Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[NH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][OH:18])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: NCCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1NCCNCCO
Temperature: 60 °C
Yield: 77.8 %

Procedure:
2 g of 4-fluoro-3-methyl nitrobenzene, 1.61 g of 2-(2-aminoethylamino)ethanol and 2.14 g of K2CO3 were added to a solution of 20 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 7 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 2.4 g of 2-[2-(4-nitro-2-methylphenylamino)ethylamino]ethanol (5) were obtained.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=[N:20][NH2:21])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([CH2:33][C:34](O)=[O:35])=[CH:32][C:27]=2[O:26][CH2:25]1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[CH:19]=[N:20]/[NH:21][C:34](=[O:35])[CH2:33][C:31]2[CH:30]=[CH:29][C:28]3[O:24][CH2:25][O:26][C:27]=3[CH:32]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: NN=Cc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cc1ccc2c(c1)OCO2)N/N=C/c1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
A solution of 2-[hydrazonomethyl]phenyl 4-(trifluoromethyl)benzenesulfonate (150 mg, 0.44 mmol) and 1,3-benzodioxol-5-ylacetic acid (1.2 equiv) in DMF (1 mL) is treated with a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (167 mg, 0.87 mmol) and 4-dimethylaminopyridine (DMAP) (106 mg, 0.87 mmol) in CH2Cl2 (10 mL). The solution is shaken overnight on an orbital shaker. The solution is evaporated to dryness using a speed. Water is added to the mixture, which is then sonicated to give a solid. The solid is filtered and washed with a large amount of water. A small amount of methanol is added and the mixture sonicated. The resulting solid is filtered and washed with more methanol to yield pure 2-((E)-{2-[2-(1,3-benzodioxol-5-yl)acetyl]hydrazono}methyl)phenyl 4-(trifluoromethyl)benzenesulfonate. The yield is 169 mg, 77%. 1H NMR (400 MHz, DMSO) □ 11.48 (2s, 1H), 8.01 (m, 6H), 7.12 (m, 6H), 5.99 (2s, 2H), 3.62 (2s, 2H). ESI− for C23H17F3N2O6S, m/z 505, (M−H)−.
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].CCC.[CH:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C=CC>C1C=CC=CC=1>[C:7]1([CH:2]([CH3:3])[CH3:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=CC
Reactant: c1ccccc1
Solvent: CCC
Product: CC(C)c1ccccc1

Procedure:
Referring now to the drawing, a feed stream comprising propylene and propane enters the process through line 33. This feed stream is admixed with a recycle stream comprising benzene which is passing through line 32 to form the material traveling through line 11. This material is admixed with the bottoms stream of a second rectification column, commonly referred to as the second rectifier, from line 10. The resultant stream is carried through heat exchanger 13 by line 12 to the junction with line 52. At this point a second benzene recycle stream is admixed with the hydrocarbons in line 12 to form a combined feed stream carried by line 14. This combined feed stream is heated in means 15 and passed into an alkylation reactor 16. The contacting of the benzene-propylene mixture with an alkylation catalyst maintained at alkylation-promoting conditions effects the reaction of benzene and propylene to form cumene in the reactor.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.[F:23][C:24]([F:31])([F:30])[CH2:25][S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:26]([CH2:25][C:24]([F:31])([F:30])[F:23])(=[O:28])=[O:27])=[CH:7][CH:6]=2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: c1ccncc1
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(NS(=O)(=O)CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.5 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (prepared in Example 3, 158 mg, 0.5 mmol) in pyridine (5 mL) at 25° C. was treated with 2,2,2-trifluoroethanesulfonyl chloride (63.5 μL, 0.57 mmol). The reaction was stirred at 25° C. for 48 h and was then concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 40/60 heptane/ethyl acetate) afforded the 3-cyclopentyl-N-thiazol-2-yl-2-[4-(2,2,2-trifluoro-ethanesulfonylamino)-phenyl]-propionamide (98.1 mg, 42.4%) as a light yellow oil: EI-HRMS m/e calcd for C19H22F3N3O3S2 (M+) 461.1054, found 461.1064.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[S:11](=[O:22])(=[O:21])[NH:12][C:13]2[C:18]([C:19]=1[OH:20])=[N:17][CH:16]=[CH:15][N:14]=2.N1C=CC=CC=1.[CH3:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32]>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[S:11](=[O:21])(=[O:22])[NH:12][C:13]2[C:18]([C:19]=1[O:20][C:31](=[O:32])[C:30]([CH3:35])([CH3:34])[CH3:29])=[N:17][CH:16]=[CH:15][N:14]=2
Reactant: O=S1(=O)Nc2nccnc2C(O)=C1c1c(F)ccc(F)c1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC1=C(c2c(F)ccc(F)c2Cl)S(=O)(=O)Nc2nccnc21
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a suspension of Compound No. A2 (Example 3.1) in dichloromethane (10 ml) was added pyridine (0.205 ml) followed by 2,2-dimethylpropionyl chloride (0.15 ml). The reaction mixture was heated to 40° C. for 4 hours and then stored at ambient temperature of 16 hours. The reaction mixture was partition between dichloromethane (30 ml) and aqueous hydrochloric acid (2M) (30 ml). The phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were concentrated. The residue was triturated with iso-hexane and dried under vacuum to give Compound No. B3 of Table B (408 mg) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].S(=O)(=O)(O)[OH:29]>>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:17])[F:15])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]([NH2:20])=[O:29])[C:3]=1[S:21]([C:24]([F:26])([F:25])[F:27])(=[O:23])=[O:22]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)C(F)(F)F
Reactant: O=S(=O)(O)O
Product: NC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)C(F)(F)F
Temperature: 100 °C
Yield: 83 %

Procedure:
A stirred mixture of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfonyl-1 H-pyrazole-3-carbonitrile (1.06 g, 2.21 mmol) and concentrated sulfuric acid (1 ml) was heated to 100° C. for 3 hours. The cooled mixture was added to ice water and the precipitate filtered off, washed with water and air-dried. Purification by flash chomatography (silica, chloroform) gave the title compound (0.869 g, yield 83%) as off-white crystals, mp 217° C., 1H NMR (DMSO-d6): 7.39 (bs, 2H, NH2), 7.57 and 7.78 (bs, 2H, C(O)NH2), and 8.25 (s, 2H, Ar—H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:22]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][CH2:25][CH2:24][CH2:23]1>>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:16])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: c1ccc2c(c1)CCCCN2
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)N2CCCCc3ccccc32)cc1[N+](=O)[O-]

Procedure:
The carboxylic acid from Example B (0.911 g, 3.08 mmol) was reacted with 2,3,4,5-tetrahydro-1H-1-benzazepine (0.453 g, 3.08 mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 50:50); yield 0.58 g (43%).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][CH:15]3[OH:20])[C@@H:11]1[CH2:10][CH2:9][C:8]1[CH2:7][C:6]([OH:21])=[CH:5][CH2:4][C:3]2=1.[CH3:22]C(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].O.[OH-].[Na+]>C1C=CC=CC=1.CC(=O)CC>[CH3:22][O:21][C:6]1[CH2:7][C:8]2[CH2:9][CH2:10][C@@H:11]3[C@@:2]([CH3:1])([C:3]=2[CH2:4][CH:5]=1)[CH2:19][CH2:18][C@@:16]1([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]1=[O:20]
Reactant: C[C@]12CC[C@]3(C)C(O)CC[C@H]3[C@@H]1CCC1=C2CC=C(O)C1
Reactant: CC(C)[O-]
Agent: [Al+3]
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: COC1=CCC2=C(CC[C@H]3[C@@H]4CCC(=O)[C@@]4(C)CC[C@]23C)C1

Procedure:
A mixture of 5.0 g of 9alpha-methylestra-2,5(10)-dien-3,17-diol 3 methyl ether and 4.5 g of aluminum isopropoxide in 45 ml of benzene and 45 ml of 2-butanone is stirred and refluxed for 22 hrs., using a water separator. After cooling, the reaction mixture is added to 100 ml. of 2N sodium hydroxide solution and a further 50 ml. of benzene are added. The organic layer is separated, washed with water and saturated sodium chloride and dried over anhydrous sodium sulphate. Removal of the solvent gives a residue which is crystallized from ether/hexane, 1/1 yielding 3-methoxy-9alpha-methyl-estra-2,5(10)-dien-17-one, m.p. 155°-158°, which may be used in Step H, below. Recrystallization from ether yields a product of m.p. 175°-177°.
Reaction SMILES: Cl[C:2]1[N:10]2[CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]3=[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[C:20]2[C:21]([CH3:26])=[N:22][O:23][C:24]=2[CH3:25])[N:3]=1.C(N(CC)CC)C.[CH3:34][CH:35]([NH2:37])[CH3:36]>CN1CCCC1=O.CO>[CH3:26][C:21]1[C:20]([C:7]2[C:8]3[O:13][CH2:12][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:10]4[C:2]([NH:37][CH:35]([CH3:36])[CH3:34])=[N:3][C:4]([C:9]=34)=[CH:5][CH:6]=2)=[C:24]([CH3:25])[O:23][N:22]=1
Reactant: CC(C)N
Reactant: Cc1noc(C)c1-c1ccc2nc(Cl)n3c2c1OCC3c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1noc(C)c1-c1ccc2nc(NC(C)C)n3c2c1OCC3c1ccccc1
Temperature: 120 °C
Yield: 28.8 %

Procedure:
To 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (9.1 mg, 0.025 mmol) in N-methylpyrrolidinone (0.40 mL), triethylamine (10 μL, 0.075 mmol) and 2-propanamine (21.2 μL, 0.25 mmol) were added and the mixture was heated at 120° C. overnight. The mixture was diluted with MeOH and purified by preparative LCMS (pH 10) to give the desired compound (2.8 mg, 29%). 1H NMR (500 MHz, DMSO-d6): δ 7.29 (3H, m); 6.92 (3H, m); 6.78 (1H, m); 6.55 (1H, m); 5.80 (1H, s); 4.68 (1H, m); 4.45 (1H, m); 4.00 (1H, m); 2.20 (3H, s); 2.02 (3H, s); 1.20 (3H, m); 1.09 (3H, m). LCMS calc. for C23H25N4O2 (M+H)+: m/z=389.2. found: 389.2.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)=[O:9])=[CH:6][C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][N:3]=1.CO.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CCOC(C)=O>[C:18]1([C:5]2[CH:6]=[C:7]3[C:8](=[O:9])[C:10]4[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=4[CH:12]=[CH:1][C:2]3=[N:3][CH:4]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ncc(-c2ccccc2)cc1C(=O)c1ccccc1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=c1c2ccccc2ccc2ncc(-c3ccccc3)cc12
Temperature: 100 °C

Procedure:
A flask was charged with 2-[(2-methyl-5-phenylpyridin-3-yl)carbonyl]benzaldehyde (6.2 mg, 0.02 mmol) and MeOH (1 mL). LiHMDS (25 μl, 1.0 M in THF) was added and the vessel was heated in the Biotage Initiator series microwave for 30 min. at 100° C. The mixture was then diluted with EtOAc, washed with water and brine, then dried over Na2SO4. The solution was concentrated in vacuo and purified by reverse phase HPLC (0-100% CH3CN/water with a 0.1% TFA modifier) to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 9.15 (d, 1H), 8.76 (d, 1H), 8.25 (d, 1H), 7.77 (m, 4H), 7.66 (t, 1H), 7.54 (t, 21), 7.45 (m, 2H0, 7.36 (d, 1H). LRMS (APCI) calculated for C20H14NO [M+H]+, 284.1; found 283.8.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[C:13]1([C:19]2[CH:20]=[C:21]([C:24](O)=[O:25])[S:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:24]([C:21]3[S:22][CH:23]=[C:19]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:20]=3)=[O:25])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cc(-c2ccccc2)cs1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc(-c2ccccc2)cs1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 4-phenylthiophene-2-carboxylic acid (Oakwood) according to methods A and C; yield 65 mg, 0.17 mmol (53%): 1H NMR (300 MHz, methanol-d4) δ 1.98 (d, J=14 Hz, 2H), 2.20 (s, 1H), 2.37 (d, J=14 Hz, 2H), 2.48 (s, 2H), 3.57 (s, 2H), 3.67 (d, J=1 Hz, 4H), 4.40 (s, 1H), 7.26-7.36 (m, 1H), 7.42 (t, J=7 Hz, 2H), 7.65-7.74 (m, 2H), 7.89 (d, J=1 Hz, 1H), 8.27 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 339 (M+H)+; Anal. C20H22N2OS.HCl.0.5H2O: C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:42])[CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23]/[CH:24]=[CH:25]/[CH3:26])[C:18]([N:27]3[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28]3)=[N:17][C:16]=2[N:15]([CH3:41])[C:13]1=[O:14])([O-])=O.O.C(O)(=O)C>C(O)C.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:42])[CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23]/[CH:24]=[CH:25]/[CH3:26])[C:18]([N:27]3[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:28]3)=[N:17][C:16]=2[N:15]([CH3:41])[C:13]1=[O:14]
Reactant: C/C=C/Cn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1[N+](=O)[O-])c(=O)n2C
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: C/C=C/Cn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1N)c(=O)n2C

Procedure:
Prepared by reduction of 6.34 g 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine with 5.15 g iron powder in a mixture of 260 ml of ethanol, 85 ml of water and 33 ml glacial acetic acid at reflux temperature.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH2:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:19][N:18]=1>>[ClH:1].[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:16][C:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:19][N:18]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: NC1=NN=C(c2ccccc2)C1
Product: COc1cc2ncnc(Nc3cc(-c4ccccc4)[nH]n3)c2cc1OC
Product: Cl
Yield: 0.1 %

Procedure:
Using a procedure analogous to that described in Example 15, 4-chloro-6,7-dimethoxyquinazoline (224 mg, 1 mol), (prepared as described for the starting material in Example 1), was reacted with 3-amino-5-phenyl-4H-pyrazole (183 mg, 1.16 mol) to give 6,7-dimethoxy-4-(5-phenylpyrazol-3-ylamino)quinazoline hydrochloride (328 mg, 94%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=[O:24].Br[CH2:26][CH2:27][CH:28]1[CH2:30][CH2:29]1>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH:28]1([CH2:27][CH2:26][C:14]2([CH3:13])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][C:15]2=[O:24])[CH2:30][CH2:29]1
Reactant: BrCCC1CC1
Reactant: CC1C(=O)CCc2ccccc21
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC1(CCC2CC2)C(=O)CCc2ccccc21
Temperature: -30 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a stirring solution of diisopropylamine (4.81 mL, 34.3 mmol) in 50 mL of tetrahydrofuran cooled to 0° C. in an ice bath was added dropwise 1.6M n-butyl lithium in tetrahydrofuran (21.45 mL, 34.3 mmol) over 30 minutes. The solution was cooled to −30° C. and 1-methyl-2-tetralone (5.0 g, 31.2 mmol) in 10 mL of tetrahydrofuran added. The resulting reaction mixture was placed in an ice bath for 2 hour. Cool the solution to −78° C., and added hexamethylphosphoric triamide 20 mL followed by the dropwise addition of (2-Bromo-ethyl)-cyclopropane (6.97 g, 46.8 mmol). The reaction was stirred at rt for 48 hours. Partition the reaction mixture between ethyl acetate and saturated aqueous NH4Cl, extract the aqueous layer 3 times with ethyl acetate. The combined organic layers were washed sequentially with saturated sodium bicarbonate, brine, and then dried over MgSO4. The product was purified by flash chromatography on SiO2, eluting with a 0-10% diethyl ether/hexane gradient yielding the product (4.488 g, 63% yield). 1H NMR (300 MHz, CDCl3): δ ppm 0.01 (m, 2 H) 0.47 (m, 2 H) 0.67 (m, 1 H) 0.98 (m, 2 H) 1.55 (s, 3 H) 1.95 (td, J=12.78, 4.60 Hz, 1 H) 2.37 (ddd, J=13.60, 12.13, 4.78 Hz, 1 H) 2.80 (m, 2 H) 3.19 (m, 2 H) 7.31 (m, 2 H) 7.44 (m, 2 H). MS (ESI+) m/z=229 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)[CH2:2][CH3:3].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:2][CH3:3]
Reactant: CCCNC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccccc1
Product: CCCNC(=O)c1ccc(-c2ccccc2)cc1
Yield: 71 %

Procedure:
Using Preparation Method 2, N-n-propyl-4-bromobenzamide from Example 9A was reacted with phenylboronic acid. The resulting reaction mixture was purified using SiO2 with CH2Cl2/Petroleum Ether 80:20 to CH2Cl2/AcOH 80:20 to give a white solid (71%). NMR 1H (ppm, CDCl3): 7.82 (d, J3=8.32 Hz, 2H), 7.63 (d, J3=8.69 Hz, 2H), 7.59 (d, J3=7.14 Hz, 2H), 7.45 (t, J3=7.09 Hz, 2H), 7.39-7.34 (m, 1H), 6.14 (br. s., 1H), 3.47-3.41 (m, 2H), 1.65 (sext., J3=7.18 Hz, 2H), 0.99 (t, J3=7.37 Hz, 3H).
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]2[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:13]=2[C:26]=1[CH3:27])C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)(C)C>[Pd].[C].O>[CH3:17][C:15]1([CH3:18])[CH:14]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[C:13]2[C:26]([CH3:27])=[C:9]([NH2:8])[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=2[O:16]1
Reactant: Cc1ccc(C2c3c(C)c(NCc4ccccc4)c(C)c(C)c3OC2(C)C)cc1
Agent: [Pd]
Solvent: O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a mixture of N-benzyl-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine (80 g), toluene (240 mL) and isopropanol (80 mL) was added 10% Pd-carbon (a product containing 50% water, 4 g), and the mixture was hydrogenated at 35° C. under atmospheric pressure. After completion of the reaction, the catalyst was filtered. Concentrated hydrochloric acid (19.2 mL) was added to the filtrate and the mixture was stirred at 10° C. or below for 1 hour. Precipitated crystals were filtered. The crystals were added to a mixture of methanol (560 mL) and water (80 mL) and the mixture was heated to 50° C. to dissolve the crystals. Then, 25% aqueous ammonia water was added dropwise to the solution to adjust to pH 8.5. Precipitated crystals were filtered to obtain the title compound (54.32 g, 88.6%).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[N:12][S:11][N:10]=2)[CH2:3]1.ClCCl.C(N(CC)CC)C.[N:32]([C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=1)=[C:33]=[O:34]>CCOC(C)=O>[F:42][C:41]([F:43])([F:44])[C:39]1[CH:40]=[C:35]([NH:32][C:33]([N:7]2[CH:6]([CH3:8])[CH2:5][N:4]([C:9]3[C:13]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)=[N:12][S:11][N:10]=3)[CH2:3][CH:2]2[CH3:1])=[O:34])[CH:36]=[C:37]([C:45]([F:48])([F:46])[F:47])[CH:38]=1
Reactant: CC1CN(c2nsnc2OCc2ccncc2)CC(C)N1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1CN(c2nsnc2OCc2ccncc2)CC(C)N1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
3,5-dimethyl-1-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine (104 mg, 0.34 mmol), dichloromethane (1.0 mL), triethylamine (0.10 mL, 0.43 mmol), and 1-isocyanato-3,5-bis-trifluoromethyl-benzene (0.075 ml, 0.43 mmol) are combined and stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with H2O (1×), sat'd NaHCO3 (2×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by column chromatography (1:1 hexanes:EtOAc, followed by 1:3 hexanes:EtOAc) to give 63 mg (33%) of 2,6-dimethyl-4-[(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide as a white solid after lyophilization from H2O—AcCN. 1H NMR (CDCl3) 8.67 (d, 2H), 7.91 (s, 2H), 7.53 (s, 1H), 7.36 (d, 2H), 6.74 (s, 1H), 5.51 (s, 2H), 4.31 (m, 2H), 4.10 (d, 2H), 3.11 (dd, 2H), 1.47 (d, 6H) ppm. LC-MS (MH+)=561.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl-].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH:16]=[N+:17]([CH3:19])[CH3:18].FC(F)(F)C1C=CC=CC=1C=O.CNC>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]([N:17]([CH3:19])[CH3:18])[C:15]1[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=1[C:13]([F:12])([F:24])[F:25]
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: C[N+](C)=Cc1ccccc1C(F)(F)F
Agent: CNC
Agent: O=Cc1ccccc1C(F)(F)F
Agent: [Cl-]
Product: CN(C)C(c1ccccc1C(F)(F)F)c1c[nH]c2ccc(Cl)cc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-chloro-1H-indole and (2-trifluoromethyl-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 2-trifluoromethyl-benzaldehyde and dimethylamine.
Reaction SMILES: [C:1]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=1O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(O)C>[C:1]1([C:11]2[O:12][C:15]3[CH:16]=[C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:19][C:14]=3[N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=Cc1nccc2ccccc12
Reactant: COC(=O)Cc1ccc(N)c(O)c1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: CCO
Product: COC(=O)Cc1ccc2nc(-c3nccc4ccccc34)oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
In ethanol (5 ml), 1-isoquinolinecarbaldehyde (252 mg, 1.60 mmol) and methyl 4-amino-3-hydroxyphenylacetate (349 mg, 1.93 mmol) were stirred at room temperature for 12 hours. Iodobenzene diacetate (619 mg, 1.92 mmol) was added and the reaction mixture was stirred further at room temperature for 15 minutes. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (4:1 to 3:1, v/v) eluate fractions, methyl (2-(1-isoquinolinyl)-6-benzoxazolyl)acetate (166 mg, 33%) was obtained as a yellow amorphous substance.