Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:22](O)=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:27][O:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]=1[CH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.Cl.CNC(NC)CCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:22]([N:46]2[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][CH2:40][CH2:39][C:30]3[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:37]=[CH:38][C:29]=3[O:28][CH3:27])[CH2:48][CH2:47]2)=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2ccccc2c1CCCCN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(C(=O)O)c2ccc(F)cc2)CC1
Agent: CCN=C=NCCC(NC)NC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2ccccc2c1CCCCN1CCN(C(=O)C(c2ccc(F)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
2.2 g of 1-t-Butoxycarbonyl-4-[carboxy-(4-fluorophenyl)methyl]piperidine was dissolved in 20 ml of dimethylformamide, and 2.0 g of 1-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine dihydrochloride, 1.9 g of 1-(3,3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.9 g of 1-hydroxybenzotriazole monohydrate and 3.5 ml of triethylamine were added, followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=3:1) to give 2.4 g of 1-t-butoxycarbonyl-4-(1-(4-fluorophenyl)-2-{4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazin-1-yl}-2-oxoethyl)piperidine as an oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[N:24]=[C:25]=[S:26].[N-]=C=S>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[NH:24][C:25]([N:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[CH2:8]1)=[S:26]
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Agent: [N-]=C=S
Solvent: CCO
Product: FC(F)(F)c1cccc(OC2CN(C(=S)Nc3c(Cl)cccc3Cl)C2)c1
Reaction time: 0.75 h
Yield: 90.2 %

Procedure:
A solution of 0.04 mole of 3-[3-(trifluoromethyl) phenoxy]azetidine in 100 ml of absolute ethanol was stirred in a tap water bath while 8.16 g (0.04 mole) of 2,6-dichlorophenyl isothiocyanate was added all at once. The reaction was slightly exothermic and as the isothiocyanate began to dissolve, product began to precipitate. After stirring for 45 minutes the reaction mixture was heated on a steam bath to assure that all the isothiocyanate dissolved, and upon cooling, filtration yielded 15.2 g of white crystalline product. A portion of this material (7.9 g) was recrystallized from absolute ethanol to give 4.3 g of pure crystalline powder, m.p. 196°-197° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]3[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]([NH:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:40]=[C:39]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([CH:14]([F:15])[F:16])[CH:11]=[C:10]([C:17]4[CH:18]=[N:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=4)[N:9]=3)[CH:3]=2)[CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)c2)c1

Procedure:
3′-[4-Difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.6) (0.43 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure III. Obtained as light yellow solid (0.62 g), which was subsequently deprotected.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[CH3:12])=[O:4].S(Cl)([Cl:17])(=O)=O>CCCCCCC>[Cl:17][C:2]([CH3:13])([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[CH3:12])=[O:4]
Reactant: Cc1ccc(C(=O)C(C)C)c(C)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCCCCCC
Product: Cc1ccc(C(=O)C(C)(C)Cl)c(C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2,2′,4′-Trimethylpropiophenone (30.0 g, 0.17 mole) was dissolved in heptane (10 ml), and sulfuryl chloride (35 g, 0.26 mole) was added at once. After about 5 min gas evolution occurred. After 3 h of stirring at room temperature the reaction mixture was concentrated. The concentrate was dissolved in heptane (200 ml) and was washed with 150 ml of a 2 wt % aqueous sodium bicarbonate solution. After drying over magnesium sulfate the solvent was removed under reduced pressure. The yield of 2-chloro-2,2′,4′-trimethylpropiophenone was 35.5 g or 99%.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:32][Si](C)(C)C.CCOCC>CC(CC)=O>[ClH:32].[CH3:31][N:2]([CH3:1])[C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2cccc(F)c2)CCC(CC(=O)NCCc2c[nH]c3ccccc23)CC1
Solvent: CCOCC
Solvent: CCC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The less polar diastereoisomer of 2-[4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]-N-[2-(1H-indol-3-yl)ethyl]acetamide (86 mg, 0.204 mmol) was dissolved in ethyl methyl ketone (5 ml), and chlorotrimethylsilane (0.038 ml, 0.3 mmol) was added. After 1 h ether (30 ml) was added to the reaction mixture and the mixture was stirred at RT for 30 min. The hydrochloride was isolated as a colourless solid in a yield of 94% (87 mg) with an m.p. of 135-140° C. (Example 50).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([N:21]([CH3:23])[CH3:22])=[C:14]([NH:16][C:17](=[O:20])[CH2:18]Cl)[CH:15]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:3]=1.[NH2:40][CH2:41][CH:42]1[CH2:44][CH2:43]1>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([N:21]([CH3:23])[CH3:22])=[C:14]([NH:16][C:17](=[O:20])[CH2:18][NH:40][CH2:41][CH:42]3[CH2:44][CH2:43]3)[CH:15]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:3]=1
Reactant: NCC1CC1
Reactant: COc1ccc(COc2ccccc2-c2cc(-c3ccc(N(C)C)c(NC(=O)CCl)c3)c(C#N)c(N)n2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccccc2-c2cc(-c3ccc(N(C)C)c(NC(=O)CNCC4CC4)c3)c(C#N)c(N)n2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
To a stirred solution of N-[5-(2-amino-3-cyano-6-{2-[(4-methoxybenzyl)oxy]phenyl}-4-pyridinyl)-2-(dimethylamino)phenyl]-2-chloroacetamide (0.400 g, 0.738 mmol) in DMF (5 mL) was added aminomethylcyclopropane (0.192 mL, 2.214 mmol). The mixture was stirred at 60° C. for 2 hrs. After cooled to room temperature, the mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification was carried out by column chromatography on silica gel (chloroform:methanol=100:2, hexane:ethyl acetate=1:2-1:3-1:5, 2 times) to give N1-[5-(2-amino-3-cyano-6-{2-[(4-methoxybenzyl)oxy]phenyl}-4-pyridinyl)-2-(dimethylamino)phenyl]-N2-(cyclopropylmethyl)-glycinamide as a yellow oil (0.130 g, yield 30%).
Reaction SMILES: [C:1]([NH:9][NH:10][C:11](=[O:16])[NH:12][CH2:13][CH2:14][CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18]C1C=CC(C(NN)=O)=CC=1.C(N=C=O)CC>>[CH3:17][O:18][C:5]1[CH:4]=[CH:3][C:2]([C:1]([NH:9][NH:10][C:11](=[O:16])[NH:12][CH2:13][CH2:14][CH3:15])=[O:8])=[CH:7][CH:6]=1
Reactant: COc1ccc(C(=O)NN)cc1
Reactant: CCCNC(=O)NNC(=O)c1ccccc1
Agent: CCCN=C=O
Product: CCCNC(=O)NNC(=O)c1ccc(OC)cc1

Procedure:
Synthesis and isolation were same as for 1-benzoyl-2-(N-propylcarbamyl)hydrazine, using 1.3 g (7.8 mmol) 4-methoxybenzoylhydrazine and 0.9 g (10.5 mmol) of n-propylisocyanate. Yield was 1.8 g (92%). MS (EI, m/e) calcd for C12H17N3O3 251, found 251 (M+, 1.6); mp 176-179° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[C:5]([CH3:12])[CH:4]=1.Br[C:14]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]2[NH:20][CH2:19][C@@H:18]3[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:17]3[C:16]=2[CH:15]=1>>[CH3:25][O:24][C:22]1[C:21]2[NH:20][CH2:19][C@@H:18]3[CH2:26][NH:27][CH2:28][C@@H:17]3[C:16]=2[CH:15]=[C:14]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH3:12])[CH:23]=1
Reactant: COc1cc(Br)cc2c1NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Reactant: COc1ccc(B(O)O)c(C)c1
Product: COc1ccc(-c2cc(OC)c3c(c2)[C@H]2CNC[C@H]2CN3)c(C)c1

Procedure:
Following the procedures described in Example 12, except that 4-methoxy-2-methylphenylboronic acid was used instead of phenylboronic acid, (±)-cis-tert-butyl 8-bromo-6-methoxy-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate from Example 11, Part A was converted into the title compound of Example 14. 1H NMR (CDCl3): δ 7.14 (d, 1H, J=8.1 Hz), 6.83-6.73 (m, 2H), 6.62 (s, 1H), 6.61 (s, 1H), 4.49 (broad s, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.78-3.70 (m, 1H), 3.62-3.05 (overlapping m, 6H), 2.83-2.75 (m, 1H), 2.28 (s, 3H). LRMS (ES)+: 325.4 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].Cl.Cl[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:31]=2[N:30]=[CH:29][CH:28]=[CH:27]3)[CH:14]=1)=[O:12].C(OCC)(=O)C.CO>CO.O1CCCC1.ClCCl.ClCCl>[NH:4]([C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:31]=2[N:30]=[CH:29][CH:28]=[CH:27]3)[CH:14]=1)=[O:12])[C:3]([NH2:5])=[NH:2]
Reactant: O=C(Cl)c1cn(-c2cccc3cccnc23)c2ccccc12
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: N=C(N)NC(=O)c1cn(-c2cccc3cccnc23)c2ccccc12
Temperature: 22 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
1.25 g (13.09 mmol) of guanidine hydrochloride are added to a solution of 0.71 mg (13.14 mmol) of sodium methoxide in 10 cm3 of methanol at a temperature in the region of 22° C. under an argon atmosphere. After stirring at a temperature in the region of 22° C. for 2 hours, the solvent is evaporated off under reduced pressure (2.7 kPa). The residue, placed under an argon atmosphere, is taken up in 20 cm3 of a tetrahydrofuran/dichloromethane (1/1 by volume) mixture and then 0.9 g (2.62 mmol) of 3-chlorocarbonyl-1-(quinol-8-yl)-1H-indole hydrochloride, dissolved in 5 cm3 of the same tetrahydrofuran/dichloromethane mixture, is added thereto. After 15 hours at a temperature in the region of 22° C. and then heating at a temperature in the region of 60° C. with stirring for 1.5 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in dichloromethane. The insoluble material is then filtered off and discarded, and the filtrate is concentrated under reduced pressure (2.7 kPa). The residue obtained is taken up in an ethyl acetate/methanol (8/2 by volume) mixture and the resulting precipitate is filtered off. A white solid is obtained, which solid is crystallised under hot conditions from 10 cm3 of ethanol. The crystals formed are filtered off and dried under vacuum (2.7 kPa) to give 0.51 g of 3-guanidinocarbonyl-1-(quinol-8-yl)-1H-indole in the form of white crystals melting at 172° C. Mass spectrum (EI): m/e 329 (M+·), m/e 271.
Reaction SMILES: [CH3:1][C:2]([S:25]([CH3:28])(=[O:27])=[O:26])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([B:16]2[O:20]C(C)(C)C(C)(C)[O:17]2)=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[NH4+].I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.Cl>[CH2:6]([O:5][C:3](=[O:4])[C:2]([CH3:1])([S:25]([CH3:28])(=[O:26])=[O:27])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([B:16]([OH:20])[OH:17])=[CH:12][CH:11]=1)[CH3:7]
Reactant: CCOC(=O)C(C)(CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)S(C)(=O)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(CCc1ccc(B(O)O)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanoate, which may be prepared as in Preparation Number 3, Step A, (4.75 g, 11.5 mmol) in acetone (90 mL) was added ammonium acetate (0.1 M in water, 232 mL, 23.2 mmol) and sodium periodate (7.43 g, 34.7 mmol). The mixture was stirred at ambient temperature overnight. The mixture was diluted with 1N HCl aq. and extracted with ether 2×. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give {4-[4-ethoxy-3-methyl-3-(methylsulfonyl)-4-oxobutyl]phenyl}boronic acid as an orange oil 3.44 g. LCMS: (M+1) 329.2
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][CH2:11][C:12]([O:14]C)=O>CO>[NH:2]1[C:12](=[O:14])[CH2:11][CH2:10][NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]1=2
Reactant: COC(=O)CCNc1ccccc1N
Agent: [Na]
Solvent: CO
Product: O=C1CCNc2ccccc2N1
Reaction time: 1 h
Yield: 49.9 %

Procedure:
Sodium (1.8 g, 77.2 mmol) was added in portions to methanol (50 mL), and the mixture was stirred for 1 h. The resulting mixture was added dropwise to a solution of methyl 3-((2-aminophenyl)amino)propanoate (9.4 g, 48.2 mmol) in methanol (150 mL) at 0° C. Once addition was completed, the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by CombiFlash (PE:EA=5:1) to give 4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one as a yellow solid (3.9 g, 50%). LRMS (M+H)+: 161 m/z. 1H NMR (300 MHz, CD3OD): δ 2.61 (t, J=6.0 Hz, 2H), 3.62 (t, J=6.0 Hz, 2H), 6.76-6.86 (m, 2H), 6.90-6.99 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]4([C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=5)OCC[O:18]4)=[CH:13][C:12]=23)[CH:5]=[CH:6][CH:7]=1.N>Cl.CO>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:17]([C:14]2[CH:15]=[CH:16][C:11]3[C:12]([CH:13]=2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[O:9][N:10]=3)=[O:18])=[CH:27][CH:26]=1
Reactant: Clc1ccc(C2(c3ccc4noc(-c5cccc(Cl)c5)c4c3)OCCO2)cc1
Agent: Cl
Agent: N
Solvent: CO
Product: O=C(c1ccc(Cl)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
A mixture of intermediate (6-a) (30 g) in HCl 3 N (220 ml) and methanol (165 ml) was stirred at 100° C. for 5 hours. The mixture was poured into ice and basified with NH3 (aq.). The precipitate was filtered off, washed with water and diethyl ether and dried, yielding 24.9 g (93%) of (4-chlorophenyl)[3-(3-chlorophenyl)-2,1-benzisoxazol-5-yl]methanone (interm. 6-b). The product was used without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[CH2:18])[N:12]=1.C(O)(=O)C>CO>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:18][CH2:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([CH3:10])[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=Cc1cccc(C)n1
Reactant: CC(=O)N1CCNCC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)N1CCN(CCc2cccc(C)n2)CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 72.8 %

Procedure:
To a stirring solution of N-acetylpiperazine (2.50 g, 20 mmol) in methanol (40 mL) at 0° C. under nitrogen was added 2-methyl-6-vinyl-pyridine (2.39 g, 20 mmol) and acetic acid (1.28 mL). The mixture was stirred for 24 hours at 80° C. and was then concentrated. The residue was partitioned between 10% aqueous K2CO3 /CH2Cl2. The organic phase was dried and concentrated to afford 3.60 g (73%) of 1-acetyl-4-[2-(6-methyl-2-pyridyl)ethyl]piperazine as a brown solid which was used directly in the next step: 1H NMR (CDCl3): δ 7.48 (m, 1H), 7.0 (d, 1H), 3.63 (t, 2H), 3.45 (t, 2H), 2.95-2.60 (m, 4H), 2.50 (m, s, 9H), 2.08 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[NH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCCCN
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCCCNc1c(C(=O)OCC)cnc2c(OC)cccc12

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (300 mg, 1.13 mmol) was treated with 1-aminobutane following general procedure B to afford 4-butylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (295 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (220 mg) following general procedure E.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([OH:15])=[O:14])=[C:8]([OH:16])[CH:7]=[CH:6]2)#[N:2].C(#N)C.[CH3:20][N:21]([CH3:26])[C:22]([CH2:24]Br)=[O:23]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH2:24][C:22](=[O:23])[N:21]([CH3:26])[CH3:20])=[O:14])=[C:8]([OH:16])[CH:7]=[CH:6]2)#[N:2]
Reactant: CN(C)C(=O)CBr
Reactant: N#Cc1ccc2c(C(=O)O)c(O)ccc2c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)C(=O)COC(=O)c1c(O)ccc2cc(C#N)ccc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 78.5 %

Procedure:
To 28.4 g of 6-cyano-1-carboxy-2-naphthol were added 350 ml of acetonitrile, 18 ml of triethylamine and 33.2 g of dimethylcarbamoylmethyl bromide, followed by stirring for 24 hours at 70° C. and further 24 hours at room temperature. The resulting precipitate was collected by filtration and washed with water to obtain 31.2 g of the desired product.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]([F:13])([CH:10]([F:12])[F:11])[CH2:8][OH:9].Cl>N1C=CC=CC=1>[C:2](=[O:3])([O:9][CH2:8][C:7]([F:13])([F:6])[CH:10]([F:12])[F:11])[O:4][CH3:5]
Reactant: COC(=O)Cl
Reactant: OCC(F)(F)C(F)F
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)OCC(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
Methyl chloroformate (130 mL, 159 g, 1.68 mol) was added slowly over a period of 3 hours to a solution of 2,2,3,3-tetrafluoropropanol (132 g, 1.00 mol) in pyridine (300 mL, anhydrous) at −10° C. to 0° C. with magnetic stirring. The reaction mixture was stirred at room temperature overnight. Then, the reaction mixture was mixed with 5% HCl (500 mL) and approximately 50 g of ice, and the resulting mixture was extracted three times with 300 mL portions of ether. The combined organic layer was washed three times with 100 mL portions of 5% HCl, followed by two washes with 100 mL portions of 5% sodium carbonate. The organic phase was then dried over anhydrous sodium sulfate. Ether was removed by rotary evaporation. The crude product (approximately 200 g) was distilled, yielding 166 g (87% yield) of pure methyl 2,2,3,3-tetrafluoropropyl carbonate, also referred to herein as “FS-C”. NMR analysis data were consistent with the literature values as reported in U.S. Pat. No. 5,659,062.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:35](O)=[O:36])=[C:8]([C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[C:17]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)[CH:16]=3)([CH3:14])[CH3:13])[NH:9]2)=[CH:5][CH:4]=1)#[N:2].CO.O>CC(N(C)C)=O.C(OC(=O)C)(=O)C.CCN(C(C)C)C(C)C>[CH2:21]([C:18]1[C:17]([N:23]2[CH2:24][CH2:25][CH:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[CH2:27][CH2:28]2)=[CH:16][C:15]2[C:12]([CH3:14])([CH3:13])[C:8]3[NH:9][C:10]4[C:6]([C:7]=3[C:35](=[O:36])[C:20]=2[CH:19]=1)=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:11]=4)[CH3:22]
Reactant: CCc1ccc(C(C)(C)c2[nH]c3cc(C#N)ccc3c2C(=O)O)cc1N1CCC(N2CCOCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: CCc1cc2c(cc1N1CCC(N3CCOCC3)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
6-Cyano-2-(2-(4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)phenyl)propan-2-yl)-1H-indole-3-carboxylic acid (500 g) was dissolved in a mixture of DMA (9.4 L), acetic anhydride (270 ml) and DIPEA (1170 ml) under nitrogen stream. The mixture was stirred at 90° C. for 1 hr. After cooling to room temperature, the mixture was added with methanol (3.525 L) and subsequently with distilled water (5.875 L). The precipitated solid was filtered, collected, washed twice with the mixture solution (methanol:water=3:5, 1.41 L), and then dried to obtain the title compound (389.6 g, 85%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)=[O:29]>>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:34]4[CH:35]=[C:30]([CH:31]=[CH:32][CH:33]=4)[CH:28]=[O:29])[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: O=Cc1cccc(B(O)O)c1
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cccc(C=O)c4)nc3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine was reacted with 3-formylphenylboronic acid in General Procedure A to yield 3-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-2-yl]-benzaldehyde. Treatment of this aldehyde with sodium borohydride (2.5 equivalents) in ethanol yielded the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].[OH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23]>>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[C:19]([OH:18])[CH:20]=3)[CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5]
Reactant: O=C(O)c1cccc(O)c1
Reactant: N#Cc1c(N)cccc1OCC1CCNCC1
Product: N#Cc1c(N)cccc1OCC1CCN(C(=O)c2cccc(O)c2)CC1

Procedure:
Prepared as in Example 24a from 2-amino-6-(piperidin-4-ylmethoxy)benzonitrile (Example 34c) and 3-hydroxybenzoic acid as an orange glass (66%). 1H NMR (400 MHz, DMSO-d6) δ 1.29 (m, 2H), 1.66-1.92 (m, 2H), 2.06 (m, 1H), 2.80 (brs, 1H), 3.05 (brs, 1H), 3.62 (brs, 1H), 3.91 (d, J=8.0 Hz, 2H), 4.49 (brs, 1H), 5.99 (s, 2H), 6.22 (d, J=8.0 Hz, 1H), 6.34 (d, J=8.0 Hz, 1H), 6172-6.83 (m, 3H), 7.15-7.24 (m, 2H), 9.65 (s, 1H). MS 352 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[CH:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=1)=[O:7]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NC(=O)c2ccnc(Br)c2)cc1

Procedure:
In a manner similar to that described in Preparation 17, 2-bromoisonicotinic acid and 4-isopropylaniline were converted to the title compound