Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([CH3:10])([CH2:4][CH2:5][C:6](Cl)([CH3:8])[CH3:7])[CH3:3].[Al+3].[Cl-].[Cl-].[Cl-].[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:21][C:15]1[CH:20]=[CH:19][C:18]2[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][C:2]([CH3:10])([CH3:3])[C:17]=2[CH:16]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
2,5-Dichloro-2,5-dimethylhexane (67.5 g, 0.369 mol) was dissolved in dry toluene (200 ml), and then AlCl3 (4.05 g, 30.4 mmol) was crushed up and added portionwise to the solution. After being left for 2 hours, the reaction mixture was poured into ice/5% HCl and the mixture was extracted with hexane. The organic layer was washed each twice with water, aqueous sodium hydrogen carbonate, and then with water, dried over MgSO4, and the solvent was removed by evaporation. The residue was distilled to give 5,6,7,8-tetrahydro-2,5,5,8,8-pentamethylnaphthalene (70.42 g, yield: 90%). bp 100° C. (solidified at room temperature).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[N+:15]([O-])([OH:17])=[O:16].S(=O)(=O)=O.S(=O)(=O)(O)O>>[Cl:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl

Procedure:
dinitrating said 4-chloro-3-nitrobenzotrifluoride organic layer with a fresh acid mixture of nitric acid, sulfur trioxide, and sulfuric acid to form 4-chloro-3,5-dinitrobenzotrifluoride product, and a partially spent acid mixture containing a portion of said product dissolved therein, said fresh acid mixture containing sufficient nitric acid to effect said nitration and to provide for said mononitration upon recycling of said partially spent acid mixture back to step (a),
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O.C1(C)C=CC=CC=1>CN(C)C=O>[C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Yield: 91 %

Procedure:
4-Benzoylbenzoic acid (BBA), 1.0 kg (4.42 moles), was added to a dry 5 liter Morton flask equipped with reflux condenser and overhead stirrer, followed by the addition of 645 ml (8.84 moles) of thionyl chloride and 725 ml of toluene. Dimethylformamide, 3.5 ml, was then added and the mixture was heated at reflux for 4 hours. After cooling, the solvents were removed under reduced pressure and the residual thionyl chloride was removed by three evaporations using 3×500 ml of toluene. The product was recrystallized from 1:4 toluene:hexane to give 988 g (91% yield) after drying in a vacuum oven. Product melting point was 92-94° C. Nuclear magnetic resonance (NMR) analysis at 80 MHz (1H NMR (CDCl3)) was consistent with the desired product: aromatic protons 7.20-8.25 (m, 9H). All chemical shift values are in ppm downfield from a tetramethylsilane internal standard. The final compound was stored for use in the preparation of a monomer used in the synthesis of photoactivatable polymers as described, for instance, in Example 3.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]([C:26]4[CH:31]=[C:30]([NH:32][CH:33]5[CH2:35][CH2:34]5)[N:29]=[C:28]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=5)[CH:27]=4)[CH:23]=[N:24][CH:25]=3)=[CH:16][CH:15]=2)[CH2:9]1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[C:22]([C:26]4[CH:31]=[C:30]([NH:32][CH:33]5[CH2:34][CH2:35]5)[N:29]=[C:28]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=5)[CH:27]=4)[CH:23]=[N:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2ccc(-c3cncc(-c4cc(NC5CC5)nc(-c5ccccn5)c4)c3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCN(Cc2ccc(-c3cncc(-c4cc(NC5CC5)nc(-c5ccccn5)c4)c3)cc2)C1

Procedure:
A solution of {(R)-1-[4-(6′-cyclopropylamino-[2,2′;4′,3″]terpyridin-5″-yl)-benzyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (step 1) (1 eq, 0.204 mmol, 115 mg) in DCM/TFA (1 ml of a 3:1 mixture) is stirred at room temperature for 30 mins. The solvent is reduced in vacuo and the residue is purified by preparative HPLC (C18, 0-100% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH and 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 463.
Reaction SMILES: [CH3:1][C:2](=[CH:4][C@H:5]([OH:10])[C@H:6]([OH:9])[CH2:7][CH3:8])[CH3:3].[C:11]1(C)[CH:16]=CC(S(O)(=O)=O)=C[CH:12]=1.COC(OC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:12][C:11]1([CH3:16])[O:10][C@@H:5]([CH2:4][CH:2]([CH3:3])[CH3:1])[C@@H:6]([CH:7]=[CH2:8])[O:9]1
Reactant: CC[C@@H](O)[C@@H](O)C=C(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: COC(C)(C)OC
Product: C=C[C@H]1OC(C)(C)O[C@H]1CC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the crude alcohol resulting from Example 9A dissolved in dichloromethane was added p-toluenesulfonic acid (500 mg) and 2,2-dimethoxypropane. The reaction was stirred at ambient temperature for 24 hours and poured into saturated sodium bicarbonate solution. The organic phase was separated, dried over magnesium sulfate and concentrated by distillation to give the title compound. 1H NMR (CDCl3, 300 MHz) δ0.92 (d, J=6 Hz, 3H), 0.96 (d, J-6 Hz, 3H), 1.17 (ddd, J=4.5, 9.0, 15 Hz, 1H), 1.38 (s, 3H), 1.48 (s, 3H), 1.75 (m, 1H), 4.24 (ddd, J=3, 6, 9 Hz, 1H), 4.48 (m, 1H), 5.22 (ddd, J=1, 2, 9 Hz, 1H), 5.27 (ddd, J=1, 2, 17 Hz, 1H), 5.81 (ddd, J=7.5, 9, 17 Hz, 1H).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:6][C:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:4][N:3]=1.[O:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[N:41]1[C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([NH2:50])[C:44]=2[CH:43]=[N:42]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][O:25][CH2:24][C:5]2[CH:6]=[C:7]([C:8]3[N:16]=[C:15]([CH3:17])[N:14]=[C:13]4[C:9]=3[N:10]=[CH:11][N:12]4[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:2]([NH:50][C:45]3[C:44]4[CH:43]=[N:42][N:41]([CH:36]5[CH2:37][CH2:38][CH2:39][CH2:40][O:35]5)[C:49]=4[CH:48]=[CH:47][CH:46]=3)=[N:3][CH:4]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(COCc2cnc(F)c(-c3nc(C)nc4c3ncn4C3CCCCO3)c2)cc1
Reactant: Nc1cccc2c1cnn2C1CCCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(COCc2cnc(Nc3cccc4c3cnn4C3CCCCO3)c(-c3nc(C)nc4c3ncn4C3CCCCO3)c2)cc1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 77.2 %

Procedure:
6-(2-Fluoro-5-((4-methoxybenzyloxy)methyl)pyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (1.223 g, 2.634 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (0.596 g, 2.74 mmol) were dissolved in THF (23.5 mL) and the flask was cooled in an ice water bath under nitrogen. Then, LiHMDS (1.0 M in THF, 7.8 mL, 7.8 mmol) was added via syringe, and the reaction was stirred under nitrogen at 0° C. for 35 minutes. Then, the reaction was quenched with water (40 mL) and diluted with water (40 mL), and then extracted with DCM and with 10:1 DCM/MeOH. Brine was added to break up emulsions. The organic extracts were combined, concentrated, and purified on a silica gel filter (about 3 inches, 50:1 DCM/2N ammonia in MeOH to 40:1 DCM/2N ammonia in MeOH) to afford N-(5-((4-methoxybenzyloxy)methyl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (1.343 g, 54% purity, 43% yield). MS (ESI pos. ion) m/z 661 (M+H)+.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:9]2[S:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:24][CH:23]=3)=[C:12]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[O:14])[C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH3:36]I.O>CS(C)=O>[CH3:36][O:3][C:4]1[C:9]2[S:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:24][CH:23]=3)=[C:12]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[O:14])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: O=C(c1ccc(F)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2c(O)cccc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc2c(C(=O)c3ccc(F)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc12
Reaction time: 1.5 h
Yield: 28.7 %

Procedure:
To a suspension of powdered KOH (177 mg, 3.15 mmol) in 1.6 mL of dry DMSO was added 4-fluorophenyl 7-hydroxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone (350370) (Example 75, Part G) (364 mg, 0.788 mmol) at room temperature. The reaction mixture turned orange in color. To the alkoxide was added slowly methyl iodide (49 μL, 0.79 mmol) over a period of 15 min. The reaction mixture was then stirred for 1.5 h. Another portion of MeI (20 μL, 0.32 mmol) was added, stirred for 1.5 h., followed by another addition of 20 μL (0.32 mmol) of MeI and stirring for an additional 30 min at room temperature. The reaction mixture was then poured into 20 mL of H2O. This mixture was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with H2O (5×10 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was then purified by flash chromatography (silica gel, 4%[10% NH4OH in MeOH]/CH2Cl2) to afford 108 mg (0.226 mmol, 29%) of a white foam.
Reaction SMILES: Cl.[F:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[C:10]([C:24]#[N:25])[C:9]2=[O:26])=[CH:5][CH:4]=1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31].C(NC(C)C)(C)C>ClCCl>[C:29]([N:21]1[CH2:20][CH2:19][N:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:28][CH:27]=3)[C:9](=[O:26])[C:10]=2[C:24]#[N:25])[CH2:23][CH2:22]1)(=[O:32])[CH:30]=[CH2:31]
Reactant: N#Cc1c(N2CCNCC2)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: C=CC(=O)N1CCN(c2c(C#N)c(=O)n(Cc3ccc(F)cc3)c3ccccc23)CC1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-(4-Fluoro-benzyl)-2-oxo-4-piperazin-1-yl-1,2-dihydro-quinoline-3-carbonitrile hydrochloride salt (1 eq, 0.150 g, 0.41 mmole) in dichloromethane at −10° C. was added acryloyl chloride (1.1 eq, 0.054 g, 0.45 mmole) followed by the addition of diisopropylamine (1.5 eq, 0.083 g, 0.62 mmole, 0.103 mL). The resulting solution stirred at 10° C. for 1 hour then warmed to RT and stirred for an additional 2 hours. The reaction was quenched into ice cooled water and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 4-(4-Acryloyl-piperazin-1-yl)-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile as a yellow solid (0.043 g, 25% calc M+H 417, obs M+H 417).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].CI.[C:14](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([O:10][CH3:14])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Cc1cc(F)cc(C=O)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C)cc(F)cc1C=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5-Fluoro-2-hydroxy-3-methylbenzaldehyde (1.24 g, 8.01 mmol) was dissolved in N,N-dimethylformamide (20 mL) and to the solution was added methyl iodide (0.8 mL, 12.71 mmol) and potassium carbonate (3.1 g, 22.52 mmol). The mixture was stirred at 100° C. for one hour, cooled to room temperature and then diluted with water (40 mL). After extraction twice with ethyl acetate (40 mL) the combined organic layer was washed with brine and then dried over Na2SO4. The solvent was removed and the solid residue was treated with methanol. After filtration and drying desired compound was obtained 1.2 g (99%). 1H NMR (400 MHz, CDCl3): δ10.12 (s, 1H), 7.23 (dd, 1H), 6.85 (dd, 1H), 3.75 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([C:12]2[N:24]([CH3:25])[C:15]3=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=[C:14]3[N:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C=O)C.[CH2:31]([S-:33])[CH3:32].[Na+]>O>[CH2:31]([S:33][C:2]1[C:3]([C:12]2[N:24]([CH3:25])[C:15]3=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=[C:14]3[N:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[CH3:32]
Reactant: Cn1c(-c2ncc(C(F)(F)F)cc2Cl)nc2cc(C(F)(F)F)cnc21
Reactant: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cc(C(F)(F)F)cnc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.71 g) and DMF (4 ml) was added sodium ethanethiolate g) while ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-(3-ethylsulfanyl-5-trifluoromethylpyridin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.76 g), which is hereinafter referred to as “the present compound 4”.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[OH:6][CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[Br:1][CH2:2][C:3]([O:6][CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: O=C(Cl)CBr
Reactant: OCc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(CBr)OCc1cccs1
Yield: 48 %

Procedure:
A solution of bromoacetyl chloride (60 mmol) and 2-hydroxymethylthiophene (60 mmol) in benzene (100 ml) was heated under reflux for 90 min, the cold solution shaken with saturated NaHCO3 aq., the dried (MgSO4) solution evaporated and the residue fractionally distilled; yield 48%, b.p. 96° C./0.05 mmHg. 1H NMR (CDCl3) δ3.80 (CH2), 5.30 (OCH2), 7.00 and 7.26 (thiophene).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][NH:12][CH2:13][CH2:14][C:3]1=2.[C:15](#[N:18])[CH:16]=[CH2:17]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].CC(O)C>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][N:12]([CH2:17][CH2:16][C:15]#[N:18])[CH2:13][CH2:14][C:3]1=2
Reactant: Cn1c2c(c3ccccc31)CNCC2
Reactant: C=CC#N
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: CC(C)O
Product: Cn1c2c(c3ccccc31)CN(CCC#N)CC2
Yield: 86.6 %

Procedure:
A mixture of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indole (0.07 mol), acrylonitrile (0.14 mol) and Aliquat 336 (3 drops) in 2-propanol (150 ml) was stirred and refluxed for 30 minutes. The reaction mixture was cooled on an ice-bath and the resulting precipitate was filtered off, washed with diisopropyl ether (50 ml) and dried, yielding 14.5 g (87%) of 1,3,4,5-tetrahydro-5-methyl-2H-pyrido[4,3-b]indole-2-propanenitrile (intermediate 15).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:33])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH:29]3[CH2:32][CH2:31][CH2:30]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH2:25][CH:26]2[CH2:28][O:27]2)[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].[Na].[NH:35]1[CH:39]=[N:38][CH:37]=[N:36]1>CN(C=O)C>[CH:1]([O:4][C:5](=[O:33])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH:29]3[CH2:30][CH2:31][CH2:32]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH2:25][CH:26]([OH:27])[CH2:28][N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[CH:16]=3)=[CH:9][CH:8]=1)([CH3:2])[CH3:3]
Reactant: c1nc[nH]n1
Reactant: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCC4CO4)cc3n2C2CCC2)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCC(O)Cn4cncn4)cc3n2C2CCC2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a solution of [4-(3-cyano-1-cyclobutyl-6-oxiranylmethoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (40 mg, 0.09 mmole) in DMF (1 mL) is added the sodium salt of 1,2,4-triazole (30 mg). The resulting mixture is stirred at 60° C. overnight. The solvent is removed under reduced pressure and the residue is diluted with ethyl acetate and then washed with water. The organic layer is concentrated and triturated with hexane. The precipitate is collected by filtration and washed well with 1/1 ethyl acetate/hexane and dried in vacuo to afford {4-[3-cyano-1-cyclobutyl-6-(2-hydroxy-3-[1,2,4]triazol-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester, compound 1420, (29 mg, 63%).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:9])=[O:5].[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>ClCCl>[Br:30][C:27]1[CH:28]=[CH:29][C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[C:3]([CH:26]=1)[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH2:16][CH2:17]1)=[O:9])=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(Br)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 4-[{N-(2-amino-5-bromobenzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)piperidine (25 mg, 0.05 mmol), methanesulfonyl chloride (0.0045 mL), triethylamine (0.026 mL) and dichloromethane (2 mL) was stirred at room temperature for 17 h. The reaction mixture was purified with column chromatography (SiO2), loaded onto Varian™ SAX column, and washed with CH3OH (5 mL). Product was eluted off using 0.1 N HCl in CH3OH (5 mL) and concentrated to afford 4-[{N-(5-bromo-2-(methylsulfonylamino)benzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)piperidine (Compound No. 1581) (5.4 mg, 19%): ESI/MS m/e 573.0 (M++H, C23H28BrClN4O4S).
Reaction SMILES: [C-:1]#[N:2].[Na+].[I:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1>CS(C)=O.O>[I:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:1]#[N:2])=[CH:7][CH:6]=1
Reactant: BrCc1ccc(I)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.1 %

Procedure:
A mixture of 4.36 g (20.0 mmol) of p-iodotoluene (purchased from Tokyo Kasei), 3.9 g (22 mmol) of N-bromosuccinimide (purchased from Tokyo Kasei) and 60 ml of carbon tetrachloride (purchased from Wako Junyaku Kogyo) was refluxed under the irradiation by means of an incandescent lamp for 4 hours to give 2.67 g (yield: 45.0%) of 4-iodobenzyl bromide (as a white crystalline). Subsequently, to 0.49 g (10 mmol) of sodium cyanide (purchased from Kokusan Kagaku) in 10 ml of dimethyl sulfoxide (purchased from Aldrich) solution heated at 50° C. was added 1.48 g (5.00 mmol) of the above 4-iodobenzyl bromide, the mixture was stirred at ambient temperature for 3 hours, the resultant reaction mass was dissolved in water and extracted with hexane, and hexane was removed to give 0.84 g (yield: 68.9%) of 4-iodophenylacetonitrile as a white crystalline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](O)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Solvent: CO
Solvent: C1CCOC1
Product: OCC1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C

Procedure:
To a solution of 1 g 1-(4-Chloro-phenyl)-cyclobutanecarboxylic acid in 15 ml THF were added dropwise at 0° C. 9.5 ml BH3*THF in THF (1M). Then the reaction mixture was heated at reflux for 2 h and then cooled again to 0° C. followed by cautious addition of 30 ml methanol. After evaporation of the solvents the residue was codestilled twice with toluene. The crude product was subjected to the subsequent reaction without further purification.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.O>N1C=CC=CC=1>[C:18]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=C(CC1CCCCC1)c1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(CC1CCCCC1)c1ccc(OC(=O)c2cccnc2)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
11 g (50 mmol) of p-cyclohexylacetylphenol and 9.6 g (54 mmol) of nicotinic acid chloride hydrochloride was mixed with 160 ml of dry pyridine and stirred for 8 hours at 40° C. Subsequently, water (66 ml) was added drop by drop until the solution was turbid. The solution was placed in the ice bath, the precipitate sucked off, freed from pyridine by washing with water and dried.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22].C1C(=O)N([I:30])C(=O)C1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.CS(O)(=O)=O.S1(CCCC1)(=O)=O>CN(C)C(=O)C.CN(C)C=O.CN1C(=O)N(C)CCC1.CN(P(N(C)C)(N(C)C)=O)C.CS(C)=O.CCOCC.C(O)(=O)C.C(O)=O>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:30])=[CH:18][C:17]=1[F:22]
Reactant: COC(=O)c1cc2scnc2c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1I
Agent: CS(=O)(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F

Procedure:
Methyl 4-fluoro-5((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylate can be reacted with halogenations reagent (such as NIS) in the presence of acid (such as trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, formic acid, acetic acid) at ambient temperature in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer N,N-dimethylformamide and N,N-dimethylacetamide) for some time (1-12 h, prefer 3-10 h). Methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylate is obtained after conventional workup.