Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[N+:18]([O-:20])=[O:19].CCOC(C)=O>CN(C=O)C>[F:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]=1[N+:18]([O-:20])=[O:19]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1c(F)cccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
252 mg of sodium hydride as a 60% suspension in oil (6.29 mmol) are placed in a 50 mL three-necked flask containing 10 mL of DMF and 0.592 g of phenol. The mixture is stirred at room temperature for 1 hour and a solution of 2,6-difluoronitrobenzene 47 (1.0 g, 6.29 mmol) in 10 mL of DMF is added. The reaction medium is left at room temperature for 24 hours. 50 mL of EtOAc are added and the mixture is washed twice with 20 mL of distilled water. The organic phase is dried over MgSO4, filtered and finally evaporated to dryness. The crude product is chromatographed on a silica cartridge (120 g) eluting with heptane/EtOAc (as an EtOAc gradient: 0 to 50%). 1.07 g of expected product 57 are obtained (yellow oil).
Reaction SMILES: [C:1]1([C:7]2[C:21]3[C:20]4[C:22]5[C:16]([CH:17]=[CH:18][CH:19]=4)=[C:15](B(O)O)[CH:14]=[CH:13][C:12]=5[C:11]=3[C:10]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:9]3[CH:32]=[CH:33][CH:34]=[CH:35][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([Br:47])[CH:43]=2)[CH:38]=1>>[Br:47][C:42]1[CH:43]=[C:44]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37]([C:15]1[CH:14]=[CH:13][C:12]3=[C:22]4[C:16]=1[CH:17]=[CH:18][CH:19]=[C:20]4[C:21]1[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[C:8]4[CH:35]=[CH:34][CH:33]=[CH:32][C:9]4=[C:10]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:11]=13)[CH:46]=[CH:45]2
Reactant: Brc1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1ccc2c3c(cccc13)-c1c-2c(-c2ccccc2)c2ccccc2c1-c1ccccc1
Product: Brc1ccc2cc(-c3ccc4c5c(cccc35)-c3c-4c(-c4ccccc4)c4ccccc4c3-c3ccccc3)ccc2c1

Procedure:
It was carried out in a similar manner as Synthesis Example 1 except that 7,12-diphenylbenzo[k]fluoranthene-3-yl boronic acid was employed instead of 9,9-dimethyl-911-fluorene-2-yl boronic acid, and that 2,6-dibromo-naphthalene was employed instead of 3-bromo-7,12-dibenzo[k]fluoranthene in Synthesis Example 1 to obtain 3-(6-bromonaphthalen-2-yl)-7,12-diphenylbenzo[k]fluoranthene.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([F:32])[CH:31]=1)[C:28](=[O:33])[CH2:27][CH2:26]2>CO>[F:21][CH:27]1[CH2:26][C:25]2[C:29](=[C:30]([F:32])[CH:31]=[C:23]([F:22])[CH:24]=2)[C:28]1=[O:33]
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: O=C1CCc2cc(F)cc(F)c21
Agent: F[B-](F)(F)F
Solvent: CO
Product: O=C1c2c(F)cc(F)cc2CC1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Selectfluor™ (1.16 g, 3.27 mmol) was added to a solution of 5,7-difluoro-1-indanone (CAS No. 84315-25-3, 500 mg, 2.97 mmol) in MeOH (20 mL) at room temperature. The mixture was refluxed for 2 hours and cooled to room temperature. Then the solvent was distilled off under reduced pressure. The residue was treated with DCM and the insoluble matter was filtered off. Then the solvent was distilled off under reduced pressure. The residue was dissolved in MeCN (10 mL) and 5 N HCl (5 mL). The solution was stirred at room temperature for 1 hour, and then concentrated in vacuo. The residue was partitioned between AcOEt and H2O. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to afford the title compound (547 mg, 2.94 mmol). 1H NMR (400 MHz, CDCl3)
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:12])=[CH:7][CH:8]=2)[N:3]=1.[NH3:13].CO>>[Cl:12][C:6]1[CH:5]=[C:4]2[C:9]([N:10]=[CH:11][C:2]([NH2:13])=[N:3]2)=[CH:8][CH:7]=1
Reactant: Clc1ccc2ncc(Cl)nc2c1
Reactant: N
Solvent: CO
Product: Nc1cnc2ccc(Cl)cc2n1
Yield: 98 %

Procedure:
At T=120° C., 30.0 g (60.0 mmol) of 2,7-dichloroquinoxaline are stirred in 400 ml of NH3/MeOH (w=22%) for 16 hours. The mixture is then evaporated to dryness under reduced pressure, and the residue is taken up in 250 ml of dichloromethane and 250 ml of water. After phase separation, the organic phase is then washed with 250 ml of water and dried over sodium sulphate, and the solvent is removed under membrane pump vacuum. The residue obtained is purified by column chromatography on silica gel (ethyl acetate/petroleum ether=1:5; silica gel: 200-300 mesh), which gives 10.5 g of 7-chloroquinoxalin-2-ylamine (yield 98%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].Br[CH2:20][C:21]([NH2:23])=[O:22].O>CN(C=O)C>[O:13]=[C:12]1[C:11]2[C:10](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:18])[N:8]1[O:7][CH2:20][C:21]([NH2:23])=[O:22]
Reactant: NC(=O)CBr
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
Potassium carbonate (2.67 g, 19.31 mmol) was added to a solution of N-hydroxyphthalimide (3.0 g, 18.39 mmol) in anhydrous DMF (37 mL) at 0° C. The reaction mixture was stirred at 0° C. for 10 min and then at room temperature for 1 h. The reaction mixture was cooled to 0° C. and 2-bromoacetamide (2.79 g, 20.23 mmol) was added. The reaction mixture was stirred at 0° C. for 10 min and then at room temperature overnight. The reaction mixture was poured into rapidly stirring water and the precipitated solid was collected by filtration and dried to afford 2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]acetamide (2.0 g, 49%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ4.63 (2H, s), 7.85-7.88 (4H, m); ESI MS m/z 221 [C10H8N2O4+H]+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Br.[Cl:16][C:17]1[CH:18]=[C:19]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[O:20][C:21]1[C:22]([CH3:28])=[N:23][NH:24][C:25]=1[CH2:26][NH2:27].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>C(O)(=O)C.ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[O:20][C:21]1[C:22]([CH3:28])=[N:23][NH:24][C:25]=1[CH2:26][NH:27][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=1
Reactant: Cc1n[nH]c(CN)c1Oc1cc(Cl)cc(Cl)c1
Reactant: O=Cc1ccc(F)cc1
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1n[nH]c(CNCc2ccc(F)cc2)c1Oc1cc(Cl)cc(Cl)c1
Reaction time: 3 h
Yield: 19.7 %

Procedure:
Sodium triacetoxyborohydride (36 mg, 0.160 mmol) was added in one portion to a stirred solution of the pyrazole of Example 109 (150 mg, 0.400 mmol), 4-fluorobenzaldehyde (11 mg, 0.080 mmol) and acetic acid (3 drops) in dichloromethane (15 ml) at room temperature under nitrogen. The reaction was stirred for 3 hours and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (90:9:1, by volume) to provide the title compound (6 mg) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9].Cl.[Br:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH2:24]Cl)[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[Br:17][C:18]1[CH:23]=[C:22]([CH2:24][N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[CH:21]=[N:20][CH:19]=1
Reactant: ClCc1cncc(Br)c1
Reactant: CC(C)CNS(=O)(=O)c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)CN(Cc1cncc(Br)c1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 10, step 3, 2-chloro-N-isobutyl-benzenesulfonamide (example 42, step 1) was reacted with 3-bromo-5-(chloromethyl)pyridine hydrochloride and cesium carbonate in N,N-dimethylacetamide to give N-(5-bromo-pyridin-3-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide as a colorless oil. MS: 417.2 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH3:18][C:19]1[CH:23]=[C:22]([CH2:24][C:25](Cl)=[O:26])[O:21][N:20]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:18][C:19]1[CH:23]=[C:22]([C:24]2[C:25](=[O:26])[NH:1][C:2]3[C:3]([C:4]=2[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:12][C:13]([CH:16]=[CH2:17])=[CH:14][CH:15]=3)[O:21][N:20]=1
Reactant: C=Cc1ccc(N)c(C(=O)c2ccccc2)c1
Reactant: Cc1cc(CC(=O)Cl)on1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1ccc2[nH]c(=O)c(-c3cc(C)no3)c(-c3ccccc3)c2c1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A mixture of 2-amino-5-vinylbenzophenone (c) (0.1 g, 0.45 mmol), (3-methyl-isoxazol-5-yl)-acetyl chloride (0.9 mmol) [from example 4], triethylamine (0.20 mL) and DCM (10 mL) was heated to reflux overnight. After the mixture was cooled to room temperature and concentrated, the residue was purified by flash chromatography on silica gel (5% methanol in DCM) to give 3-(3-methyl-isoxazol-5-yl)-4-phenyl-6-vinyl-1H-quinolin-2-one (d) (0.12 g, 81%). 1H NMR (300 MHz, CDCl3) 8 12.68 (s, 1H), 7.74-7.65 (m, 1H), 7.52-7.41 (m, 4H), 7.30-7.13 (m, 3H), 6.58 (dd, J=11, 19.6 Hz, 1H), 6.45 (s, 1H), 5.62 (d, J=19.6 Hz, 1H), 5.18 (d, J=11 Hz,1H), 2.27 (s, 3H). MS: 329.2 (M+H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9](F)=[C:8]2[C:3]=1[CH:4]=[C:5]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[N:6]=[CH:7]2.[F:21][C:22]([F:36])([F:35])[O:23]C1C=C2C(C=C(O)N=C2)=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.CCN(CC)CC>C(Cl)Cl>[F:21][C:22]([F:36])([F:35])[O:23][C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[C:5]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[N:6]=[CH:7]2)=[CH:2][CH:11]=1
Reactant: O=S(=O)(Oc1cc2c(Cl)ccc(F)c2cn1)C(F)(F)F
Reactant: Oc1cc2ccc(OC(F)(F)F)cc2cn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Oc1cc2ccc(OC(F)(F)F)cc2cn1)C(F)(F)F

Procedure:
By following the procedure for the preparation of trifluoromethanesulfonic acid 5-chloro-8-fluoroisoquinolin-3-yl ester, the title compound was prepared from 7-trifluoromethoxyisoquinolin-3-ol (0.98 g, 4.3 mmol), triflic anhydride (0.17 mL, 1.0 mmol), NEt3 (0.8 mL, 3.0 mmol) and CH2Cl2 (10 mL). 1H NMR (CDCl3, 300 MHz): δ=7.63 (s, 1H), 7.65 (d, J=6.0 Hz, 1H), 7.89 (s, 1H), 7.98 (d, J=9.0 Hz, 1H), 9.10 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[O-:18][C:19]#[N:20].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:19]([NH2:20])=[O:18])=[CH:11][CH:12]=1
Reactant: COc1ccc(Nc2ccc(OC)cc2)cc1
Reactant: N#C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(N(C(N)=O)c2ccc(OC)cc2)cc1

Procedure:
A solution of 423 mg (1.85 mmol) bis-(4-methoxy-phenyl)-amine in 8 ml acetic acid is treated with 120 mg (1.85 mmol)sodium cyanate. After 4.5 h the reaction mixture is poured onto a solution of 8 g sodium hydroxide in 100 ml water. The resultant precipitate is filtered off and dried.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[C:5]([O:20][CH3:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>>[C:15]([CH2:14][CH:13]([N:11]1[CH:12]=[C:8]([C:6]2[C:5]([O:20][CH3:21])=[CH:4][N:3]=[C:2]([NH:22][C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=[O:27])[N:7]=2)[CH:9]=[N:10]1)[CH:17]1[CH2:19][CH2:18]1)#[N:16]
Reactant: COc1cnc(Cl)nc1-c1cnn(C(CC#N)C2CC2)c1
Reactant: Nc1cccc(C(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: COc1cnc(Nc2cccc(C(=O)O)c2)nc1-c1cnn(C(CC#N)C2CC2)c1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A mixture of 3-[4-(2-chloro-5-methoxypyrimidin-4-yl)-1H-pyrazol-1-yl]-3-cyclopropylpropanenitrile (from example 320 step 1, 250 mg, 0.00082 mol), 3-aminobenzoic acid (169 mg, 0.00123 mol), and p-toluenesulfonic acid (120 mg, 0.00070 mol) in dry 1,4-dioxane (5 mL, 0.07 mol) was refluxed overnight, then cooled to room temperature. The insoluble material was filtered off. The filtration was evaporated to dryness to give the crude product (330 mg, 99.14%). LCMS (M+H) 405.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:16])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of 4-(1-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (18.24 g, 79.54 mmol) in dichloromethane (400 mL) and triethylamine (12.20 mL, 87.49 mmol) at 0° C. is added methanesulfonyl chloride (9.23 mL, 119.30 mmol). The reaction is allowed to warm to room temperature over 16 h. The mixture is washed with 0.1 M hydrochloric acid, saturated aqueous sodium bicarbonate, water, and brine. The material is dried over magnesium sulfate, filtered, and concentrated to dryness. The crude material is purified by flash chromatography over silica gel to afford 22.65 g of the title compound as a colourless oil. 1H NMR (CDCl3) δ (ppm): 1.19-1.30 (m, 2H), 1.39 (d, 3H), 1.44 (s, 9H), 1.6-1.8 (m, 3H), 2.66 (m, 2H), 2.99 (s, 3H), 4.16 (m, 2H), 4.62 (t, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:10][C:9]=2[O:26][CH2:27][CH3:28])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>CN(C)C=O>[NH2:24][C:21]1[N:20]=[C:19]([NH2:25])[C:18]([CH2:17][C:11]2[CH:12]=[C:13]([O:14][CH2:15][CH3:16])[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[CH:3]=3)=[C:9]([O:26][CH2:27][CH3:28])[CH:10]=2)=[CH:23][N:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1cccc(N)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1cccc(NS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5-(3′-Amino-2,6-diethoxy-biphenyl-4-ylmethyl)-pyrimidine-2,4-diamine (228 mg; 0.6 mmol) is dissolved in dimethylformamide (6 ml; dried over a molecular sieve), triethylamine (0.090 ml; 0.66 mmol) is added at room temperature, and the mixture is cooled to 0° C. and a solution of methanesulphonyl chloride (0.051 ml; 0.66 mmol) in dimethylformamide (1.0 ml) is added in the course of 5 minutes. After 1 hour at 0-5° C. the reaction mixture is concentrated and the residue is taken up in water, after which the pH is adjusted to 10 by addition of NH4OH conc. After stirring for 15 minutes the mixture is filtered with suction and the residue is dried under a high vacuum and chromatographed over silica gel (60 g) with methylene chloride/methanol/NH4OH conc. (19/1/0.05).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.[CH:9]1([C:12]2[CH:13]=[C:14]([CH3:33])[C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=4)=[O:25])[CH2:20][CH2:19]3)=[N:16][CH:17]=2)[CH2:11][CH2:10]1>>[CH:9]1([C:12]2[CH:13]=[C:14]([CH3:33])[C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4[CH:31]=[CH:30][C:29]([N:4]5[CH2:3][C@@H:2]([CH3:1])[CH2:6][S:5]5(=[O:8])=[O:7])=[CH:28][CH:27]=4)=[O:25])[CH2:20][CH2:19]3)=[N:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Reactant: C[C@@H]1CNS(=O)(=O)C1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C[C@@H](C)CS3(=O)=O)cc2)CC1
Yield: 34.4 %

Procedure:
Using (R)-4-methylisothiazolidine 1,1-dioxide (91 mg) described in Preparation Example 7 and [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (200 mg) described in Preparation Example 117 and by the reaction and treatment in the same manner as in Example 1, the title compound (70 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][NH:13][C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])[CH:6]=[CH:5]2.Br[CH2:36][C:37]#[N:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:37]([CH2:36][O:1][C:2]1[C:3]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][NH:13][C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])[CH:6]=[CH:5]2)#[N:38]
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccccc3)c(O)ccc2c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccccc3)c(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid (6-hydroxy-5-phenyl-naphthalen-2-ylmethyl)-amide (366 mg, 0.813 mmol), prepared in the previous step, bromoacetonitrile (68 μL, 0.976 mmol) and potassium carbonate (562 mg, 4.07 mmol) in 20 mL of DMF was stirred under nitrogen at room temperature for 23 h (overnight). The reaction was diluted with ethyl acetate, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give a brown solid. Purification of the solid on 20 g of silica gel (230-400 mesh) using hexane-ethyl acetate as the eluent gave 2-butyl-benzofuran-3-carboxylic acid (6-cyanomethoxy-5-phenyl-naphthalen-2-ylmethyl)-amide (342 mg, 86%) as a light brown solid, mp 135-138° C.
Reaction SMILES: ClC1C=CC=CC=1C([NH:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])[N:10]=[C:9]([CH3:21])[C:8]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])=O.Br.O>C(O)(=O)C>[NH2:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])[N:10]=[C:9]([CH3:21])[C:8]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29]
Reactant: Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(NC(=O)c2ccccc2Cl)c1C(=O)c1ccccc1Cl
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(=O)c1ccccc1Cl

Procedure:
A solution of 1.94 g (3.50 mmol of the product of Step B in 20 mL of glacial acetic acid was treated with 20 mL of 48% hydrogen bromide and stirred at reflux for 8 hours. The cooled reaction mixture was treated with water to crystallize the product which was separated by filtration, washed with water and air dried to give the title product, 1.45 g (100%), m.p. softens about 210° C. and melts at 222° C. Anal. Calcd. for C17H11ON3Cl4: 412.9656. Found: 412.9722.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[C:10]1[C:15]([CH2:16][CH2:17][OH:18])=[C:14]([I:19])[CH:13]=[CH:12][N:11]=1>O1CCOCC1>[I:19][C:14]1[CH:13]=[CH:12][N:11]=[C:10]2[O:18][CH2:17][CH2:16][C:15]=12
Reactant: OCCc1c(I)ccnc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Ic1ccnc2c1CCO2

Procedure:
Potassium phosphate (10.0 g, 47.1 mmol) was added to a solution of 2-(2-fluoro-4-iodopyridin-3-yl)ethanol (3.13 g, 11.7 mmol) in 1,4-dioxane (100 mL). The mixture was heated under reflux for 36 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc. The combined filtrates were concentrated under reduced pressure. The residue was dissolved in DCM (100 mL), washed with brine (2×100 mL), dried over Na2SO4 and concentrated under reduced. The resulting residue (2.55 g) containing the sub-title compound was used in the next step directly without further purification. LCMS calc. for C7H7INO (M+H)+: m/z=247.9. found 248.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[N:12][NH:13][N:14]=2)[N:7]=[C:6]([NH:15][C@H:16]([CH2:18][CH3:19])[CH3:17])[CH:5]=1.F[B-](F)(F)F.[CH3:26][O+](C)C>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[N:12][N:13]([CH3:26])[N:14]=2)[N:7]=[C:6]([NH:15][C@H:16]([CH2:18][CH3:19])[CH3:17])[CH:5]=1
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(-c2nn[nH]n2)n1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(-c2nnn(C)n2)n1

Procedure:
Treat a solution of (S)-2-sec-butylamino-6-(2H-tetrazol-5-yl)-isonicotinic acid methyl ester (350 mg, 1.26 mmol) in ethyl acetate (8 mL) with trimethyloxonium tetrafluoroborate at room temperature for 3 h. Dilute with ethyl acetate (50 mL) and wash with saturated sodium bicarbonate and saturated aqueous sodium chloride. Dry (sodium sulfate) and concentrate to give the title compound which is used directly in the next step without further purification.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[CH2:13][CH2:12]1)=[O:9].[OH-].[Li+].O1CCCC1.Cl>O>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:15][CH2:16]1)=[O:9]
Reactant: COC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Yield: 100 %

Procedure:
A stirred solution of the product of Step (a) (902 mg, 2.37 mmol) and lithium hydroxide (171 mg, 7.11 mmol) in a 50% mixture of tetrahydrofuran (12 mL) and water (12 mL) was heated at 30° C. overnight and then acidified with concentrated hydrochloric acid. The resulting'mixture was lyophilized to give the title compound (˜100% yield, containing some lithium chloride).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[OH:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:4]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC1CCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OC1CCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.1 %

Procedure:
To a stirred suspension of 1.37 g (10.0 mmol) of 3-hydroxypiperidine hydrochloride and 2.53 g (3.5 mL) of triethylamine in 30 mL of dichloromethane at 0° C. was added dropwise 2.93 g (10.5 mmol) of trityl chloride. The mixture was stirred at ambient temperature overnight, diluted with 100 mL of dichloromethane, washed sequentially with water, 5% aqueous citric acid solution, saturated sodium bicarbonate solution, and brine, dried over sodium sulfate, and concentrated to give 3.85 g of the title compound as a white foam.