Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[C:24]([O:33][CH3:34])(=[O:32])[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[NH2:27].[OH-].[Na+]>CN(C=O)C.CO>[CH3:34][O:33][C:24]([C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH:27]/[C:13](=[C:6]1\[C:5](=[O:23])[NH:4][C:12]2[C:7]\1=[CH:8][CH:9]=[CH:10][CH:11]=2)/[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:32]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: COC(=O)c1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1N/C(=C1\C(=O)Nc2ccccc21)c1ccccc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and methyl anthranilate in DMF and subsequent brief treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>CN(C=O)C.O>[O:24]=[C:21]1[N:20]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:10]2=[N:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:25])=[CH:6][CH:5]=3)[N:8]=[C:9]2[CH2:23][CH2:22]1
Reactant: CCOC(=O)CCCCCCCCBr
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NC(=O)CC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCCCN1C(=O)CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one ((prepared according to the preparation procedures disclosed in PCT patent application PCT/EP2011/062028, Example 12.1 step 1) (500 mg, 1.518 mmol) and potassium carbonate (1049 mg, 7.59 mmol) in DMF (15 ml) under N2 was treated with ethyl 9-bromononanoate (805 mg, 3.04 mmol) and stirred at RT overnight. A further portion of ethyl 9-bromononanoate (805 mg, 3.04 mmol) was added and stirring continued at RT for 3 days. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine (×3), dried (MgSO4) and the solvent was removed under reduced pressure to afford the titled compound as a yellow oil;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:11][O-:12].[Na+]>CO>[CH3:11][O:12][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: Cc1cc(Br)cnc1C#N
Agent: [Na+]
Solvent: CO
Product: COc1cnc(C#N)c(C)c1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
5-Bromo-3-methylpicolinonitrile (50, 35 g, 0.18 mol) was added to a solution of sodium methoxide (18 g, 0.54 mol) in methanol (200 mL), and the mixture was heated at reflux for 12 h. The solution was cooled to room temperature and concentrated to one third of its volume. The concentrated solution was diluted with water (150 mL), and the products were extracted with chloroform (3×50 mL). The combined extracts were washed with water (2×50 mL), brine (50 mL), dried with sodium sulfate and filtered through a pad of silica gel, washing with chloroform, to produce 51 as an off-white solid (21 g, 79%): mp 80-81° C. IR (film) 2225, 1645, 1589 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J=2.6 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 3.83 (s, 3H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 157.65, 139.99, 137.68, 125.05, 120.52, 116.76, 55.84, 18.71; EIMS m/z (rel intensity): 148 (M+, 100); CIMS m/z (rel intensity): 149 (MH+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]2[C:19]([F:22])([F:21])[F:20])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[O:23]=[C:24]1[C:28]2[CH:29]=[CH:30][C:31]([CH2:33][CH:34]=O)=[CH:32][C:27]=2[CH2:26][O:25]1.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:34][CH2:33][C:31]3[CH:30]=[CH:29][C:28]4[C:24](=[O:23])[O:25][CH2:26][C:27]=4[CH:32]=3)[CH2:15][CH:14]2[C:19]([F:21])([F:22])[F:20])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: COc1cc(CCN2CCNCC2C(F)(F)F)ccc1C#N
Reactant: O=CCc1ccc2c(c1)COC2=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2C(F)(F)F)ccc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 2-methoxy-4-{2-[2-(trifluoromethyl)piperazin-1-yl]ethyl}benzonitrile (116 mg, 0.28 mmol) and (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (49 mg, 0.28 mmol) in methanol (1.0 mL) at 0° C. was added sodium cyanoborohydride (18 mg, 0.28 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by mass-directed HPLC to provide 2-methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(trifluoromethyl)piperazin-1-yl}ethyl)benzonitrile. LC-MS (IE, m/z): 474.4 [M+1]+. (0.27 μM)
Reaction SMILES: [CH3:1][C@@H:2]([NH2:6])[CH2:3][CH2:4][CH3:5].ClCCl.F[C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:13]([NH2:26])[N:12]=1>C(O)CO>[CH3:1][C@@H:2]([NH:6][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:13]([NH2:26])[N:12]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Reactant: CCC[C@@H](C)N
Solvent: ClCCl
Solvent: OCCO
Product: CCC[C@@H](C)Nc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 110 °C

Procedure:
A crude sample of (2R)-2-pentanamine containing dichloromethane (11.12 g containing ca 3.1 g, 35.6 mmol of amine) was added to a suspension of 2-fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (5.00 g, 21.08 mmol) in ethylene glycol (50 ml). The mixture was heated at 110° C. for 20 hours and then cooled to room temperature and partitioned between water (200 ml) and ethyl acetate (200 ml). The organic phase was separated, washed with saturated brine, dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was dissolved in dichloromethane and purified on a 110 g aminopropyl (NH2) cartridge using a 0-100% ethyl acetate-cyclohexane gradient over 40 mins. The appropriate fractions were combined and evaporated in vacuo and the residue triturated with diethyl ether and some insoluble starting material removed by filtration. Evaporation of the ether filtrate afforded the title compound as an off-white foam (2.34 g).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[C:24]1([C:30]2[CH:39]=[CH:38][C:33]([C:34](=[O:37])[CH2:35]Br)=[CH:32][CH:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:35]=1[C:34](=[O:37])[C:33]1[CH:38]=[CH:39][C:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:31][CH:32]=1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Product: COC(=O)Cc1c(C(=O)c2ccc(-c3ccccc3)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 4-phenylphenacyl bromide.
Reaction SMILES: [CH3:1][C@@:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]4)[CH:14]=3)[CH:9]=2)[CH2:6][O:5]C(=O)[NH:3]1.C(O)C.O.[OH-].[Li+]>O>[NH2:3][C@@:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]3[CH2:20][CH2:21][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:24]3)[CH:14]=2)[CH:9]=1)([CH3:1])[CH2:6][OH:5]
Reactant: CCCC1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC1CCC(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Temperature: 80 °C
Yield: 94 %

Procedure:
(R)-4-methyl-4-(6-(4-propylcyclohexyloxy)naphthalen-2-yl)oxazolidin-2-one (0.4786 g, 0.001302 mol) was dissolved in ethanol (5.00 mL, 0.0856 mol) in a capped 40 mL vial equipped with a magnetic stir bar. 4.2 M Lithium hydroxide, monohydrate in water (2.8 mL) was added and the mixture was heated overnight at 80° C. TLC analysis showed that the reaction was complete. The reaction mixture was concentrated under vacuum. The product was dissolved in methylene chloride (5 mL) and washed with water (2×5 mL). The layers were separated (phase separator cartridge) and the organic layer was concentrated under vacuum and purified by HPLC to give 0.418 g of the title compound (9% yield). MS: m/z=325.35 [M-NH2]+. 1H NMR (400 MHz, MeOD) δ 0.95 (t, J=7.28 Hz, 3 H), 1.10-1.23 (m, 1 H), 1.25-1.33 (m, 2 H), 1.35-1.51 (m, 5 H), 1.57-1.74 (m, 3 H), 1.80 (s, 3 H), 1.87-1.95 (m, 1 H), 2.04-2.13 (m, 2 H), 2.21-2.28 (m, 1 H), 3.80-3.86 (m, 1 H), 3.91-3.97 (m, 1 H), 4.36-4.46 (m, 0.3 H), 4.73-4.78 (m, 0.7 H), 7.19 (dd, J=8.91, 2.38 Hz, 0.3 H), 7.24 (dd, J=8.91, 2.38 Hz, 0.7 H), 7.28 (d, J=2.26 Hz, 1 H), 7.53 (dd, J=8.78, 2.01 Hz, 1 H), 7.80-7.90 (m, 3 H)
Reaction SMILES: [CH2:1]([C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:17]([O:12][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][C:14]([OH:16])=[O:15])=[O:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCCCCCCCCCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)CCCCCCCCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1,10-decanedicarboxylic acid, benzyl bromide and potassium carbonate in N,N-dimethylformamide was stirred at room temperature for 16 hours. The reaction mixture was poured into a mixture of ethyl acetate and diluted hydrochloric acid, and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on a silica gel column to give the object compound.
Reaction SMILES: O[Li].O.C[O:5][C:6]([C:8]1([OH:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[O:11][CH2:10][CH2:9]1)=[O:7]>O.C1COCC1>[F:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH2:9][C:8]2([C:6]([OH:7])=[O:5])[OH:19]
Reactant: COC(=O)C1(O)CCOc2ccc(F)cc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(O)CCOc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of LiOH.H2O (0.95 g; 22.6 mmol) in water (30 mL) was added to a solution of 6-fluoro-4-hydroxychroman-4-yl-carboxylic acid, methyl ester (2.47 g; 10.9 mmol; from step (i) above) in THF (10 mL). The reaction mixture was stirred at room temperature for 2 days, THF was evaporated and the water phase was acidified with HCl (2M) and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and evaporated, yielding the sub-title compound. Yield: 1.41 g (61%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][CH2:19][C:20]([CH2:22]Cl)=O>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[O:14][CH:22]=[C:20]([CH2:19][Cl:18])[N:15]=2)=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(-c2ccc(OCc3ccccc3)cc2)n1
Yield: 33 %

Procedure:
In substantially the same manner as in Reference Example 31, 4-benzyloxybenzamide was allowed to react with 1,3-dichloroacetone to give 2-(4-benzyloxyphenyl)-4-chloromethyloxazole. The yield was 33%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 119-120° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>CC(O)C>[NH:11]([C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1)[NH2:12]
Reactant: OCc1ccnc(Cl)c1
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: NNc1cc(CO)ccn1
Temperature: 100 °C
Reaction time: 24 h
Yield: 26 %

Procedure:
To a stirred suspension of (2-chloro-4-pyridinyl) methanol (0.885 g, 6.16 mmol) in 2-propanol (9 mL) was added hydrazine monohydrate (6.0 mL, 124 mmol). The resulting suspension was allowed to stir for 24 h at 100° C. Solvent was evaporated. The residue was purified by silica gel column chromatography with gradient of MeOH (5-20%) in CH2Cl2 to afford 36 (223 mg, 26%) as a white solid. LRMS: calc 139.1; found 140.2 (MH)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=[O:4].NC([C:23]1[NH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)CC.[BH4-].[Na+]>C(#N)C>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH2:2][NH:24][CH2:25][CH2:26][CH2:28][N:24]2[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=[CH:23]2)=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(N)c1nc2ccccc2[nH]1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: OC(CNCCCn1cnc2ccccc21)c1ccc(OCc2ccccc2)cc1

Procedure:
30.5 gm of 2-bromo-p-benzyloxyacetophenone and 35 gm of 1-aminopropyl-benzimidazole were stirred for 1 hour at 30°-40° C. in 150 ml of acetonitrile. After separation of the hydrobromide, the mother liquor was acidified with 12 gm of maleic acid, and the precipitated α-[3-(1-benzimidazolyl)-propylamino]-4-benzyloxyacetophenone maleate (m.p. 145°-148° C.) was collected by suction of filtiation. Aqueous ammonia was used to prepare the base, which was reduced in 200 ml of alcohol with sodium borohydride to form 1-(4-benzyloxyphenyl)-2-[3-(1-benzimidazolyl)-propylamino]-ethanol (m.p. 83°-85° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:27][CH2:28][O:29]C1CCCCO1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:27][CH2:28][OH:29])[CH:20]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: BrCCOC1CCCCO1
Reactant: Cc1c(C(=O)Nc2cccc(O)c2)nnn1Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2cccc(OCCO)c2)nnn1Cc1ccc(Cl)c(Cl)c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[(3,4-dichlorophenyl)methyl]-N-(3-hydroxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide (Example 31) (0.1 g, 0.29 mmol) in acetonitrile (10 mL) and a couple of drops of DMF, were added 2-[(2-bromoethyl)oxy]tetrahydro-2H-pyran (0.09 μl, 2 eq) and potassium carbonate (0.08 g, 2 eq). The reaction was heated at 40° C. for 1 week. After evaporation, the residue was dissolved in DCM, washed with water and dried over sodium sulphate. After purification by flash chromatography eluting with DCM/MeOH, 98/2, the crude compound was dissolved in MeOH and some drops of a concentrated HCl solution in AcOEt were added and the solution was stirred at room temperature for 3 hours. After evaporation, the compound was recrystallised (twice) from methanol and washed with a mixture of ether and pentane. The title compound was obtained as a green solid (45 mg, 36%). HRMS calculated for C19H18Cl2N4O3 (M+H)+421.0834, found: 421.0804, Rt: 2.87 min. MP: 144.9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl-].[NH4+].O>CO.[Fe]>[NH2:13][C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([Cl:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Cl)cc(N)c1C
Temperature: 70 °C
Yield: 95.2 %

Procedure:
To a solution of methyl 5-chloro-2-methyl-3-nitrobenzoate (9.19 g, 40 mmol) in methanol (200 ml) at room temperature was added ammonium chloride (21 g, 400 mmol) followed by deionized water (100 ml). The mixture was heated to 70° C. before the addition of iron (13.4 g, 240 mmol). The reaction turned to a dark colour over the 2.5 hours it was stirred at 70° C. This mixture was allowed to cool to room temperature and was filtered through Kieselgel. The filter pad was washed with MeOH (100 ml) and the filtrate concentrated under reduced pressure. The residue was dissolved in deionized water (100 ml) and EtOAc (100 ml). The phases were separated and the aqueous phase was extracted with EtOAc (2×100 ml). The combined organic extracts were washed with brine (100 ml), dried over MgSO4, filtered and concentrated under reduced pressure to give 7.6 g of the title compound as a viscous orange oil that solidified upon standing. This material was used without further purification. LC-MS 63%, m/z=200.3/202.0, 1H NMR (500 MHz, Chloroform-d) δ 7.20 (1H, d, J=2.21 Hz), 6.80 (1H, d, J=2.05 Hz), 3.89 (3H, s), 3.74-3.87 (2H, m), 2.30 (3H, s).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1.I([O-])(=O)(=O)=O.[Na+]>CO.O>[CH:12]12[CH2:13][CH:14]([CH:10]=[CH:11]1)[N:2]([C:3]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:9])[O:1]2
Reactant: CC(C)(C)OC(=O)NO
Reactant: C1=CCC=C1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1OC2C=CC1C2
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a solution of tert-butyl N-hydroxycarbamate (9.2 g, 69.10 mmol, 1.00 equiv) and cyclopenta-1,3-diene (20.2 g, 305.59 mmol, 4.42 equiv) in methanol (600 mL) was added of a solution of sodium periodate (17 g, 79.48 mmol, 1.15 equiv) in water (180 mL) dropwise at 0° C. with stirring in 30 min. The reaction mixture was stirred for another 30 min at 0° C. and then diluted with 600 mL of water. The solution was extracted with 3×300 mL of ethyl acetate. The combined organic layers was washed with 2×200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 9.1 g (67%) of tert-butyl 2-oxa-3-azabicyclo[2.2.1]hept-5-ene-3-carboxylate as a white solid. 1HNMR (400 MHz, D2O, ppm) δ 6.42 (2H, s), 5.22 (1H, s), 4.99 (1H, s), 1.99 (1H, d, J=8.4 Hz), 1.73 (1H, d, J=8.4 Hz), 1.47 (9H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:12]=2[NH:11][C:10](=S)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]([NH:23][NH2:24])=O.CS(C)=O>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2[N:11]([CH:21]=[N:23][N:24]=2)[C:12]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:13]=2[CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NNC=O
Reactant: CC(C)(C)OC(=O)N1CC(=S)Nc2cc(F)ccc2C1
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1Cc2ccc(F)cc2-n2cnnc2C1
Temperature: 80 °C
Yield: 60 %

Procedure:
To a solution of 8-fluoro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (2.36 g, 7.97 mmol) in dry benzene (25 mL), was added formic acid hydrazide dissolved in 5 mL of dry DMSO (1.43 g, 23.91 mmol) at room temperature. The reaction mixture was heated at 80° C., using Dean-Stark apparatus for 18 h. After the completion of the reaction, as confirmed by TLC, distilled water (40 mL) was added and the crude compound was extracted with diethyl ether (3×40 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford the crude compound which, was purified by column chromatography [silica gel, 1.5:8.5 Acetone:Pet. ether] to afford 9-fluoro-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester, (1.455 g, 60%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:12])=[C:4]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[N:6][CH:7]=1.[CH:13](OCC)(OCC)OCC>>[Cl:1][C:2]1[C:3]2[N:12]=[CH:13][N:8]([CH2:9][CH2:10][CH3:11])[C:4]=2[N:5]=[N:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: CCCNc1nncc(Cl)c1N
Product: CCCn1cnc2c(Cl)cnnc21
Temperature: 140 °C
Yield: 47 %

Procedure:
A mixture of 5-chloro-N3-propylpyridazine-3,4-diamine (Preparation 100, 800 mg, 4.30 mmol) and triethyl orthoformate (10 mL) was heated at 140° C. for 4 hours. After evaporation in vacuo, the crude residue was purified by silica gel column chromatography eluting with CH2Cl2:MeOH 98:2 to afford the title compound as a brown solid in 47% yield, 400 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH3:11][N:12]([CH3:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([N:12]([CH3:11])[CH3:22])[CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1cccc(C(=O)Nc2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.9 %

Procedure:
3-Nitroaniline (3.84 g) in methylene chloride (50 ml) was added dropwise to an ice-cooled solution of 3-dimethylaminobenzoyl chloride (9.74 g crude weight) and 4-dimethylaminopyridine (308 mg) in methylene chloride (30 ml) and triethylamine (8.8 ml). The reaction was stirred at ambient temperature for 72 hours and then partitioned between methylene chloride and saturated sodium bicarbonate. The organic phase was then washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness affording N-(3-nitrophenyl)-3-dimethylaminobenzamide as a solid (8.64 g, 99.9%); NMR (CDCl3) 3.02 (s, 6H), 6.9 (m, 1H), 7.09 (s, 1H), 7.25 (m, 1H), 7.35 (t, 1H), 7.53 (t, 1H), 7.99 (m, 1H), 8.05 (broad s, 1H), 8.1 (m, 1H), 8.5 (m, 1H); m/s: M+H+ 286.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:9]2)=[CH:6][CH:7]=1.[C:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])[CH3:28].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([C:27](=[O:29])[CH3:28])[CH:35]=3)=[CH:3][N:4]=2)[CH2:9][C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[N:11]1
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cn2)C1
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)c1cccc(-c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)nc2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 20.2 %

Procedure:
5-(3-Bromo-pyridin-6-yl)-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (20.0 mg, 0.04 mmol) prepared in Step 4 of Preparation 3, 3-acetylphenylboronic acid (11.0 mg, 0.07 mmol), Pd(PPh3)4 (2.0 mg, cat.) and a 2N sodium carbonate solution (210.0 uL) were added to a mixed solvent of ethanol (210.0 uL) and toluene (310.0 uL). The reaction mixture was stirred at 80° C. for 1 hour and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 4.0 mg of the titled compound as a white liquid.