Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[F:20][CH:21]([F:32])[O:22][C:23]1[C:30]([CH3:31])=[CH:29][C:26]([CH:27]=O)=[CH:25][N:24]=1>>[F:32][CH:21]([F:20])[O:22][C:23]1[N:24]=[CH:25][C:26]([CH2:27][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])=[CH:29][C:30]=1[CH3:31]
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: Cc1cc(C=O)cnc1OC(F)F
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cnc(OC(F)F)c(C)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 6-(difluoromethoxy)-5-methylnicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.86 min.; [M+H]+: 406.88 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13]1([CH2:19][C:20](O)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>>[CH2:19]([C:20]1[S:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Nc1cnc2ccccc2c1S
Agent: [Na+]
Agent: [OH-]
Product: c1ccc(Cc2nc3cnc4ccccc4c3s2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
A mixture of 17.62 g (0.1 mole) of 3-amino-4-mercapto-quinoline, 15 g (0.11 mole) of phenyl acetic acid and 200 g of polyphosphoric acid is slowly heated to 140° C. under stirring. The reaction mixture is allowed to stand at this temperature for 2 hours, cooled and added to 1000 g of crushed ice under vigorous stirring. The mixture is made alkaline with an aqueous sodium hydroxide solution, extracted three times with 250 ml of chloroform each and the chloroform extract is evaporated. Thus 16.5 g of 2-benzyl-thiazolo[4,5-c]quinoline are obtained, m.p.: 111°-113° C., yield 60%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([S:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NS(=O)(=O)c4ccccc4)cc3c2C1
Yield: 32.9 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.6 μL (0.051 mMol) benzenesulfonyl chloride, 5.6 mg (34%) of the title compound were recovered as a light beige solid.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33](B(O)O)=[CH:32][N:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:33]3[C:34]([O:36][CH3:37])=[N:35][C:30]([O:29][CH3:28])=[N:31][CH:32]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC[C@@H](O)C2)c(OC)n1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1, 150 mg, 0.324 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (71.6 mg, 0.389 mmol), PdCl2(dppf)-(CH2Cl2) (39.7 mg, 0.049 mmol) and K3PO4 (206 mg, 0.973 mmol) were added to a vial and flushed with argon. Dioxane (1.5 mL) was added and the mixture was stirred at 120° C. overnight. The solvent was evaporated off under reduced pressure, the residue was treated with Si-Thiol (Biotage, load: 1.3 mmol/g) in MeOH and purified by preparative SFC (Column DEAP, from 18% to 23% in 6 min) to afford the title compound as an off-white powder after lyophilization from water/MeCN. UPLC-MS (Condition 11), tR=1.05 min, m/z=522.3/524.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.92 (m, 2H) 2.89-3.43 (m, 4H) 3.91 (br. s, 3H) 3.95 (s, 3H) 4.21 (br. s, 1H) 4.74-5.00 (m, 1H) 7.33 (d, J=8.91 Hz, 2H) 7.83-7.90 (m, 3H) 8.32 (br. s, 1H) 8.74 (d, J=2.26 Hz, 1H) 10.11 (s, 1H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH2:6]([CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]1)[C:7]#[CH:8]>CC(C)=O.CCOCC.[O-2].[O-2].[O-2].[Cr+6]>[CH2:6]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:2])=[O:16])[CH2:11][CH2:10]1)[C:7]#[CH:8]
Reactant: O=S(=O)(O)O
Reactant: C#CCC1CCC(CO)CC1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: CCOCC
Product: C#CCC1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of chromium trioxide (1.1 g, 11 mmol) in 1.5 M sulfuric acid (40 mL, 27 mmol) was maintained at 0° C. while 5.3 (0.46 g, 3 mmol) in 80 mL of acetone was added over 2 hours. The reaction was then stirred for an additional 2 hours at room temperature. The reaction mixture was diluted with ether (200 mL) and extracted 2 times with water. The organics were dried with sodium sulfate. The solvent was removed under reduced pressure and the product was purified by chromatography on silica gel column eluting with acetone-dichloromethane (70:30) to give 5.4 (75%). 1H NMR (300 MHz, CDCl3) δ 2.24 (dt, J=3.66, 12.1 Hz, 1H), 2.10 (dd, J=2.7, 6.5 Hz, 2H), 2.04–1.89 (m, 5H), 1.76 (d, J=2.3 Hz, 1H), 1.43 (dq, J=3.28, 13.1 Hz, 2H), 1.03 (dq, J=3.28, 13.1 Hz, 2H). 13C NMR (300 MHz, CDCl3) δ183.2, 83.3, 69.9, 43.4, 36.7, 31.8, 28.9, 26.3.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:15]([NH:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:18]([CH:15]([CH3:17])[CH3:16])[NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:8]
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: N#Cc1ccc(OCC(=O)O)c(Br)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(C#N)cc1Br
Yield: 28.1 %

Procedure:
A solution of (2-bromo-4-cyano-phenoxy)-acetic acid (910 mg, 3.5 mmol) and benzoic acid N′-isopropyl-hydrazide (749 mg, 4.2 mmol) in DMF (20 ml) was treated with diisopropylethyl amine (1.52 mL, 8.75 mmol) and PyBroP (2.45 g, 5.25 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white solid (410 mg, 0.9849 mmol, 28%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27]>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:12]([C:5]1([CH2:15][CH2:16][CH3:17])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[CH:3]=2)[S:8][CH2:7][CH2:6]1)[CH2:13][CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: CCCC1(CCC)CCSc2ccc(Br)cc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCC1(CCC)CCSc2ccc(C#C[Si](C)(C)C)cc21
Temperature: 0 °C

Procedure:
A mixture of 2.04 g (6.54 mmol) of 6-bromo-4,4-dipropylthiochroman (Compound 29), 0.12 g (0.64 mmol) of copper (I) iodide and 5.4 g (54 mmol) of triethylamine was degassed using argon for 15 minutes at -78° C. To the suspension was added 1.95 g (19.8 mmol) of (trimethylsilyl)acetylene then 0.41 g (58 mmol) of bis(triphenylphosphine)palladium (II) chloride. The solution was degassed with argon for an additional 5 minutes and the resulting mixture was allowed to warm to 0° C. The tube was sealed and the mixture heated to 55° C. for 15 hours.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.Cl.[CH3:12]O>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: CO
Reactant: Cc1ccc(C(=O)O)cn1
Agent: Cl
Product: COC(=O)c1ccc(C)nc1

Procedure:
6-Methylnicotinic acid (0.1 mole) is refluxed in 100 ml. of methanol saturated with gaseous hydrogen chloride for 1 hour and then evaporated to dryness. The residue is stirred saturated aqueous sodium bicarbonate solution and the product is extracted into chloroform. The chloroform extract is dried and concentrated to dryness to give methyl 6-methylnicotinate.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[S:22](Cl)(=[O:24])=[O:23]>C([O-])(O)=O.[Na+].C(OCC)C.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=1[S:22]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Cl
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cc(C(F)(F)F)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 2-chloro-5-trifluoromethylbenzenesulfonyl chloride (2.79 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 3% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (1.50 g, 41%). 1H-NMR (300 MHz, CDCl3) δ 8.24 (d, J=1.9 Hz, 1H), 7.83 (dd, J=8.3, 2.1 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 6.57 (s, 1H), 6.55 (s, 1H), 6.46 (s, 1H), 5.07 (br s, 1H), 2.24 (s, 3H).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].C(O[SiH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:22]([F:23])=[CH:21][C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)=[C:19]([F:35])[CH:18]=2)[CH2:13][CH2:12]1)C>C1COCC1>[CH2:1]([Si@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]2[C:22]([F:23])=[CH:21][C:20]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:28][CH:29]=3)=[C:19]([F:35])[CH:18]=2)[CH2:13][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCO[SiH]1CCC(c2cc(F)c(-c3ccc(OC(F)(F)F)cc3)cc2F)CC1
Reactant: CCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](c2cc(F)c(-c3ccc(OC(F)(F)F)cc3)cc2F)CC1

Procedure:
3.0 g (20 mmol) of n-pentyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 8.8 g (20 mmol) of 4'-(4-ethoxy-4-silacyclohexyl)-2',5'-difluoro-4-trifluoromethoxybiphenyl to obtain 4'-(trans-4-n-pentyl-4-silacyclohexyl)-2',5'-difluoro-4-trifluoromethoxybiphenyl. The silacyclohexane rings of this product were a mixture of trans and cis isomers. They were separated by means of chromatography to obtain 7.5 g of the trans isomer (yield 85%).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1C(O)=O.[OH:13][C:14]1C2C(=C(C)C(OC)=CC=2)[N:17]=[C:16]([C:27]2[S:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[N:31]=2)[CH:15]=1>>[F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[N:17]=[C:16]([C:27]1[S:28][CH:29]=[C:30]([CH:32]([CH3:33])[CH3:34])[N:31]=1)[CH:15]=[C:14]2[OH:13]
Reactant: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1C
Reactant: COc1cccc(C(=O)O)c1F
Product: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1F

Procedure:
The title compound was prepared from 2-fluoro-3-methoxybenzoic acid following the procedure (steps 1-5) reported for the preparation of 4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinoline (36): m/z=319 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([N:11]([CH2:13][C:14]1[N:15]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([C:42]([O:44]C)=[O:43])=[O:41])=[CH:30][CH:29]=2)[C:16]([C:23]([O:25]C)=[O:24])=[C:17]([C:19]([OH:22])([CH3:21])[CH3:20])[N:18]=1)[CH3:12])=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.O1CCOCC1>[C:4]([O:8][C:9]([N:11]([CH2:13][C:14]1[N:15]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([C:42]([OH:44])=[O:43])=[O:41])=[CH:30][CH:29]=2)[C:16]([C:23]([OH:25])=[O:24])=[C:17]([C:19]([OH:22])([CH3:21])[CH3:20])[N:18]=1)[CH3:12])=[O:10])([CH3:5])([CH3:6])[CH3:7]
Reactant: COC(=O)C(=O)c1ccccc1-c1ccc(Cn2c(CN(C)C(=O)OC(C)(C)C)nc(C(C)(C)O)c2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN(Cc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.7 %

Procedure:
A solution of 81 mg of lithium hydroxide monohydrate dissolved in 5 ml of water was added to a solution of 380 mg of methyl 2-(N-t-butoxycarbonyl-N-methylaminomethyl)-4-(1-hydroxy-1-methylethyl)-1-[(2'-methoxalylbiphenyl-4-yl)methyl]imidazole-5-carboxylate [prepared as described in step (a) above] dissolved in 5 mg of dioxane, and the resulting mixture was stirred at room temperature for 2.5 hours. At the end of this time, the dioxane was removed by distillation under reduced pressure, and then 1.93 ml of 1N aqueous hydrochloric acid was added to the residue. The material which precipitated was collected by filtration to give 339 mg of the title compound as an amorphous powder.
Reaction SMILES: [Li+].[Cl-].[Cl:3][C:4]1[CH:5]=[N:6][C:7]([F:18])=[C:8]([C:16]=1[F:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[I:19]I>C1COCC1>[Cl:3][C:4]1[C:5]([I:19])=[N:6][C:7]([F:18])=[C:8]([C:16]=1[F:17])[C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10]
Reactant: II
Reactant: CC(C)(C)OC(=O)c1c(F)ncc(Cl)c1F
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(F)nc(I)c(Cl)c1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 66.6 %

Procedure:
Into a solution of TMPMgCl LiCl (1.0 M×2.4 mL, 2.4 mmol) in THF at −45° C. was added dropwise a solution of tert-butyl 5-chloro-2,4-difluoronicotinate (0.4 g, 1.6 mmol) in THF (3.0 mL). The mixture was stirred for 20 min then iodine (0.61 g, 2.4 mmol) was added. After 15 min at −45° C., the temperature was allowed to warm to 0° C. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and evaporated. The residue was purified by silica chromatography (0-5% ethyl acetate in hexanes) to give tert-butyl 5-chloro-2,4-difluoro-6-iodonicotinate (0.4 g, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH:14]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]([CH3:20])([CH3:19])[C:16](O)=[O:17])(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(Cl)(=O)C(Cl)=O.C[Si]([NH:41][OH:42])(C)C>C(Cl)Cl>[OH:42][NH:41][C:16](=[O:17])[C:15]([CH3:20])([CH3:19])[CH:14]([S:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:13])=[O:12])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(S(=O)(=O)C(CCCCc2ccccc2)C(C)(C)C(=O)O)cc1OC
Reactant: C[Si](C)(C)NO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C(CCCCc2ccccc2)C(C)(C)C(=O)NO)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
3-(3,4-Dimethoxyphenylsulfonyl)-2,2-dimethyl-7-phenylheptanoic acid (0.5 g, 1.2 mmol) is dissolved in CH2Cl2 (6 mL), cooled in ice and 2 M oxalyl chloride in CH2Cl2 (1.7 mL, 3.5 mmol) is added. The reaction is warmed to room temperature and after 4 hours the solvent is removed in vacuo and the residue azeotroped twice with chloroform. The residue is dissolved in CH2Cl2 (4 mL) and trimethylsilylhydroxylamine (0.42 mL, 3.6 mmol) is added. The reaction is stirred 15 minutes and then the solvent is removed in vacuo, CH2Cl2 (10 mL) added and the solution washed with 1 N HCl. The organic layer is dried over MgSO4 and the solvent removed in vacuo to yield 3-(3,4-dimethoxybenzenesulfonyl)-2,2-dimethyl-7-phenylheptanoic acid hydroxyamide (0.34 g, 83%): 1H NMR (300 MHz, CD3OD) δ 7.45 (dd, J=8.3, 2.0 Hz, 1H), 7.38 (d, J=2.2 Hz, 1H), 7.21-7.05 (m, 4H), 6.98-6.95 (m, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.86-3.84 (m, 1H), 2.38-2.33 (m, 2H), 1.93-1.84 (m, 1H), 1.69-1.64 (m, 1H), 1.43 (s, 3H), 1.34-1.23 (m, 3H), 1.23 (s, 3H), 0.98-0.85 (m, 1H); MS (FAB) m/e 450 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:7]2=[CH:8][S:9][CH:10]=[C:6]2[N:5]=[C:4]1[S:11][CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:21]([O:1][CH2:2][N:3]1[C:7]2=[CH:8][S:9][CH:10]=[C:6]2[N:5]=[C:4]1[S:11][CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=1)(=[O:23])[CH3:22]
Reactant: COc1ccnc(CSc2nc3cscc3n2CO)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccnc(CSc2nc3cscc3n2COC(C)=O)c1

Procedure:
1.3 g (4.2 mmol) of the title compound from Example 28 were dissolved in 25 ml of anhydrous pyridine, and 50 mg of 4-dimethylaminopyridine were added. Under a nitrogen atmosphere and while stirring, 6.3 ml acetic anhydride were added dropwise, and the mixture was stirred at room temperature for one hour. It was then poured onto ice water, extracted with methylene chloride, and the organic phase was dried over MgSO4 and concentrated in vacuo. The crystalline solid was recrystallized from ethanol. Melting point 111°-113° C.
Reaction SMILES: Cl[C:2]1[CH:19]=[C:18]([F:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][NH:13]2)=[CH:9][CH:8]=1)=[O:5].[NH4+:24].[OH-]>O1CCOCC1>[NH2:24][C:2]1[CH:19]=[C:18]([F:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][NH:13]2)=[CH:9][CH:8]=1)=[O:5]
Reactant: [NH4+]
Reactant: O=C(Nc1ccc2cn[nH]c2c1)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cc(F)c([N+](=O)[O-])cc1C(=O)Nc1ccc2cn[nH]c2c1
Temperature: 60 °C

Procedure:
To a solution of 2-chloro-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide (3 mmol) in dioxane (6 mL) was added concentrated aqueous NH4OH (3 mL). The resulting mixture was heated at 60° C. for 2-3 h. The completed reaction afforded the product, 2-amino-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide. To the crude reaction mixture was added diethylamine (45 mmol). The mixture then heated at 60° C. for 6 h. After the reaction was complete, the volatiles were removed in vacuo, and the residue was suspended in cold water. The solid was collected by filtration, washed with water, and dried in vacuo to provide 4-amino-2-diethylamino-N-(1H-indazol-6-yl)-5-nitrobenzamide.
Reaction SMILES: Cl.[C:2]1([CH3:19])[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]([CH2:13][NH2:14])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[N:9]2)[CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:24]=[CH:25][C:26]=1[N:27]1[CH2:30][CH:29]([OH:31])[CH2:28]1>C(#N)C>[F:20][C:21]1[CH:22]=[C:23]([NH:32][C:33]([NH:14][CH2:13][C:12]2[N:8]([C:4]3[CH:3]=[C:2]([CH3:19])[CH:7]=[CH:6][CH:5]=3)[N:9]=[C:10]([C:15]([F:17])([F:16])[F:18])[CH:11]=2)=[O:34])[CH:24]=[CH:25][C:26]=1[N:27]1[CH2:30][CH:29]([OH:31])[CH2:28]1
Reactant: Cc1cccc(-n2nc(C(F)(F)F)cc2CN)c1
Reactant: O=C(Nc1ccc(N2CC(O)C2)c(F)c1)Oc1ccccc1
Agent: Cl
Solvent: CC#N
Product: Cc1cccc(-n2nc(C(F)(F)F)cc2CNC(=O)Nc2ccc(N3CC(O)C3)c(F)c2)c1
Yield: 59.6 %

Procedure:
To a stirred solution of (1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (75 mg, 0.257 mmol, 1.0 eq) in acetonitrile (6 mL) was added TEA (0.14 mL, 1.0 mmol, 4.0 eq) followed by phenyl 3-fluoro-4-(3-hydroxyazetidin-1-yl)phenylcarbamate (78 mg, 0.262 mmol, 1.02 eq) and stirred at reflux for 16 h. The solvent of the reaction mixture was evaporated and the residue was purified by column chromatography (EtOAc/cyclohexane (4:1) as eluent) to get 1-(3-fluoro-4-(3-hydroxyazetidin-1-yl)phenyl)-3-((1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea (71 mg, 71%).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH2:17]>Cl>[CH2:13]([O:12][C:10](=[O:11])[CH:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:17][CH2:16][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:14]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: C=Cc1ccccn1
Agent: Cl
Agent: [Na]
Product: CCOC(=O)C(CCc1ccccn1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 90.5 %

Procedure:
A sample of 120 g (0.62 mole) of ethyl benzoylacetate was added to 1.44 g (0.062 mole) of sodium and 32.8 g (0.31 mole) of 2-vinylpyridine added under an atmosphere of nitrogen. The mixture was heated with mechanical stirring on the steam bath for 17 h. After cooling the reaction mixture to room temperature, 100 mL of 3N hydrochloric acid was added, and the aqueous mixture washed with ether. The hydrochloric acid layer was made basic with 10% potassium carbonate solution, and extracted with ether. The ether layer was washed with brine, dried (MgSO4), and the ether evaporated in vacuo to give 83.4 g (90% yield) of the crude title compound as a red oil.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=1)=[CH:9][C:8]([F:18])=[CH:7][CH:6]=2)[CH3:2]>CO.[Pd]>[CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)=[CH:9][C:8]([F:18])=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1[nH]c2ccc(F)cc2c1C1=CCNCC1
Agent: [Pd]
Solvent: CO
Product: CCc1[nH]c2ccc(F)cc2c1C1CCNCC1

Procedure:
2.83 g 2-ethyl-5-fluoro-3-(1.2.3.6-tetrahydropyridin-4-yl)-1H-indole are suspended in 50 ml of methanol and hydrogenated with 0.3 g Pd/C 10% at normal pressure and ambient temperature. The catalyst is suction filtered and the filtrate is evaporated to dryness. 2.3 g (V-1) are obtained in the form of a solid. 1H NMR (400 MHz, DMSO): 2.70 (2H, q); 1.19 (3H, t).
Reaction SMILES: C([NH:4][C:5]1[C:6]([C:18]([OH:20])=[O:19])=[CH:7][C:8]2[C:13]([C:14]=1[N+:15]([O-:17])=[O:16])=[CH:12][CH:11]=[CH:10][CH:9]=2)(=O)C>Cl>[NH2:4][C:5]1[C:6]([C:18]([OH:20])=[O:19])=[CH:7][C:8]2[C:13]([C:14]=1[N+:15]([O-:17])=[O:16])=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: CC(=O)Nc1c(C(=O)O)cc2ccccc2c1[N+](=O)[O-]
Agent: Cl
Product: Nc1c(C(=O)O)cc2ccccc2c1[N+](=O)[O-]

Procedure:
A solution of 1 g of the compound obtained in Step 1 in 18 ml of hydrochloric acid is refluxed for 4 hours and then poured onto ice. The precipitate formed is filtered off, washed with water until the pH is 5–6 and then dried, allowing the expected product to be isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:20][CH2:19][CH:18]([N:15]3[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]3)[CH2:23][CH2:22]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: OB(O)c1cccc(Br)c1
Product: CN1CCN(C2CCN(c3cccc(Br)c3)CC2)CC1

Procedure:
1-[1-(3-Bromo-phenyl)-piperidin-4-yl]-4-methyl-piperazine was prepared from 3-bromophenylboronic acid (0.50 g, 2.5 mmol) and 1-methyl-4-piperidin-4-yl-piperazine (0.23 g, 1.2 mmol) in a manner analogous to Step 49a. The reaction product was isolated as a brown viscous oil (0.069 mg, 16%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.08 (t, J=8.0 Hz, 1H), 7.03 (s, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 3.72 (d, J=11.7 Hz, 2H), 2.78-2.33 (m, 11H), 2.30 (s, 3H), 1.93 (d, J=12.9 Hz, 2H), 1.69-1.57 (m, 2H). MS=338, 340 (MH)+.