Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:32])=[C:27](B(O)O)[CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:25]3[CH:24]=[C:23]([Cl:22])[CH:28]=[CH:27][C:26]=3[CH3:32])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)cc1B(O)O
Reactant: Brc1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
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: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(Cl)cc1-c1ccc(CN2CCNC(Cc3ccccc3)C2)cc1
Temperature: 85 °C
Yield: 68 %

Procedure:
0.1 g of 3-(S)-benzyl-1-(4-bromo-benzyl)-piperazine were combined with 1.5 equiv. of 5-chloro-2-methylphenyl boronic acid, 0.05 equiv. of tetrakis(triphenylphosphine)palladium(0), 6 equiv. of 2M aqueous sodium carbonate solution, toluene and ethanol. The reaction mixture was heated at 85° C. under nitrogen overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography to afford 0.077 g of the title compound. Yield 68% ES MS (+) m/z 391.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].C1CCN2C(=NCCC2)CC1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C1COCC1>[CH3:20][C:19]1[O:21][CH:2]=[N:1][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: [C-]#[N+]CC(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)c1ncoc1C
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A stirred mixture of methyl isocyanoacetate (7.0 g, 70 mmol, 1 eq) and DBU (10.06 g, 70 mmol, 1 eq) in THF was cooled to 0° C., and a solution of acetic anhydride (7.14 g, 70 mmol, 1 eq) in THF was added dropwise over 15 min. The reaction mixture was stirred for 12 h at room temperature. The solvent was removed by Rota-vapor and water was added. The mixture was extracted with EtOAc. The crude product was purified by silica gel (230-400) column chromatography using 30% EtOAc/hexane. Yield: 6.8 g (98%). 1H NMR (400 MHz, CDCl3): δ2.54 (s, 3H), 3.80 (s, 3H), 7.69 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH2:14])([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[F:11][C:10]([F:12])([F:13])[C:8]1[CH:9]=[C:4]([NH2:1])[C:5]([NH2:14])=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(C(F)(F)F)cc1N

Procedure:
2-Nitro-4-trifluoromethyl-phenylamine was purchased from Aldrich. It was reduced with tin (11) chloride dihydrate in ethanol to give 4-trifluoromethyl-benzene-1,2-diamine (Scheme 3). The diamine was reacted with hexaketocyclohexane octahydrate to give [(HATNA)(CF3)3]. The product contains two isomers (from HPLC). The product is a yellow solid. It is soluble in common organic solvent including dichloromethane, THF and hot methanol. It was purified by flash chromatography on silica gel eluting with dichloromethane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[C:14]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: O=C1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)CCCC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a cold (−78° C.) solution of 1,4-dibromobenzene (33 g, 139.8 mmol) in tetrahydrofuran (200 mL) was added n-butyllithium (59.0 mL, 146.8 mmol, 2.49 M in hexane) dropwise. The viscous solution was stirred at −78° C. for 45 min, and cyclopentanone (13.6 mL, 153.8 mmol) was then added dropwise over 30 min. The resulting solution was stirred at −78° C. for 1 h and was then quenched by the addition of 0.5M HCl (200 mL) and ethyl acetate (200 mL). The layers were separated, and the organics were washed with water (1×100 mL), brine (1×100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 5% ethyl acetate in hexane to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.71-1.76 (m, 2H), 1.78-1.88 (m, 6H), 4.85 (s, 1H), 7.39-7.43 (m, 2H), 7.44-7.49 (m, 2H).
Reaction SMILES: BrC1C(OC)=C(C=CC=1CSC1C=CC=CC=1C)C(OCC)=O.[Br:24][C:25]1[C:26]([O:37][CH3:38])=[C:27]([C:32]([CH2:35]Br)=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29].[Br:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[SH:46]>>[Br:24][C:25]1[C:26]([O:37][CH3:38])=[C:27]([C:32]([CH2:35][S:46][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[Br:39])=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Reactant: Sc1ccccc1Br
Agent: CCOC(=O)c1ccc(CSc2ccccc2C)c(Br)c1OC
Product: COC(=O)c1c(CSc2ccccc2Br)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 77, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and 2-bromothiophenol.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([NH:9][C:10]1[C:17]([CH2:18][CH2:19]Br)=[CH:16][C:15]([Br:21])=[CH:14][C:11]=1CBr)(=[O:8])[CH3:7]>C(Cl)(Cl)(Cl)Cl>[C:6]([NH:9][C:10]1[C:11]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:14][C:15]([Br:21])=[CH:16][C:17]=1[CH:18]([CH3:19])[N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])(=[O:8])[CH3:7]
Reactant: CCNCC
Reactant: CC(=O)Nc1c(CBr)cc(Br)cc1CCBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCN(CC)c1cc(Br)cc(C(C)N(CC)CC)c1NC(C)=O

Procedure:
24 gm of diethylamine were added to a solution of 16.5 gm of 2-acetylamino-5-bromo-3-bromoethyl-benzyl bromide in 1.6 liters of carbon tetrachloride, and the mixture was refluxed for 1 hour. Subsequently, the reaction solution was evaporated, the residue was dissolved in 0.7 liter of 2 N hydrochloric acid, and the solution was extracted twice with chloroform. The hydrochloric acid phase was made alkaline with concentrated ammonia and extracted three times with chloroform. The organic phase was dried with sodium sulfate, and the solvent was distilled off. The residue was purified by column-chromatography on silicagel with ethylacetate/methanol (1:1), the corresponding fractions were united, and 2-acetylamino-5-bromo-N,N-diethyl-3-diethylamino-methyl-benzylamine, m.p. 91.5°-93°C, was obtained by recrystallization from petroleum ether.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[CH:6]=[C:5]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:3][CH2:2]1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][CH2:32][NH2:33].C(N(CC)CC)C>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([NH:33][CH2:32][CH2:31][NH:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[C:12]=3[F:14])[C:7](=[O:18])[CH:6]=[C:5]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(=O)c2c(F)c(F)c(F)c(F)c2n1C1CC1
Reactant: NCCNc1ccccn1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(=O)c2c(F)c(F)c(NCCNc3ccccn3)c(F)c2n1C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
A solution ethyl 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-2-carboxylate (688 mg, 2.09 mmol), N-2-pyridyl-1,2-ethanediamine (570 mg, 4.16 mmol) and triethylamine (0.87 mL, 6.24 mmol) in DMSO (20 mL) was stirred at 70° C. After 1 h, the reaction mixture was poured into ice water and the resulting solution was extracted with EtOAc, and the organic layer washed with water, brine, and then dried. The solvent was removed and the crude product was purified by column chromatography (Hexane:EtOAc 1:1) to yield ethyl 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-2-carboxylate (773 mg, 83%) as yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:12][N:13]([C:15]1[CH:31]=[CH:30][C:18]([CH:19](O)[C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1)[CH3:14].COC.O1CCCC1>CS(O)(=O)=O.CN(C)C(=N)N(C)C.CCCCCC>[CH3:28][N:26]([CH3:27])[C:23]1[CH:22]=[CH:21][C:20]([CH:19]([C:18]2[CH:30]=[CH:31][C:15]([N:13]([CH3:14])[CH3:12])=[CH:16][CH:17]=2)[O:1][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])=[CH:25][CH:24]=1
Reactant: O=C(CO)Nc1ccccc1
Reactant: CN(C)c1ccc(C(O)c2ccc(N(C)C)cc2)cc1
Agent: CN(C)C(=N)N(C)C
Agent: COC
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)c1ccc(C(OCC(=O)Nc2ccccc2)c2ccc(N(C)C)cc2)cc1

Procedure:
A solution of alpha-hydroxyacetanilide (3.62 g, 0.024 mole), 4,4'-bis(N,N-dimethylamino)benzhydrol, methyl ether (6.81 g, 0.024 mole) 50 ml of tetrahydrofuran, 153 ml of n-hexane, and one drop of methanesulfonic acid was refluxed for 11 hours, during which time an additional 300 ml of solvent was added. The blue-green solution was decolorized with 4 drops of tetramethylguanidine and the reaction mixture was filtered hot and the filtrate chilled. Yellow-green crystals formed, which were recrystallized from 30 ml petroleum ether/15 ml acetone to give a white solid, mp 118°-128° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13]3=[C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[N:12]3[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]2([CH3:23])[CH3:22])[CH:15]=1.C([Li])CCC.[B:29](OC)([O:32]C)[O:30]C>C1COCC1.C1CCCCC1>[CH3:22][C:5]1([CH3:23])[C:4]2[C:13]3=[C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[N:12]3[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=3)[CH:15]=[C:2]([B:29]([OH:32])[OH:30])[CH:3]=2
Reactant: CC1(C)c2ccccc2-n2c3ccccc3c3cc(Br)cc1c32
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC1(C)c2ccccc2-n2c3ccccc3c3cc(B(O)O)cc1c32
Temperature: 25 °C

Procedure:
93.7 g (259 mmol) of 6-bromo-8,8-dimethyl-8H-indolo[3,2,1-de]acridine are dissolved in 1500 ml of dry THF, 135 ml (337 mmol) of a 2.5 M solution of n-butyllithium in cyclohexane are added dropwise at −70° C., after 1 h 37 ml of trimethyl borate (336 mmol) are added dropwise, the mixture is warmed to room temperature over the course of 1 h, the solvent is removed, and the residue, which is uniform according to 1H-NMR, is employed in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[NH:15][N:14]=[C:13]([NH2:16])[CH:12]=3)[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.CN1C2C=CC(C3NN=C(N)C=3)=CC=2N=C1.[O:33]1[CH2:35][CH:34]1[CH2:36][N:37]1[CH2:46][CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38]1.CCN(C(C)C)C(C)C>CCO>[CH2:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:45][CH2:46][N:37]1[CH2:36][CH:34]([OH:33])[CH2:35][NH:16][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:4]=[CH:3][N:2]([CH3:1])[C:6]=3[CH:7]=2)[NH:15][N:14]=1
Reactant: Cn1cnc2ccc(-c3cc(N)n[nH]3)cc21
Reactant: c1ccc2c(c1)CCN(CC1CO1)C2
Agent: Cn1cnc2cc(-c3cc(N)n[nH]3)ccc21
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc2ccc(-c3cc(NCC(O)CN4CCc5ccccc5C4)n[nH]3)cc21
Yield: 4.1 %

Procedure:
A solution of 5-(1-methyl-1H-benzo[d]imidazol-6-yl)-1H-pyrazol-3-amine and 5-(1-methyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazol-3-amine (60 mg, 0.27 mmol), 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (54 mg, 0.27 mmol) and DIPEA (72 mg, 0.54 mmol) in EtOH (5 mL) was stirred overnight at 120° C. The mixture was concentrated and then purified by prep-HPLC and prep-TLC to give the desired 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-((5-(1-methyl-1H-benzo[d]imidazol-6-yl)-1H-pyrazol-3-yl)amino)propan-2-ol (4.5 mg, Yield 4.1%) 1H NMR (400 MHz, MeOD) 8.21-8.16 (m, 1H), 7.86 (s, 1H), 7.71-7.64 (m, 2H), 7.20-7.06 (m, 4H), 5.96 (s, 1H), 4.50-4.39 (m, 1H), 4.29-4.00 (m, 4H), 3.97-3.89 (m, 3H), 3.30-3.11 (m, 2H), 3.08-2.92 (m, 4H). LCMS: RT=0.788 min, M+H+=403.2.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25](=[O:26])[CH:24]=[C:23]([CH3:27])[NH:22]2)=[CH:17][C:16]=1[CH3:28]>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25](=[O:26])[CH:24]=[C:23]([CH3:27])[NH:22]2)=[CH:17][C:16]=1[CH3:28])=[O:8])=[O:5]
Reactant: Cc1cc(=O)n(-c2ccc(N)c(C)c2)[nH]1
Reactant: O=C=NC(=O)c1ccc(F)cc1Cl
Solvent: CC#N
Product: Cc1cc(=O)n(-c2ccc(NC(=O)NC(=O)c3ccc(F)cc3Cl)c(C)c2)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of equivalent amounts of 2-chloro-4-fluorobenzoyl isocyanate in acetonitrile was added dropwise to the solution of 71 mg of 2-(4-amino-3-methylphenyl)-5-methyl-1,2-dihydropyrazol-3-one in 6 ml of acetonitrile and the mixture was stirred at room temperature overnight. The solid formed was filtered off with suction and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH3:31])[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]3[CH:27]=[N:26][C:25]([C:28]#[N:29])=[C:24](Cl)[N:23]=3)[CH2:17]2)=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH3:31])[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]3[CH:27]=[N:26][C:25]([C:28]#[N:29])=[C:24]([NH:35][CH:32]4[CH2:34][CH2:33]4)[N:23]=3)[CH2:17]2)=[O:14])[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: NC1CC1
Reactant: CN(C(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1)c1cc(Cl)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CN(C(=O)N[C@@H]1CCCN(c2cnc(C#N)c(NC3CC3)n2)C1)c1cc(Cl)cc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
(R)-1-(3-Chloro-5-(trifluoromethyl)phenyl)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1-methylurea (521, 50 mg, 0.10 mmol) was dissolved in 2 mL NMP in a sealed tube. To it was added cyclopropylamine (210 μL, 3.0 mmol), and the mixture was stirred in 70° C. bath for overnight. It was diluted with 50 mL EtOAc, washed with saturated NH4Cl (aq) solution and water ×2, concentrated in vacuo to give crude (R)-1-(3-chloro-5-(trifluoromethyl)phenyl)-3-(1-(5-cyano-6-(cyclopropylamino)pyrazin-2-yl)piperidin-3-yl)-1-methylurea (522). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were added one NaOH solid pellet (about 50-100 mg) and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 1 hour, diluted with 10 mL MeCN, stirred for 5 min, concentrated on rotavap. The residue was treated with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (R)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)-3-(cyclopropylamino)pyrazine-2-carboxamide (523 as HCl salt (32 mg, 62% yield). LC-MS (ESI): m/z (M+1) 512.2 (chloro pattern). UV: λ=282, 318, 369 nm. Proton NMR (CD3OD): δ 7.53 (1H, m), 7.51 (1H, broad s), 7.48 (1H, broad s), 7.46 (1H, s), 3.98 (1H, dd, J=13.5; 3.5 Hz), 3.90 (1H, m), 3.81 (1H, m), 3.66 (1H, m), 3.52 (1H, m), 3.25 (3H, s), 2.71 (1H, m), 1.96 (1H, m), 1.78 (2H, m), 1.62 (1H, m), 0.76 (2H, m), 0.45 (2H, m) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:7]2[S:8][C:9](=[O:11])[S:10][C:6]=2[C:5](=O)[C:4](=O)[O:3]1.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>>[CH3:1][C:2]1([CH3:14])[O:3][C:4]2[C:5](=[N:21][C:16]3[C:15]([N:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]2[S:10][C:9](=[O:11])[S:8][C:7]1=2
Reactant: Nc1ccccc1N
Reactant: CC1(C)OC(=O)C(=O)c2sc(=O)sc21
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Product: CC1(C)Oc2nc3ccccc3nc2-c2sc(=O)sc21

Procedure:
4,4-Dimethyl-4H-[1,3]dithiolo[4,5-c]pyran-2,6,7-trione (5) (150 mg, 0.65 mmol), o-phenylenediamine (75 mg, 0.65 mmol) and montmorillonite KSF (100 mg) were mixed in a mortar until a homogeneous solid was obtained then the solid mixture was transferred into a test tube and irradiated with microwaves for 4 min. The resulting mixture was purified by chromatography (silica gel, CH2Cl2) to give pure 4,4-dimethyl-4H-5-oxa-1,3-dithia-6,11-diaza-cyclopenta[a]anthracen-2-one (7). Yield: 90 mg (45%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:63]1([CH2:68][CH:69]2[CH2:74][CH2:73][CH2:72][NH:71][CH2:70]2)[CH2:67][CH2:66][CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:71]1[CH2:72][CH2:73][CH2:74][CH:69]([CH2:68][N:63]3[CH2:64][CH2:65][CH2:66][CH2:67]3)[CH2:70]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: C1CNCC(CN2CCCC2)C1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCCC(CN4CCCC4)C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 3-(pyrrolidin-1-ylmethyl)-piperidine in DMSO at ambient temperature.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH2:11])[CH2:6]1.[F:14][CH:15]([F:26])[C:16]1[C:20]([C:21](Cl)=[O:22])=[C:19]([F:24])[N:18]([CH3:25])[N:17]=1>>[F:26][CH:15]([F:14])[C:16]1[C:20]([C:21]([NH:11][CH:7]2[CH2:8][CH2:9][CH2:10][CH:5]([CH2:4][CH2:3][C:2]([CH3:13])([CH3:12])[CH3:1])[CH2:6]2)=[O:22])=[C:19]([F:24])[N:18]([CH3:25])[N:17]=1
Reactant: CC(C)(C)CCC1CCCC(N)C1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Product: Cn1nc(C(F)F)c(C(=O)NC2CCCC(CCC(C)(C)C)C2)c1F
Yield: 54 %

Procedure:
As for example 1—step 6, condensation of 0.50 g 3-(3,3-dimethylbutyl)cyclohexanamine over 0.638 g of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride gives 0.65 (54% of theory) of 3-(difluoromethyl)-N-[3-(3,3-dimethylbutyl)cyclohexyl]-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide. log P=4.80.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:27]O>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:27])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCCCCCCCCc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCCCCCCCc1ccccc1

Procedure:
13-Phenyltridecanoic acid (22.4 g, 77 mmol) was reacted for 1 h in methanol (60 ml) and sulfuric acid (2.2 g) under reflux. The reaction mixture was concentrated, poured into H2O (100 ml) and extracted with dichloromethane. The organic layer was washed with H2O, dried over anhydrous MgSO4 and evaporated under reduced pressure. The residue (33 g) was chromatographed on silica gel (Wako Gel C-200) with dichloromethane as eluent to give the title compound as a white solid; yield: 17.6 g; mp 30.5°-31.5° C.
Reaction SMILES: [CH:1]1([C:4]([O:6][CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)=[O:5])[CH2:3][CH2:2]1.S(Cl)([Cl:21])=O.CN(C)C=O>CCOCC>[CH:1]1([C:4]([O:6][CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([Cl:21])=[O:15])=[CH:12][CH:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(OCCOC(=O)C2CC2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cl)c1ccc(OCCOC(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 3.2 g (12.8 mmol) of 4-(2-cyclopropylcarbonyloxyethoxy)benzoic acid, 80 ml of ether and 1.5 ml (20.5 mmol) of thionyl chloride, at RT, is added 0.3 ml (3.8 mmol) of dimethylformamide. This mixture is stirred, at RT, for 1 day. The top phase is decanted (the residue is discarded), and solvent and other volatiles are removed from it by rotoevaporation to give 4-(2-cyclopropylcarbonyloxyethoxy)benzoic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][N:18]([C:21](SC)=[N:22][C:23]#[N:24])[CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([CH2:38][NH2:39])=[CH:37][C:32]=2[O:31][CH2:30]1>O.C(Cl)Cl>[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([CH2:38][NH:39][C:21]([N:18]3[CH2:19][CH2:20][N:15]([CH:6]4[C:7]5=[N:8][CH:9]=[CH:10][CH:11]=[C:12]5[CH2:13][S:14][C:4]5[CH:3]=[C:2]([Cl:1])[CH:28]=[CH:27][C:5]4=5)[CH2:16][CH2:17]3)=[N:22][C:23]#[N:24])=[CH:37][C:32]=2[O:31][CH2:30]1
Reactant: CSC(=NC#N)N1CCN(C2c3ccc(Cl)cc3SCc3cccnc32)CC1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: O
Product: N#CN=C(NCc1ccc2c(c1)OCO2)N1CCN(C2c3ccc(Cl)cc3SCc3cccnc32)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Methyl 4-(8-chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-yl)-N-cyano-1-piperazine-carboximidothioate (184 mg, 0.428 mmol) was combined with 1 ,3-benzodioxol-5-ylmethylamine [piperonylamine] (1.07 ml, 8.56 mmol) in a 10 ml flask, and the mixture was stirred at 100° C. for three hours. The reaction mixture was cooled to room temperature and diluted with water and CH2Cl2. The layers were shaken together and separated, and the aqueous extract was extracted several times with CH2Cl2. The combined organic layers were washed with brine, dried (MgSO4), filtered through `Celite` and concentrated. The residue (over 2 g) was first filtered through a plug of silica gel and eluted with 15%acetone/CH2Cl2), and then further chromatographed more carefully and eluted with 2%EtOH/CH2Cl2, increasing gradually to 40%EtOH/CH2Cl2, to afford the pure product, 155 mg (68%); MS (FAB, M+H)=533.6.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12](Cl)=[O:13])[CH:5]=[CH:4][C:3]1=2.[OH:16][C:17]1[CH:26]=[C:25]([C:27]#[C:28][Si](C)(C)C)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>>[OH:16][C:17]1[CH:26]=[C:25]([C:27]#[C:28][C:12](=[O:13])[C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:15])([CH3:1])[CH2:11][CH2:10][CH2:9][C:8]=3[CH:7]=2)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1O
Reactant: CC1(C)CCCc2cc(C(=O)Cl)ccc21
Product: COC(=O)c1ccc(C#CC(=O)c2ccc3c(c2)CCCC3(C)C)cc1O

Procedure:
In a similar manner to Example 14(a), by reaction of 4.7 g (21 mmol) of 5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthoyl chloride with 5.7 g (22.8 mmol) of methyl 2-hydroxy-4-trimethylsilylethynylbenzoate (prepared in Example 5(a) of patent EP 0,661,258), 5.14 g (68.5%) of the expected methyl ester are obtained, with a melting point of 89-90° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14]CC)=O)=[C:7]2[OH:17].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.CCOCC>O>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([NH:31][CH2:30][C:29]1[CH:32]=[CH:33][C:26]([Cl:25])=[CH:27][CH:28]=1)=[O:14])=[C:7]2[OH:17]
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(N)cc(CN3CCOCC3)cc2c1O
Solvent: CCOCC
Solvent: O
Product: Nc1cc(CN2CCOCC2)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Temperature: 180 °C

Procedure:
A mixture of ethyl 8-amino-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxylate (Preparation 2, 1.0 g) and 4-chlorobenzylamine (4 mL) is heated at 180° C. The solution is cooled and stirred with ether (6 mL) and water (6 mL). The resulting precipitate is removed by filtration, washed with water followed by ether and dried to afford 1.05 g of the title compound. Physical characteristics: 1H NMR (DMSO-d6) δ2.35, 3.45, 3.57, 4.54, 5.65, 7.02, 7.39, 8.62, 10.6, 11.1.