Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)(=[O:3])[CH3:2].N[C@H:33](C1C=CC=CC=1)CCN1CCC(C2C=C(NC(=O)C(C)C)C=CC=2)CC1.C(Cl)(=O)CC>>[CH3:23][CH:22]([CH3:24])[C:21]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][C@@H:5]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:4][C:1](=[O:3])[CH2:2][CH3:33])[CH2:9][CH2:10]2)[CH:15]=1)=[O:25]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: CC(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1
Agent: CCC(=O)Cl
Product: CCC(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1
Yield: 97 %

Procedure:
According to the procedure used for the synthesis of N-(3-{1-[(3S)-3-(acetylamino)-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide, N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (11.0 mg, 0.0280 mmol) and propionyl chloride (3.80 mg, 0.0420 mmol) provided 2-methyl-N-(3-{1-[(3S)-3-phenyl-3-(propionylamino)propyl]-4-piperidinyl}phenyl)propanamide (12 mg, 97% yield). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.59 (s, 1H), 7.40-7.20 (m, 7H), 6.96 (s, 1H), 5.19-5.12 (m, 1H), 3.18 (d, 1H, J=12.0 Hz), 2.99 (d, 1H, J=10.4 Hz), 2.93-2.86 (m, 1H), 2.61-2.40 (m, 3H), 2.38-2.23 (m, 3H), 2.19-1.75 (m, 8H), 1.25 (d, 6H, J=6.9 Hz), 1.22-1.08 (m, 3H); ESMS m/e: 436.4 (M+H)+.
Reaction SMILES: [CH3:1][SH:2].[Na].[F:4][C:5]([F:17])([F:16])[C:6]1[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10][C:11]=1Cl>C(O)C>[CH3:1][S:2][C:11]1[CH:10]=[CH:9][C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:6]=1[C:5]([F:17])([F:16])[F:4]
Reactant: CS
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Na]
Solvent: CCO
Product: CSc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reaction time: 17 h
Yield: 33.2 %

Procedure:
A mixture of 30 g of methyl mercaptan in 50 ml of ethanol was added at 10° C to a mixture of 12.5 g of sodium in 500 ml of ethanol and then 63 g of 3-trifluoromethyl-4-chloro-nitrobenzene were added thereto. The mixture stood at room temperature for 17 hours and was vacuum filtered. The recovered precipitate was washed with water and dried to obtain 22 g of 4-methylthio-3-trifluoromethyl-nitrobenzene melting at 158° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[C:9]1([O:17][CH3:18])[C:10](=[CH:13][CH:14]=[CH:15][CH:16]=1)[O:11][CH3:12]>>[OH:8][CH:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[C:16]1[CH:15]=[CH:14][CH:13]=[C:10]([O:11][CH3:12])[C:9]=1[O:17][CH3:18]
Reactant: COc1ccccc1OC
Reactant: O=Cc1ccncc1
Product: COc1cccc(C(O)c2ccncc2)c1OC

Procedure:
In Scheme F, step d, 4-pyridinecarboxaldehyde (9) is reacted with lithiated veratrole to give 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.O.[C:21]([OH:25])(=[O:24])[CH:22]=O.[BH3-]C#N.[Na+]>CCO>[CH2:8]([C:6]1[CH:7]=[C:2]([NH:1][CH2:22][C:21]([OH:25])=[O:24])[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ncc(Cc2ccccc2)cc1N
Reactant: O=CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ncc(Cc2ccccc2)cc1NCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 3-amino-5-benzylpyridine-2-carboxylate (0.543 g, 2.12 mmol) and glyoxylic acid monohydrate (0.254 g, 2.76 mmol) in EtOH (6 mL) was heated at reflux for 1 h. The mixture was allowed to cool to rt and NaCNBH3 (266 mg, 4.23 mmol) was added. After stirring 2 h at rt, the reaction was quenched with water and the EtOH was removed at reduced pressure. The aqueous mixture was extracted with CH2Cl2 and the organic layers were dried and concentrated. Trituration of the remaining material with EtOAc/hexanes and filtration afforded the product as a beige solid: 1H NMR (d6-DMSO) δ 13.2 (1H, br), 7.92 (1H, br t, J=4.8 Hz), 7.76 (1H, s), 7.26 (4H, m), 7.17 (1H, t, J=7 Hz), 7.00 (1H, s), 4.24 (2H, q, J=7 Hz), 3.90 (2H, s), 3.86 (2H, br), 1.27 (3H, t, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:30][CH3:31])[C:10](=[O:29])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23]S(C)(=O)=O)[C:16](=[O:28])[C:12]3=2)[C:7]1=[O:32].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:30][CH3:31])[C:10](=[O:29])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[C:16](=[O:28])[C:12]3=2)[C:7]1=[O:32]
Reactant: COc1c2c(c3n(c1=O)CCCCN(CCS(C)(=O)=O)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c2c(c3n(c1=O)CCCCN(CCN1CCOCC1)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-(2-methane-sulfonylethyl)-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione (97 mg, 0.17 mmol), morpholine (30 mg, 0.35 mmol), and diisopropylethylamine (006 mL, 0.355 mmol) in THF (1.7 mL) was stirred at 40° C. overnight. The product mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with gradient mixture of methanol in dichloromethane. Collection and concentration of appropriate fractions afforded the title compound.
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:10]=[N:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)=[CH:4][C:3]=1[CH3:17].[F:18][C:19]1[CH:20]=[CH:21][C:22](B2OC(C)(C)C(C)(C)O2)=[C:23]2[C:27]=1[C@H:26]([O:28][C:29]1[CH:42]=[CH:41][C:32]3[C@H:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][O:35][C:31]=3[CH:30]=1)[CH2:25][CH2:24]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:17][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[N:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)[CH:6]=[C:7]([CH3:8])[C:2]=1[C:22]1[CH:21]=[CH:20][C:19]([F:18])=[C:27]2[C:23]=1[CH2:24][CH2:25][C@H:26]2[O:28][C:29]1[CH:42]=[CH:41][C:32]2[C@H:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][O:35][C:31]=2[CH:30]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2cnc(=O)n(C)c2)cc(C)c1I
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cnc(=O)n(C)c6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 5-(4-iodo-3,5-dimethylphenyl)-1-methylpyrimidin-2(1H)-one and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 14): tR=1.08 min; Mass spectrum (ESI+): m/z=555 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=1.C(N(CC)CC)C>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:13]=[CH:14][CH:15]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(Nc2cc(Cl)ncn2)c1
Temperature: 80 °C

Procedure:
4,6-Dichloropyrimidine (1.5 g, 10 mmol), tert-butyl 3-aminophenylcarbamate (2.1 g, 10 mmol) and triethylamine (2.2 g, 20 mmol) were mixed in ethanol (20 mL), heated at 80° C. for 16 hr. The reaction mixture was cooled to RT and solvent was removed in vacuo. The gummy crude product was mixed with 20 mL of DCM and was stirred at RT to give an off-white solid, which was filtered and dried under vacuum (1.6 g, 5 mmol). MS (m/z): MH+=321, 323.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[C:4]1=[O:16])[CH3:2].[C:17](OC)(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[SH:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[S:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[C:17](=[O:25])[N:15]=3)[CH:9]=2)[C:4]1=[O:16])[CH3:2]
Reactant: COC(=O)c1ccccc1S
Reactant: CCN1CCN(c2ccnc(C#N)c2)C1=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN1CCN(c2ccnc(-c3nc(=O)c4ccccc4s3)c2)C1=O
Yield: 52.3 %

Procedure:
4-(3-Ethyl-2-oxo-1-imidazolidinyl)-2-pyridinecarbonitrile (0.16 g, 0.76 mmol) and methyl thiosalicylate (0.42 g, 2.5 mmol) was dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 9 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate were collected, concentrated and recrystallized from tetrahydrofuran-hexane to give the titled compound (0.14 g, 51%) as white crystals.
Reaction SMILES: Cl.[F:2][CH2:3][C:4]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:38])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:26][N:25]=3)=[CH:18][CH:17]=2)[CH:9]=1)([CH3:7])[CH2:5][F:6].Cl.[C:40](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=C(OC4CCNCC4)C=CN=3)=CC=2)C=1)(C)(C)[CH3:41]>>[F:2][CH2:3][C:4]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:38])[NH:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:32][CH2:33][N:34]([CH2:40][CH3:41])[CH2:35][CH2:36]4)=[CH:26][N:25]=3)=[CH:20][CH:21]=2)[CH:9]=1)([CH3:7])[CH2:5][F:6]
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3cc(OC4CCNCC4)ccn3)cc2)no1
Agent: Cl
Product: CCN1CCC(Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(CF)CF)on4)cc3)nc2)CC1
Yield: 94 %

Procedure:
N-(4-(3-(5-(1,3-Difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(1-ethylpiperidin-4-yloxy)picolinamide (65 mg, 94%) was prepared as a white powder using a procedure analogous to that described in Example 2, substituting N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride from Step 3 of this example for N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-4-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 2. LC-MS (ESI) m/z 543 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.60 (s, 1H), 8.79 (s, 1H), 8.38 (s, 1H), 8.10 (d, J=8.85 Hz, 1H), 7.81 (d, J=9.04 Hz, 2H), 7.63-7.72 (m, 1H), 7.42 (d, J=9.04 Hz, 2H), 6.79 (s, 1H), 4.73 (s, 2H), 4.58 (s, 2H), 2.73 (br. s., 1H), 2.27 (br. s., 3H), 1.97-2.17 (m, 2H), 1.91 (s, 2H), 1.75 (s, 2H), 1.34 (s, 3H), 0.90-1.20 (m, 4H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH:14]=[CH:13][C:12]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18](N1CCOCC1)=[O:19].P(Cl)(Cl)(Cl)=O.[OH-].[NH4+]>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][C:14]([CH:18]=[O:19])=[CH:13][C:12]=2[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=Cc2cc(Oc3ccccc3)ccc2OC1
Reactant: O=CN1CCOCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=CC1=Cc2cc(Oc3ccccc3)ccc2OC1
Temperature: 60 °C

Procedure:
6-Phenoxy-2H-1-benzopyran (3.36 g, 15 mmol) and N-formylmorpholine (10.4 g, 90 mmol) are dissolved in 10.5 ml of methylene chloride and treated with phosphorus oxychloride (13.8 g, 90 mmol) at 0° C. over 15 minutes. The mixture is then heated at 60° C. for 27 hours, cooled and poured slowly into an ice-water mixture. The mixture is then neutralized with aqueous ammonium hydroxide, and extracted twice with methylene chloride. The combined organic extracts are washed with water, dried (MgSO4), and evaporated to give crude 6-phenoxy-2H-1-benzopyran-3-carboxaldehyde, which is used without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:12]([NH2:16])[CH2:13][CH:14]=[CH2:15].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH2:12]([NH:16][C:2](=[O:3])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:13][CH:14]=[CH2:15]
Reactant: C=CCCN
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CCCNC(=O)OCc1ccccc1

Procedure:
Benzyl chloroformate (38 g, 0.22 mol) was added at 0° C. over 15 minutes to a mixture of but-3-en-1-amine (10 g, 0.14 mol) and sodium bicarbonate (35 g, 0.52 mol) in DCM (500 mL) and water (40 mL). The mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc) to afford benzyl but-3-en-1-ylcarbamate. MS ESI calc'd. for C12H16NO2 [M+H]+ 206. found 206. 1H NMR (400 MHz, CDCl3) δ 7.36-7.30 (m, 5H), 5.80-5.70 (m, 1H), 5.11-5.01 (m, 4H), 3.79-3.25 (m, 2H), 2.29-2.24 (m, 2H).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[S:10][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:12][C:8]=2[CH:7]=1)([OH:3])=[O:2].[CH2:19](O)[CH3:20]>S(=O)(=O)(O)O>[C:1]([CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[S:10][C:11]([S:13](=[O:15])(=[O:14])[NH2:16])=[CH:12][C:8]=2[CH:7]=1)([O:3][CH2:19][CH3:20])=[O:2]
Reactant: NS(=O)(=O)c1cc2cc(OCC(=O)O)ccc2s1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)COc1ccc2sc(S(N)(=O)=O)cc2c1
Reaction time: 5 h
Yield: 87 %

Procedure:
A mixture of 5-(carboxymethoxy)benzo[b]thiophene-2-sulfonamide (1.50 g, 0.0052 m) in ethanol (15 ml) and concentrated sulfuric acid (3 ml) was refluxed with stirring for 5 hours. Ethanol was evaporated under reduced pressure, the residue was treated with H2O (25 ml) and extracted with ethyl acetate (50 ml and 2×25 ml). The combined extracts were washed with H2O, saturated sodium bicarbonate solution (2×25 ml), and three times with H2O. After drying over Na2SO4, the solvent was evaporated under reduced pressure to afford 1.43 g (87%) of product. Recrystallization from nitromethane afforded 1.12 g of analytically pure product melting at 167.5°-168° C.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15]N)=[CH:11][CH:10]=1)[CH3:8].[CH3:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=O>O1CCOCC1>[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]2[NH:15][C:21]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][C:20]=3[C:11]=2[CH:10]=1)[CH3:8]
Reactant: CCc1ccc(NN)cc1
Reactant: CN1CCCCC1=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CCc1ccc2[nH]c3c(c2c1)CN(C)CC3
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sulfuric acid is added to a solution of 4-ethyl phenyl hydrazine hydrochloride (1 equiv.) in dioxane, and stirred for 5 min. at RT. N-Methyl piperidone (0.76-1.4 equiv.) is added and the mixture is heated at 80° C. for 3 h. After completion, as monitored by TLC, the reaction mixture is concentrated under reduced pressure and basified to pH 10 using 10% aqueous KOH solution, extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to provide the desired compound.
Reaction SMILES: O.[CH2:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])[CH2:3][CH3:4].[N+:12]([O-])([OH:14])=[O:13]>CCOCC>[CH2:2]([C:5]1[C:6]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH2:3][CH3:4]
Reactant: CCCc1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Solvent: O
Product: CCCc1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 288 h

Procedure:
To a stirred mixture of 100 ml of water, 100 ml of ether and 10.0 g of 2-n-propylphenol was added dropwise 11.0 ml of 61% nitric acid and the reaction was carried out with stirring at room temperature for 12 days. The reaction mixture was extracted with 200 ml of ethyl acetate and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform-n-hexane (1 : 1)]to give 3.76 g of 6-n-propyl-2-nitrophenol.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:23](O)=[O:24])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:39][NH:40][O:41][CH3:42]>N1C=CC=CC=1>[CH3:42][O:41][N:40]([CH3:39])[C:23]([C:11]1[C:10]2[C:15](=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:9]=2)[CH:14]=[CH:13][CH:12]=1)=[O:24]
Reactant: CNOC
Reactant: O=C(O)c1cccc2c(-c3ccccc3)n(Cc3ccccc3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cccc2c(-c3ccccc3)n(Cc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Benzyl-3-phenyl-7-trifluoromethyl-2H-indazole (353 mg, 1 mmol), prepared similarly to that of Example 1, was treated with 3 ml of 70% aq H2SO4 at 90° C. for 4 hours. After cooling, 10 volumes of water were added and the product was extracted with dichloromethane. Flash column chromatography (SiO2, dichloromethane as an eluant) afforded 2-benzyl-3-phenyl-2H-indazole-7-carboxylic acid in 60% yleld. The 2-benzyl-3-phenyl-2H-indazole-7-carboxylic acid (1.64 g, 5 mmol) was dissolved in 20 ml of pyridine followed by addition of 1-(-3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.34 g, 7 mmol) and N,O-dimethyhydroxylamine hydrochloride (585 mg, 6 mmol). The reaction mixture was stirred at room temperature overnight. Pyridine was evaporated and the residue was shaken with 0.5M aq HCl and dichloromethane. The product was extracted with dichloromethane, and flash column chromatography (SiO2, dichloromethane as an eluant) afforded 2-benzyl-3-phenyl-2H-indazole-7-carboxylic acid methoxy-methyl-amide in 79% yleld.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.C([Sn](CCCC)(CCCC)[C:23]1[S:24][CH:25]=[CH:26][N:27]=1)CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([C:23]2[S:24][CH:25]=[CH:26][N:27]=2)[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2nccs2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 120 °C
Reaction time: 72 h
Yield: 49.6 %

Procedure:
A mixture of 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (200 mg, 0.82 mmol), 2-tributylstannylthiazole (Frontier Scientific) (338 mg, 0.90 mmol), tris(dibenzylideneacetone)dipalladium(0) (Aldrich Chemical Company) (19 mg, 0.021 mmol) and triphenylphosphine (Aldrich Chemical Company) (43 mg, 0.16 mmol) in anhydrous toluene (2 mL) was refluxed under N2 for 4 d. TLC showed that the reaction was not complete. Therefore, additional portions of 2-tributylstannylthiazole (338 mg, 0.90 mmol), tris(dibenzylideneacetone)dipalladium(0) (19 mg, 0.021 mmol) and triphenylphosphine (43 mg, 0.16 mmol) were added to the reaction mixture, and the mixture was stirred at 120° C. for 3 d. Upon cooling to the room temperature, the reaction was quenched with 5% HCl (50 mL) and the solution was extracted with CHCl3 (3×100 mL). The organic extracts were washed with H2O (2×150 mL), filtered through a pad of Celite, washed with saturated NaCl (150 ml), dried over Na2SO4 and concentrated with a rotary evaporator. Chromatography on silica gel with a gradient eluant of MeOH (1-3%):CH2Cl2 (99-97%) afforded 119 mg (50%) of the title compound as a yellow solid. Mp: 248-250° C. 1H NMR (acetone-d6; 400 MHz): δ 2.69 (s, 3), 7.01(s, 1), 7.57-7.47 (m, 3), 8.06 (d, 2, J=7.17), 8.97 (s, 1), 9.18 (s, 1), 10.76 (s, 1). MS m/z: 293 (M+1), 291 (M−1). HRMS: Calcd for M+H: 293.0861. Found: 293.0866.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].O=[C:7]1[NH:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]2[S:19][C:20]([CH3:22])=[CH:21][C:8]1=2.CN(C)C1C=CC=CC=1>>[Cl:3][C:7]1[C:8]2[CH:21]=[C:20]([CH3:22])[S:19][C:9]=2[N:10]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:12]=1
Reactant: Cc1cc2c(=O)[nH]c(-c3cccnc3)nc2s1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1cc2c(Cl)nc(-c3cccnc3)nc2s1

Procedure:
The replacement of the keto group by Cl under the formation of the aromatic pyrimidine ring takes place under standard conditions. A mixture of POCl3 (18 ml) with 3,4-dihydro-4-oxo-2-(pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine (6 g) is refluxed for 4 hours under the addition of N,N-dimethylaniline (1,8 m). The usual workup yields 4-chloro-2-(pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine (5 g)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[NH2:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=2)=[N:14]1>>[Cl:26][C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][N:13]([CH2:12][C@@H:11]([NH:10][C:7](=[O:9])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH3:27])[N:14]=2)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1ccccn1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ccccn1
Yield: 73.7 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)picolinamide was prepared using the method of Example 34(d) starting from picolinic acid (0.227 g, 1.841 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g, 1.534 mmol). Yield 73.7%. 1H-NMR (400 MHz; CDCl3): δ 1.26 (d, 3H), 4.31 (dd, 1H), 4.45 (dd, 1H), 4.62 (m, 1H), 6.63 (d, 1H), 7.46 (m, 1H), 7.50 (d, 1H), 7.67 (d, 1H), 7.81 (dd, 1H), 7.86 (m, 1H), 8.09 (d, 1H), 8.19 (m, 1H), 8.65 (m, 1H), 8.86 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.C([O-])(O)=O.[Na+].[Cl:18][CH2:19][C:20](Cl)=[O:21]>CCOC(C)=O>[Cl:18][CH2:19][C:20]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc2ccc(O)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1cccc2ccc(O)cc12
Reaction time: 0.33 h

Procedure:
To a solution of 8-amino-2-naphthol (10.0 g, 62.8 mmol) in 240 mL of 1:1 EtOAc/saturated NaHCO3 solution was added chloroacetyl chloride dropwise (5.5 mL, 69.1 mmol). After 20 minutes, the solution was filtered, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product.
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH2:7][C@@H:8]([CH2:10][CH2:11][CH2:12][C@@H:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])\[CH3:4].[CH3:22][O-:23].[Na+]>CO.C(OCC)(=O)C>[CH2:1]([O:23][CH3:22])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH2:7][C@@H:8]([CH2:10][CH2:11][CH2:12][C@@H:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])\[CH3:4]
Reactant: C[O-]
Reactant: C/C(=C\CCl)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
10.0 g of phytyl chloride was dropped into a solution of 2.0 g of sodium methoxide dissolved in 70 ml of methanol. The resulting mixture was stirred for 4 hours at 60° C. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in 30 ml of ethyl acetate, and the resulting solution was washed with water. The solution was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue thus obtained was subjected to distillation (b.p.: 148°-150° C., 1.5 mmHg) to obtain 9.4 g (yield: 95%) of oily methyl phytyl ether.