formamidine acetic acid salt (0.185 g) was added to a stirred solution of N1-(6-chloro-2,3-methylenedioxyphenyl)-2,4,6-trifluorobenzamidine (0.204 g) in toluene (5 ml) and the reaction mixture was heated to reflux for 16 hours. A second portion (0.185 g) of formamidine acetic acid salt was added and the reaction mixture was heated to reflux for a further 16 hours. Triethylamine (0.25 ml) was added and the reaction mixture was heated to reflux for a further 3 days. The resultant reaction mixture was cooled to ambient temperature and partitioned between methylene chloride (25 ml) and a saturated aqueous sodium bicarbonate solution (25 ml). The organic solution was washed with 10% aqueous citric acid (25 ml), dried over magnesium sulphate and evaporated. The resultant oil was purified by column chromatography on silica gel using increasingly polar mixtures of isohexane and ethyl acetate as eluent. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-5,7-difluoroquinazoline (0.068 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([C:56]([F:58])([F:57])[F:59])=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(C(F)(F)F)cn2)cc1Cl
Temperature: 0 °C
Yield: 42.1 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it was completely dissolved and became light purple in color. The reaction mixture was then treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 92, 200 mg, 0.61 mmol) and stirred at 0° C. for 20 min and then warmed to 25° C. where it was stirred for 30 min. After such time, the reaction mixture was treated with 2-amino-5-trifluoromethyl-pyridine (147 mg, 0.91 mmol) and pyridine (0.088 mL, 1.09 mmol), and the reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (10 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide (122 mg, 43%) as a white foam: EI-HRMS m/e calcd for C20H22 ClF3N2O3S (M+) 474.0992, found 474.0990.
Reaction SMILES: [OH2:1].[OH2:2].O.O.O.O.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#N)=[CH:16][C:15]=1[C:22]([F:25])([F:24])[F:23].[OH-].[Na+].Cl>C(O)C.O>[N:7]1([C:14]2[CH:21]=[CH:20][C:17]([C:18]([OH:2])=[O:1])=[CH:16][C:15]=2[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: O
Reactant: C1CNCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(N2CCNCC2)c(C(F)(F)F)c1
Temperature: 10 °C
Reaction time: 15 h

Procedure:
37.9 g (195 mmol) piperazine hexahydrate are refluxed for 2 hours with 12.4 g (66 mmol) 4-fluoro-3-trifluoromethyl-benzonitrile suspended in 40 ml of ethanol. Then 13.7 ml (261 mmol) 50% sodium hydroxide solution and 13.7 ml of water are added and the mixture is refluxed for a further 3.5 hours and kept at ambient temperature for a further 15 hours. Then 43.5 ml of conc. hydrochloric acid are added and the mixture is cooled to 10° C. for 30 minutes with stirring. The precipitate obtained is suction filtered, washed with a little water and dried at 40° C. in the circulating air dryer for 24 hours.
Reaction SMILES: Cl[C:2]1[N:3]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[S:4](=[O:11])(=[O:10])[N:5]=[C:6]([O:8][CH3:9])[N:7]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([O-:20])=[O:19].N1C=CC=CC=1>C(Cl)Cl.C1COCC1.C>[CH:12]1([N:3]2[C:2]([O:27][C:24]3[CH:25]=[CH:26][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=3)=[N:7][C:6]([O:8][CH3:9])=[N:5][S:4]2(=[O:11])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC1=NS(=O)(=O)N(C2CCCCC2)C(Cl)=N1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC1=NS(=O)(=O)N(C2CCCCC2)C(Oc2ccc([N+](=O)[O-])cc2)=N1

Procedure:
A solution of the chlorothiatriazine obtained in Step 3. above (92.3 g) in methylene chloride (250 ml) is added dropwise to a stirred solution of para-nitrophenol (49.4 g) and pyridine (70.2 g) in methylene chloride (500 ml) and refluxed for 3 hours. The reaction mixture is washed with 3N HCl and sodium bicarbonate solution. The methylene chloride layer is dried, filtered, washed and evaporated yielding a solid which is dissolved in hot THF with charcoal, filtered and evaporated. The resulting solid is washed with diethyl ether, dissolved in methylene chloride, filtered through silica gel, washed with methylene chloride, filtered through Celite®, evaporated, and triturated with diethyl ether affording a yellow solid. The solid is recrystallized from hot THF, yielding the desired product as a solid used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[CH:4][N:3]=1.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=O)=[CH:16][CH:15]=1)([O-:13])=[O:12]>O=P(Cl)(Cl)Cl>[Cl:10][C:5]1[C:6]([Cl:9])=[C:7]2[N:8]=[C:18]([C:17]3[CH:21]=[CH:22][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(Cl)c1N
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(-c2nc3c(Cl)c(Cl)cnc3[nH]2)cc1
Temperature: 105 °C
Yield: 57.8 %

Procedure:
2,3-Diamino-4,5-dichloropyridine (Example 206a) (2.5 g, 14 mmol) and 4-nitrobenzoic acid (2.3 g, 14 mmol) were dissolved in POCl3 (40 ml) and heated to 105° C. for 5 h. The excess of POCl3 was evaporated off and the residue was dissolved in EtOAc and aqueous K2CO3. The aqueous phase was basified with 10M KOH and extracted three times with EtOAc. The combined organic phase was washed with brine, dried (Na2SO4) and evaporated in vacuo to afford the title compound (2.5 g, 58%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[N:7][CH:8]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:21]3[CH2:27][CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:4]=[CH:5][C:6]([C:9]5[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=5)=[N:7][CH:8]=4)[CH2:23][CH2:22]3)=[CH:8][N:7]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: C1CNCCNC1
Reactant: COc1cc(-c2ccc(CCl)cn2)cc(OC)c1OC
Product: COc1cc(-c2ccc(CN3CCCN(Cc4ccc(-c5cc(OC)c(OC)c(OC)c5)nc4)CC3)cn2)cc(OC)c1OC

Procedure:
5-Chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (294 mg) and homopiperazine (50 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[N:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:27])[CH3:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:25]([N:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:9](=[O:11])[CH2:8][C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=3)=[N:18][CH:17]=2)[CH2:24][CH2:23]1)(=[O:27])[CH3:26]
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(I)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-iodophenyl)acetic acid 177-1 (524 mg, 2.0 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (440 mg, 2.0 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (798 mg, 2.1 mmol) in DMF (10 mL) was added DIEA (1.04 mL, 6.0 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into ethyl acetate, washed with saturated NaHCO3 then brine, dried over Na2SO4. The solvent was removed by rotary evaporation to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-iodophenyl)acetamide 177-2 as tan solid. MS m/z 465.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10]N)[CH3:2].Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.Cl.O>C(O)C.O1CCOCC1>[CH2:1]([O:3][C:4]1[C:5]2[NH:10][C:16]3[CH2:17][CH2:18][NH:13][CH2:14][C:15]=3[C:6]=2[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccccc1NN
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cccc2c3c([nH]c12)CCNC3
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
(2-ethoxyphenyl)-hydrazine (1.22 g 8.00 mmol) and 4-piperidone hydrochloride (1.09 g 8.00 mmol) in ethanol (20 mL) were heated to reflux for 1 h. The 4M HCl (1 mL) in dioxane was added (immediate darkening) and heating continued for 4 h. The reaction was cooled to RT. The solvent was evaporated and the residue triturated with ether (c.f. 10 mL) to give a dark brown solid. The solid was slurried with the minimum of water, filtered and dried (MgSO4). This was repeated to give an off white solid (1.19 g, 59%). Material used without further purification.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[S:20][C:21]([CH2:24][CH2:25][CH2:26][CH3:27])=[CH:22][CH:23]=1>>[CH2:24]([C:21]1[S:20][C:19]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)=[CH:23][CH:22]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1ccc(Br)s1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Product: CCCCc1ccc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)s1

Procedure:
rac-3,4-Dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 2.3 g (10 mmol) was reacted with 2.4 g (11 mmol) of 2-bromo-5-butylthiophene under the conditions described in Example 15. Chromatography of the crude product over 100 g of silica gel and crystallization from petroleum ether yielded colorless crystals with m.p. 80°-82°.