Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:38]([F:39])=[CH:37][C:17]3[N:18]=[C:19]([CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:20]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:20]2[C:16]3[CH:15]=[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:38]([F:39])=[CH:37][C:17]=3[N:18]=[C:19]2[CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(Cl)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(Cl)cc3)c2cc1N1CCNCC1

Procedure:
4.2 g of 4-[3-(4-chloro-benzyl)-6-fluoro-2-phenoxymethyl-3H-benzoimidazol-5-yl]-piperazine-1-carboxylic acid tert-butyl ester (7.6 mmol) were stirred in 50 ml trifluoroacetic acid (651 mmol) for 2 h at rt. The reaction mixture was diluted with 500 ml water and the pH adjusted to 8 with solid sodium bicarbonate and then to 9-10 with ammonium hydroxide, extracted with ethylacetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo, leading to 3.34 g of 1-(4-chloro-benzyl)-5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1H-benzoimidazole as a light yellow solid (99%). MS(ISP): 451.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13]1(B(O)O)[CH2:15][CH2:14]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].P(C1CCCCC1)(C1CCCCC1)C1CCCCC1>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH:13]2[CH2:15][CH2:14]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1cc(Br)ccc1N
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C2CC2)ccc1N
Temperature: 100 °C
Yield: 88.3 %

Procedure:
In a schlenck tube, a mixture of methyl 2-amino-5-bromobenzoate (43.47 mmol, 10 g), cyclopropylboronic acid (112.92 mmol, 9.700 g), K3PO4 (144.16 mmol, 30.6 g), Pd (AcO)2 (3.47 mmol, 0.780 g), P(Cy)3 (7.85 mmol, 2.2 g) in toluene (170 ml) and water (10 ml) was heated for 2 hours at 100° C., under nitrogen atmosphere. The reaction mixture was filtered through celite and the organic phase was separated and evaporated affording 7.34 g (yield 77%) of the expected product.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](OCC)=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([Cl:14])[CH:3]=1.O.[NH2:16][NH2:17]>C(O)C.O>[Cl:14][C:4]1[N:5]=[C:6]([CH3:13])[C:7]2[C:8](=[O:9])[NH:16][NH:17][C:2]=2[CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1c(Cl)cc(Cl)nc1C
Solvent: CCO
Solvent: O
Product: Cc1nc(Cl)cc2[nH][nH]c(=O)c12
Temperature: 80 °C
Reaction time: 17.5 h

Procedure:
A mixture of ethyl 4,6-dichloro-2-methylnicotinate (5.00 g, 21.36 mmol) and hydrazine monohydrate (2.1 mL, 43.3 mmol) in ethanol (22 mL) was heated to 80° C. and stirred for 17.5 h. The reaction was cooled to room temperature, diluted with water, filtered, rinsed with water, and dried under vacuum to provide 6-chloro-4-methyl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one, which was carried onto the next step without further purification. MS ESI calc'd. for C7H6ClN3O [M+1]+ 184. found 184.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=O)C1C=CC=CC=1.[NH:37]1[C:45]2[CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41][C:40]=2[CH:39]=[N:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(#N)C>[CH2:28]([O:27][C:23]1[CH:22]=[C:21]([Cl:35])[C:20]([CH2:19][C@@H:15]2[CH2:16][CH2:17][N:46]([CH:43]3[CH2:44][C:45]4[NH:37][N:38]=[CH:39][C:40]=4[CH2:41][CH2:42]3)[C:14]2=[O:36])=[C:25]([Cl:26])[CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: NC1CCc2cn[nH]c2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1C1CCc2cn[nH]c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
Add a solution of (R)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde, Preparation 38, (8.17 g, 15.5 mmol) in CH2Cl2 (100 mL) to a solution of 4,5,6,7-tetrahydro-1H-indazol-6-ylamine (2.13 g, 15.5 mmol) in acetonitrile (200 mL) and stir for 30 minutes at room temperature under N2. Add sodium triacetoxyborohydride (9.89 g, 46.7 mmol) to the reaction and stir for 18 hours. Remove the solvent in vacuo and extract solid with ethyl acetate, water and saturated NaHCO3. Dry the organic layer (Na2SO4), filter and concentrate under vacuum. Purify the residue by silica gel chromatography with a gradient of 0 to 10% methanol in CH2Cl2 to afford 3.93 g (54%) of the title compound. MS (m/z): 470 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.Cl[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][CH2:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Oc1ccc2c(c1)CCC2
Reactant: O=C(CCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(COc1ccc2c(c1)CCC2)c1ccccc1

Procedure:
Using the method of Example 1, step A, 5-hydroxyindane is reacted with α-chloroacetophenone in benzene in the presence of sodium carbonate to provide α-(5-indanoxy)acetophenone as a yellow solid.
Reaction SMILES: O=[C:2]1[C:11]2[C:10]([C:12](OC)=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.O=C1C2C(C(OCC)=O)=CC=CC=2NC(C2C=CC=CN=2)C1C1C=CC=CN=1.O.[NH2:57][NH2:58]>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:4]1[NH:5][C:6]2[C:11]3[C:2](=[N:57][NH:58][C:12](=[O:13])[C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccccn1)C(c1ccccn1)N2
Reactant: NN
Agent: CCOC(=O)c1cccc2c1C(=O)C(c1ccccn1)C(c1ccccn1)N2
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccn1)C2c1ccccn1
Temperature: 25 °C
Yield: 37 %

Procedure:
A mixture of methyl 4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (68 mg, 0.19 mmol) in hydrazine monohydrate (7 mL) was heated to reflux for 4 hr. Then the mixture was cooled to room temperature and solvent was removed in vacuum to give crude product. The crude product was purified by pre-HPLC to give 8,9-di(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (24 mg, yield 37%) as a light yellow solid. 1H-NMR (400 MHz, DMSO) δ 5.42-5.43 (d, J=5.2 Hz, 1H), 5.56-5.57 (d, J=5.2 Hz, 1H), 7.30-7.32 (d, J=8.0 Hz, 1H), 7.37-7.39 (d, J=8.0 Hz, 1H), 7.63-7.66 (t, J=6.6 Hz, 1H), 7.68-7.70 (m, 2H), 7.78-7.80 (d, J=7.2 Hz, 1H), 7.87-7.89 (d, J=8.0 Hz, 1H), 8.11-8.16 (m, 2H), 8.66-8.67 (d, J=4.8 Hz, 1H), 8.74-8.76 (d, J=5.6 Hz, 1H); LC-MS (ESI) m/z: 342(M+1)+.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:16]([O:18]CC)=[CH2:17])CCC.Cl>CN1C(=O)CCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:10]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:16](=[O:18])[CH3:17])[C:7]=2[CH:8]=[CH:9]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1nccc2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: CC(=O)c1nccc2[nH]ccc12
Temperature: 140 °C
Reaction time: 18 h
Yield: 64.5 %

Procedure:
A mixture of 4-chloro-1H-pyrrolo[3,2-c]pyridine (1.0 g, 6.58 mmol), Pd(PPh3)4 (763 mg, 0.66 mmol), and tributyl(1-ethoxyvinyl)stannane (2.61 g, 7.23 mmol) in NMP (20 mL) was stirred under N2 at 140° C. for 18 h. The reaction mixture was poured into aqueous HCl solution (2 N, 150 mL), stirred at RT for 2 h, and washed with DCM (50 mL×3). The aqueous layer was adjusted to pH 8 with NaHCO3 (solid), extracted with EtOAc (50 mL×3), and concentrated under reduced pressure to afford 680 mg (64.6%) of 1-(1H-pyrrolo[3,2-c]pyridin-4-yl)ethanone as yellow solid: MS (ESI) nilz: 161.1 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][CH:10]([CH2:16][CH2:17][O:18][CH3:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:19][O:18][CH2:17][CH2:16][CH:10]([CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:27]2[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)=[CH:3][CH:4]=1)=[O:20])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CCOC(=O)C(CCOC)CC(=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)C(CCOC)CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
To a 150 mL 3-neck flask fitted with a reflux condenser was added ethyl 4-(4-bromophenyl)-2-(2-methoxyethyl)-4-oxobutanoate (1.06 g, 3.09 mmol) and 4-nitro-phenyl boronic acid (0.62 g, 3.70 mmol) dissolved in toluene (30 mL) and dioxane (8.50 mL), followed by addition of saturated aqueous sodium carbonate solution (8.50 mL). A thin-gauge needle was inserted into the bi-phasic mixture and degassed with argon over 30 minutes, at which point 1,2-bis[(diphenylphosphino)ferrocene]dichloropalladium(II) (0.13 g, 0.15 mmol) was added, followed by an additional 15 minutes of degassing. The reaction mixture was heated at 85° C. for 16 h, and then the resulting dark-colored reaction mixture was allowed to cool, and was diluted with ethyl acetate (75 mL) and saturated aqueous sodium chloride solution (75 mL). The layers were separated, the aqueous layer was extracted twice with ethyl acetate (50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (75 mL), dried over anhydrous magnesium sulfate, and filtered in vacuo through 2 cm Celite®/2 cm silica. The filtrate was concentrated in vacuo, leaving a dark red-brown oil, that was purified by flash chromatography (4:1 hexane/ethyl acetate, then 3:1 hexane/ethyl acetate, then 2:1 hexane/ethyl acetate) to afford ethyl 2-(2-methoxyethyl)-4-(4′-nitro-1,1′-biphenyl-4-yl)-4-oxobutanoate (1.04 g, 88%). LC-MS ret. time 3.38 min, m/z 385.9 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.27 (t, 3H), 1.80-1.95 (m, 1H), 1.95-2.10 (m, 1H), 3.10-3.25 (m, 2H), 3.40-3.58 (m, 3H), 4.17 (q, 2H), 7.67-7.82 (2d, 4H), 8.10 (d, 2H), 8.33 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:13])[CH3:12])=[CH:6][C:4]=1[NH2:5].[CH3:14][O:15][CH:16]([O:21][CH3:22])[CH2:17][C:18](O)=[O:19].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:14][O:15][CH:16]([O:21][CH3:22])[CH2:17][C:18]([NH:5][C:4]1[CH:6]=[C:7]([O:10][C:11](=[O:13])[CH3:12])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:19]
Reactant: COc1ccc(OC(C)=O)cc1N
Reactant: COC(CC(=O)O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(OC(C)=O)cc1NC(=O)CC(OC)OC
Temperature: 5 °C
Reaction time: 4 h
Yield: 93.8 %

Procedure:
To a cooled solution (0° C.) of 2-methoxy-5-acetyloxy-aniline (5 g, 0.0276 mole), 3,3-dimethoxy-propanoic acid (5 g, 0.0373 mole) in 75 ml of methylene chloride was added DCC (5.7 g, 0.0276 mole) in 20 ml of methylene chloride. After completion of the addition, the solution was stirred for a further 4 hours. The reaction medium was concentrated to 25 ml, diluted with 200 ml of isopropyl ether, cooled to 5° C. and the resulting precipitate was isolated by filtration, giving N-(3,3-dimethoxypropanoyl)-2-methoxy-5-acetoxy-aniline 7.7 g (Yield=95%).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+].Cl.[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Cl>C(O)C.O>[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][S:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Sc1cnc2ccccc2n1
Reactant: CN(C)c1ccccc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)c1ccccc1CSc1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.4 %

Procedure:
To a solution of 1 g of 2-mercaptoquinoxaline in 40 ml of ethanol was added a solution of 530 mg of sodium hydroxide in 2 ml of water, and subsequently added 1.27 g of 2-dimethylaminobenzyl chloride hydrochloride. The resulting mixture was stirred at room temperature for 18 hrs., and the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous sodium hydroxide solution, water, and saturated aqueous sodium chloride solution, and dried over soidum sulfate. The sodium sulfate was removed by filtration, and the filtrate was placed under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (hexane/acetone) to give 1.5 g of 2-(2-dimethylaminobenzylthio)quinoxaline as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][C:17]=1[C:24]([F:27])([F:26])[F:25]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][C:17]=1[C:24]([F:25])([F:26])[F:27]
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(Cl)c(C(F)(F)F)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)c(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-3-(trifluoromethyl)phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.25 (2H, s), 5.76 (1H, d, J=1.6 Hz), 7.42 (1H, dd, J=1.6, 5.2 Hz), 7.54 (2H, s), 7.58 (1H, d, J=2.0 Hz), 7.89 (1H, s), 8.00 (1H, s), 8.06 (1H, s), 8.69 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H10ClF3N4O, 379. Found, 379.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1([CH3:19])[C:14](=[O:15])[CH2:13][C:12](=[O:16])[C:11]([CH3:18])([CH3:17])[O:10]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:32][C:33]1[CH:38]=[CH:37][C:36]([Pb+3])=[C:35]([CH2:40][CH3:41])[CH:34]=1.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Br:32][C:33]1[CH:38]=[CH:37][C:36]([CH:13]2[C:14](=[O:15])[C:9]([CH3:19])([CH3:8])[O:10][C:11]([CH3:18])([CH3:17])[C:12]2=[O:16])=[C:35]([CH2:40][CH3:41])[CH:34]=1
Reactant: CC1(C)OC(C)(C)C(=O)CC1=O
Reactant: CCc1cc(Br)ccc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1cc(Br)ccc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
4-Dimethylaminopyridine (3.13 g, 25.7 mmol) and toluene (10 ml) are added to a solution of 2,2,6,6-tetramethylpyran-3,5-dione (0.87 g, 5.13 mmol) in chloroform (40 ml) and the reaction mixture is heated to 80° C. 4-Bromo-2-ethylphenyllead triacetate (3.50 g, 6.16 mmol) is added portionwise over 5 minutes, and once the addition is complete the reaction mixture is stirred at 80° C. for a further 4 hours. The mixture is cooled to room temperature, 2M aqueous hydrochloric acid (40 ml) is added, and the mixture is stirred vigorously for 20 minutes, then filtered through a small plug of diatomaceous earth, washing with dichloromethane (40 ml). The organic phase is separated, and the aqueous phase is extracted with dichloromethane (2×40 ml). The organic solutions are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-(4-bromo-2-ethylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]1[CH2:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:14]2[S:10][C:11](=[O:16])[NH:12][C:13]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(=Cc2ccc(O)cc2)S1
Yield: 90.4 %

Procedure:
To a mixture of 4-hydroxybenzaldehyde (3.67 g, 30 mmol), 2,4-thiazolidinedione (3.51 g, 30 mmol) and benzoic acid (4.40 g, 36 mmol) in toluene (100 mL) was added piperidine (4.5 mL, 45 mmol) and the mixture was equipped with a Dean Stark apparatus and brought to a vigorous reflux. After 45 min the mixture was cooled in an ice bath and the supernatant was decanted. The bright yellow solid was made into a suspension by the addition of glacial acetic acid (100 mL) and filtered through a Buchner funnel to yield a pale yellow solid (6.00 g, 90%). 1H NMR: (400 MHz, DMSO-d6): δ 12.45 (bs, 1H), 10.30 (s, 1H), 7.70 (s, 1H), 7.45 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[C:6](Cl)[C:5]=1[N+:18]([O-:20])=[O:19].[CH3:22][OH:23].C[O-].[Na+].[Na+].[Cl-]>O>[CH3:1][N:2]([CH3:21])[NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[C:6]([O:23][CH3:22])[C:5]=1[N+:18]([O-:20])=[O:19]
Reactant: CO
Reactant: CN(C)Nc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1c(C(F)(F)F)cc([N+](=O)[O-])c(NN(C)C)c1[N+](=O)[O-]

Procedure:
To a stirred solution of 5.0 g. (0.015 mole) of N-(dimethylamino)-3-chloro-2,6-dinitro-4-trifluoromethylaniline and 50 ml. of anhydrous methanol was added 3.77 g. (0.015 mole) of a 21.8% methanolic sodium methoxide solution. The resultant mixture was stirred at room temperature for 6 hours and was then refluxed overnight for 16 hours. The methanol was then evapaorated under vacuum leaving a yellow-solid residue. To the residue was added 150 ml. of water and the mixture stirred for 30 minutes to dissolve the NaCl and any other water-soluble materials. The mixture was then filtered and the water-insoluble solids were washed well with water. The solids were then dissolved in 30 ml. of refluxing 95% ethanol. On cooling, the product crystallized and was isolated by filtration to give 3.83 g. (77.7%) of a yellow crystalline solid; m.p. 109° - 110.5° C. After recrystallization from 95% ethanol, the product melts at 110° - 111.5° C.
Reaction SMILES: [C:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)#[N:2].C([O-])([O-])=O.[Na+].[Na+].[Cl:24]Cl>C(Cl)Cl>[C:1]([N:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]([Cl:24])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)#[N:2]
Reactant: ClCl
Reactant: N#CN1c2ccccc2CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: N#CN1c2ccccc2CC(Cl)c2ccccc21
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
50 ml of CH2Cl2 and 5 g (0.0227 mols) of (I) are loaded into a 250 ml pyrex round-bottom flask, under nitrogen and stirring, then 2.4 g of Na2CO3 (0.045 mols) are added thereto. The mixture is cooled to 0-5° C., irradiated from the outside with a 300 watt halogen lamp while adding a 1:1 chlorine and nitrogen gaseous mixture with 6 ml/minute flow, for 3 hours, then nitrogen for 10 minutes at the same flow rate. The mixture is filtered at 30° C. and methylene chloride is evaporated off. The residue is taken up with 15 ml of hexane and 4 ml of ethyl acetate, refluxed for 15 minutes, then cooled to 0° C. for 2 hours. The solid residue is recrystallized twice with the same solvent, to obtain 2.5 g (43% yield) of 5-cyano-10-chloro-10,11-dihydro-5H-dibenz[b,f]azepine (III) with melting point 139-140° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][N:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][NH:31][CH:32]=2)O1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)=[CH:3][CH:4]=2)[CH2:9][N:10]([CH3:12])[CH3:11])=[CH:14][CH:15]=1
Reactant: CN(C)CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CN(C)CC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
[2,2-Bis-(4-chloro-phenyl)-ethyl]-dimethyl-amine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-B2) Rt 3.07 [M+H]+325.99. 1H NMR (Me-d3-OD) δ 2.5 (OH, s), 2.98 (2H, dd), 4.34 (1H, t), 7.31-7.36 (6H, m), 7.50 (2H, d), 7.92 (2H, s).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[C:12](=[O:22])[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([F:21])[CH:14]=1)C.[Li+].[OH-].O.Cl>O1CCCC1>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:23])=[O:3])=[C:6]([C:12](=[O:22])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([F:21])[CH:14]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(Br)cc1C(=O)c1cc(F)cc(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)cc(C(=O)c2cc(Br)ccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-Bromo-2-(3-fluoro-5-methoxy-benzoyl)-benzoic acid ethyl ester (165 mg; 0.43 mmol) in 900 μl tetrahydrofuran is added a 1 M solution of LiOH in water (866 μl; 0.87 mmol). It is stirred at ambient temperature for 2 hours. The reaction mixture is acidified with 1 N HCl and washed with methylene dichloride several times. The organic layers are pooled, dried over MgSO4 and evaporated to dryness.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][S:14][CH:15]=1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>C(O)(C)(C)C>[C:17]([NH:21][CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][S:14][CH:15]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: c1ccc(-c2csnn2)c(OCC2CO2)c1
Reactant: CC(C)(C)N
Solvent: CC(C)(C)O
Product: CC(C)(C)NCC(O)COc1ccccc1-c1csnn1

Procedure:
To a solution of 1.95 g. of 4-[2(2,3-epoxypropoxy)phenyl]-1,2,3-thiadiazole in 45 ml. of t-butylamine is added 5 ml. of t-butanol, and the reaction mixture is stirred at room temperature for 5 days. It is then evaporated to dryness under vacuo. Crystallization of the residue from methylene chloride-benzene affords the pure 4-[2(3-t-butylamino-2-hydroxypropoxy)phenyl]1,2,3-thiadiazole, m.p. 99°-100° C λmax 244, 290 nm (ε 10,500, 4,600) ir 3355, 1600 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.Cl.CCN(C(C)C)C(C)C.[CH3:42][N:43]([CH3:47])[C:44]([Cl:46])=[O:45]>CN1C(=O)CCC1>[CH3:42][N:43]([CH3:47])[C:44]([N:25]1[CH2:26][CH2:27][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:8]3[CH:7]=[C:6]([NH:5][CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[CH:31][C:2]=4[F:1])[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1)=[O:45].[ClH:46]
Reactant: CN(C)C(=O)Cl
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1ccccc1F
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N1CCC(c2ccc(Nc3cc(NCc4ccccc4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 4-(2-fluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 106) HCl salt (100 mg, 0.2 mmol) was stirred in 5 mL NMP. To the solution were added DIEA (0.18 mL, 1.0 mmol) and dimethylcarbamylchloride (0.055 mL, 0.6 mmol). The mixture was stirred at RT for 1 h and quenched with Me2NH. The mixture was concentrated in vacuo and subjected to reverse phase prep HPLC to isolate the title compound as HCl salt. UV=259 nm. M+H found for C27H31FN6O2: 491.5. NMR (CD3OD): 8.12 (1H, s), 7.37 (1H, m), 7.34 (2H, d, J=8.4 Hz), 7.28 (1H, m), 7.17 (1H, m), 7.16-7.10 (3H, m), 5.88 (1H, s), 4.51 (2H, s), 3.82 (2H, m), 2.94 (2H, m), 2.88 (6H, s), 2.80 (1H, m), 1.86 (2H, m), 1.72 (2H, m) ppm.