Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([OH:26])=[CH:10][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:12][C:13]=2[O:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.[CH:27]([S:31](Cl)(=[O:33])=[O:32])([CH2:29][CH3:30])[CH3:28]>>[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][S:31]([CH:27]([CH2:29][CH3:30])[CH3:28])(=[O:33])=[O:32])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(O)c1-c1cccc(N)c1
Reactant: CCC(C)S(=O)(=O)Cl
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C(C)CC)c1-c1cccc(N)c1
Yield: 67.4 %

Procedure:
Starting from 3′-amino-4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-biphenyl-2-ol (176 mg; 0.50 mmol) and sec-butyl-sulphonyl chloride (94 mg; 0.60 mmol), 159 mg of the title compound are isolated as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]2[N:7]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=4)[CH:25]=3)[CH2:21][C:20](=[O:37])[NH:19][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(C(F)(F)F)c(Cl)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M91) (0.36 g, 0.66 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (250 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccccc1Cl

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 2-chlorobenzoic acid to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 343.1 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[C:24]1([C@H:30]2[CH2:35][NH:34][CH2:33][CH2:32][NH:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:34]4[CH2:33][CH2:32][NH:31][C@@H:30]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:35]4)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: c1ccc([C@H]2CNCCN2)cc1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCN[C@@H](c5ccccc5)C4)c(F)cc3cc2c1=O
Yield: 73.4 %

Procedure:
Working under the conditions of Example 25, but starting with 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (0.8 g) and (S)-2-phenylpiperazine (0.5 g), (S)-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine (0.85 g) is obtained in the form of a yellow solid, mp. 226° C.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[CH:6]=[C:7]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([NH:19][CH:20]4[CH2:25][CH2:24][N:23]([C:26]5[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=5)[CH2:22][CH2:21]4)[C:15](=[O:32])[CH2:14]3)(=[O:12])=[O:11])[CH2:8][O:9][C:4]=2[CH:3]=1.[OH-].[Na+].Cl.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[CH:6]=[C:7]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([N:19]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]5[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=5)[CH2:22][CH2:21]4)[C:38](=[O:40])[CH3:39])[C:15](=[O:32])[CH2:14]3)(=[O:11])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1CN(S(=O)(=O)C2=Cc3ccc(Cl)cc3OC2)CCN1NC1CCN(c2ccncc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(=O)N(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)C2=Cc3ccc(Cl)cc3OC2)CC1=O

Procedure:
A solution of 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[1-(4-pyridyl)-4-piperidinylamino]-2-piperazinone (95 mg) in acetic anhydride (4 ml) was stirred at 80° C. for 10 hours. The reaction mixture was concentrated and the residue obtained was combined with a 1N aqueous solution of sodium hydroxide and extracted with dichloromethane. The organic phase was washed with aqueous sodium bicarbonate and brine, dried and concentrated to obtain N-[(7-chloro-2H-benzopyran-3-sulfonyl)-2-oxo-1-piperazinyl]-N-[1-(4-pyridyl)-4-piperidinyllacetamide. The resultant free form was dissolved in ethyl acetate, and combined with a solution of hydrochloric acid in ethyl acetate to form a precipitate, which was collected by filtration, washed with ethyl acetate, dried under reduced pressure to obtain the title compound (90 mg) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH2:10])[C:6]([F:11])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CC(O)C>[F:11][C:6]1[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH2:9][CH2:10][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C=Cc1cc(OC)c([N+](=O)[O-])cc1F
Reactant: C1CCNCC1
Solvent: CC(C)O
Product: COc1cc(CCN2CCCCC2)c(F)cc1[N+](=O)[O-]
Temperature: 180 °C
Yield: 56.3 %

Procedure:
To 5-ethenyl-4-fluoro-2-nitrophenyl methyl ether (1.0 g, 5.1 mmol) in 10 mL of iPrOH was added, piperidine (1.3 g, 15.2 mmol). The mixture was heated to 180° C. 17 min in the microwave. The solvent was rotovaped down and the crude product was purified by flash chromatography to give the title compound of step C (0.81 g, 2.87 mmol, 57%). 1H NMR (400 MHz, CDCl3) δ ppm 7.59 (d, J=8.97 Hz, 1H), 7.01 (d, J=5.86 Hz, 1H), 3.92 (s, 3H), 2.82-2.88 (m, 2H), 2.53-2.58 (m, 2H), 2.40-2.48 (m, 4H), 1.55-1.61 (m, J=5.49, 5.49, 5.49, 5.49 Hz, 4H), 1.40-1.47 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[N:4]1)[CH3:2].[Cl-:11].[NH4+]>CCO.[Fe]>[Cl:11][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=1[NH2:8]
Reactant: CCn1cc([N+](=O)[O-])cn1
Reactant: [Cl-]
Agent: [Fe]
Agent: [NH4+]
Solvent: CCO
Product: CCn1ncc(N)c1Cl
Temperature: 80 °C
Yield: 30 %

Procedure:
To a suspension of 1-ethyl-4-nitro-1H pyrazole (1 equiv) and iron dust (5 equiv) in EtOH (0.285 M) was added ammonium chloride (10 equiv). The mixture was heated to 80° C. for 20 h then cooled to room temperature. The solvent was removed under reduced pressure to give crude material that was purified by silica gel chromatography (1.5% MeOH in DCM) to provide the desired product (30% yield) as a yellow oil. MS (ESI) m/z 146.0 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:20]=[CH:19][C:11]([N:12]([CH2:16][CH2:17]I)[CH2:13][CH2:14]I)=[CH:10][CH:9]=1.[Br:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:38])[N:28]2C(OC(C)(C)C)=O)=[CH:24][CH:23]=1>CN(C=O)C.O>[Br:21][C:22]1[CH:30]=[C:29]2[NH:28][C:27](=[O:38])[C:26]3([CH2:17][CH2:16][N:12]([C:11]4[CH:19]=[CH:20][C:8]([Cl:7])=[CH:9][CH:10]=4)[CH2:13][CH2:14]3)[C:25]2=[CH:24][CH:23]=1
Reactant: Clc1ccc(N(CCI)CCI)cc1
Reactant: CC(C)(C)OC(=O)N1C(=O)Cc2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2cc(Br)ccc2C12CCN(c1ccc(Cl)cc1)CC2
Temperature: 70 °C
Reaction time: 48 h
Yield: 17.6 %

Procedure:
Cesium carbonate (2.09 g, 6.4 mmol) was added in portions over 5 mins to a solution of 4-chloro-N,N-bis(2-iodoethyl)aniline (preparation 14c, 0.73 g, 1.68 mmol) and tert-butyl 6-bromo-2-oxoindoline-1-carboxylate (preparation 8a, 0.50 g, 1.60 mmol) in N,N′-dimethylformamide (20 mL) was added and the mixture was stirred for 48 hours. The mixture was diluted with water and extracted with ethyl acetate and the organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was taken up in 1,4-dioxane (15 mL) and 5M aqueous hydrochloric acid (5 mL) and the mixture was stirred and heated to 70° C. After 30 minutes, the mixture was evaporated and partitioned between ethyl acetate and 2M aqueous hydrochloric acid. The organic layer was combined with an insoluble solid which separated and the mixture was evaporated. The residue was purified by flash chromatography (3:1 hexanes/ethyl acetate) to give the title compound (0.11 g, 17%) as a pink solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH2:25][CH:26]=[CH2:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH2:25]([O:24][C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:28])[CH:26]=[CH2:27]
Reactant: C=CCOc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCOc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
The mixture of 2-(2-allyloxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (4) (168 mg, 0.44 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (5 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (5) as white solid (150 mg, 97%).
Reaction SMILES: CC[N:3](C1C=CC=CC=1)CC.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:14]>ClCCl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13](=[O:14])[NH2:3])=[CH:17][CH:18]=1
Reactant: CCN(CC)c1ccccc1
Reactant: COc1ccc(OC(=O)Cl)cc1
Solvent: ClCCl
Product: COc1ccc(OC(N)=O)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 256.4 %

Procedure:
Diethylaniline (0.33 μL, 2.1 μmol, 1.1 equiv) and 4-methoxyphenyl chloroformate (0.85 μL, 5.7 μmol, 3.0 equiv) were added separately, each in one portion, to a stirred solution of the amine (1.0 mg, 1.9 μmol, 1 equiv) in dichloromethane (0.15 mL) at 0° C. under an argon atmosphere. The reaction mixture was stirred at 0° C. for 40 min, then was quenched by the addition of a 1:1 mixture of water and saturated aqueous sodium hydrogen carbonate solution (3 mL). The mixture was extracted with ethyl acetate (2×10 mL) and the combined organic layer was washed with a 1:1 mixture of brine solution and saturated aqueous sodium hydrogen carbonate solution (5 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to leave a colorless oil. Purification by flash column chromatography (50%→70% ethyl acetate-hexanes) gave the carbamic acid 4-methoxyphenyl ester derivative (0.9 mg, 70%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[C@H:7]3[CH3:17])=[CH:4][C:3]=1[C@@H:18]1[CH2:23][CH2:22][NH:21][CH2:20][C@@H:19]1[CH3:24].C=O.[BH3-][C:28]#N.[Na+].C([O-])(O)=O.[Na+]>CC(O)=O.CO>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[C@H:7]3[CH3:17])=[CH:4][C:3]=1[C@@H:18]1[CH2:23][CH2:22][N:21]([CH3:28])[CH2:20][C@@H:19]1[CH3:24]
Reactant: [BH3-]C#N
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(Br)c([C@@H]4CCNC[C@@H]4C)cc3N21
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1C(=O)NN=C2COc3cc(Br)c([C@@H]4CCN(C)C[C@@H]4C)cc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of (R)-7-bromo-4-methyl-6-((3R,4R)-3-methyl-piperidin-4-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.2 g, 5.59 mmol) in AcOH (10 mL) and MeOH (100 mL) was added paraformaldehyde (0.839 g, 28.0 mmol). The reaction mixture was stirred at ambient temperature for 1 h. NaBH3CN (0.557 g, 14.0 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. Aqueous saturated NaHCO3 solution (30 mL) was added and the reaction mixture was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by a reverse-phase preparatory HPLC (Table 3, Method 35) to give (R)-7-bromo-6-((3R,4R)-1,3-dimethyl-piperidin-4-yl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (1.8 g, 79%). 1H NMR (400 MHz, CD3OD) δ 7.22 (s, 1H), 6.86 (s, 1H), 4.87-4.91 (m, 1H), 4.58 (d, J=13.2 Hz, 2H), 3.15 (m, 1H), 3.04 (m, 1H), 2.84 (m, 1H), 2.23-2.39 (m, 6H), 2.07-2.18 (m, 1H), 1.55 (m, 1H), 1.43 (d, J=6.5 Hz, 3H), 0.83 (d, J=7.0 Hz, 3H). LC/MS (Table 1, Method 25) Rt=0.681 min.; MS m/z: 407 [M+H]+& 409 [M+H+2]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:9][CH2:10][CH2:11][CH2:12]Br)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:14][SH:15].[Na]>>[CH3:1][O:2][C:3]([C:5]1([CH2:9][CH2:10][CH2:11][CH2:12][S:15][CH3:14])[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CCCCBr)CCC1
Reactant: CS
Agent: [Na]
Product: COC(=O)C1(CCCCSC)CCC1

Procedure:
1-[4-(Methylthio)butyl]cyclobutane carboxylic acid methyl ester was prepared from 1-(4-bromobutyl)cyclobutane carboxylic acid methyl ester and sodium methylmercaptan using the procedure described in example 172.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]([CH3:14])([N:6]1[CH:10]=[C:9]([N+:11]([O-])=O)[N:8]=[CH:7]1)[CH3:5].[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([F:27])[CH:26]=1)[CH2:23][CH:22]([NH:28][CH:29]([CH3:33])[C:30](O)=[O:31])[CH2:21][CH2:20]2>>[CH3:1][O:2][C:3](=[O:15])[C:4]([N:6]1[CH:10]=[C:9]([NH:11][C:30](=[O:31])[CH:29]([NH:28][CH:22]2[CH2:21][CH2:20][C:19]3[C:24](=[C:25]([F:27])[CH:26]=[C:17]([F:16])[CH:18]=3)[CH2:23]2)[CH3:33])[N:8]=[CH:7]1)([CH3:14])[CH3:5]
Reactant: CC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: COC(=O)C(C)(C)n1cnc([N+](=O)[O-])c1
Product: COC(=O)C(C)(C)n1cnc(NC(=O)C(C)NC2CCc3cc(F)cc(F)c3C2)c1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionic acid methyl ester was reduced and coupled with 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propionic acid to afford the title compound; MS 421.5 m/z (M+1).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:11][CH2:12][CH2:13][C:14]1[C:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][C:17]2[CH2:18][CH:19]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:16]=2[CH:15]=1.Cl>CN(C)C=O>[CH2:32]([O:31][C:30]1[C:14]([CH2:13][CH2:12][CH2:11][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:15][C:16]2[O:20][CH:19]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][C:17]=2[CH:29]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCCCc1cc2c(cc1OCc1ccccc1)CC(CCc1ccccc1)O2
Reactant: Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCC2Cc3cc(OCc4ccccc4)c(CCCOc4ccccc4)cc3O2)cc1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Dry phenol (14 gm, 152 mmoles) was added to 50% sodium hydride dispersion (7 gm; 145 mmoles) in dimethylformamide (200 mL) under nitrogen atmosphere. After stirring for 30 minutes, a solution of 6-(3-bromopropyl)-5-benzyloxy-2-(2-phenylethyl)-2,3-dihydrobenzofuran, E88, (8.7 gm; 16.9 mmoles) in dimethylformamide (25 mL). The mixture was stirred at room temperature for 3 hours, poured into excess 1N hydrochloric acid and extracted with diethylether. The ether layer was washed with 1N sodium hydroxide twice, dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel using 5% ethyl acetate in hexane to yield 6.3 g (82%) of 5-benzyloxy-2-(2-phenylethyl)-6-(3-phenoxypropyl)-2,3-dihydrobenzofuran, E38, as an oil.
Reaction SMILES: [I:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][CH3:15])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C-]#N.[Na+].CN(C)[CH2:21][CH2:22][C:23]([C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1)=[O:24]>CN(C=O)C>[I:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][CH3:15])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([C:7](=[O:8])[CH2:21][CH2:22][C:23]([C:25]2[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=2)=[O:24])[CH:9]=1
Reactant: CCCOc1c(I)cc(C=O)cc1OC
Reactant: COc1cc(C(=O)CCN(C)C)cc(OC)c1OC
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1c(I)cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1OC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 5-iodo 3-methoxy-4-n-propoxybenzaldehyde (26 g, 0.08 mol) in DMF (75 ml) was added over 15 minutes to a stirred solution of sodium cyanide (4 g, 0.08 mol) in DMF (100 ml) at 35° C. After stirring for 20 minutes, a solution of 3-dimethylamino-1-(3,4,5-trimethoxyphenyl)-1-propanone (18 g, 0.07 mol) in DMF (100 ml) was added over 0.5 hour. The mixture was stirred at 35° C. for 1 hour and kept at room temperature overnight. It was poured into ice-cold 20% hydrochloric acid (2 1), and the solid was filtered, dried by suction, and taken up in ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was evaporated to dryness. Crystallization from Et2O-hexane gave 1-(5-iodo-3-methoxy-4-n-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione, m.p. 120°-121° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[CH:16]=[CH:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=3[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[CH:22]=[CH:23][C:24](B2OC(C)(C)C(C)(C)O2)=[C:25]([CH:28]=1)[C:26]#[N:27]>>[F:20][C:21]1[CH:28]=[C:25]([C:26]#[N:27])[C:24]([C:2]2[CH:3]=[C:4]([N:9]3[C:17]4[CH:16]=[CH:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=4[N:11]=[CH:10]3)[CH:5]=[CH:6][C:7]=2[F:8])=[CH:23][CH:22]=1
Reactant: CC1(C)OB(c2ccc(F)cc2C#N)OC1(C)C
Reactant: Cn1ccc2c(ncn2-c2ccc(F)c(Br)c2)c1=O
Product: Cn1ccc2c(ncn2-c2ccc(F)c(-c3ccc(F)cc3C#N)c2)c1=O
Yield: 55 %

Procedure:
1-(3-Bromo-4-fluorophenyl)-5-methyl-1,5-dihydroimidazo[4,5-c]pyridin-4-one was coupled to 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile, in the same way as in Example 1, to give 4,2′-difluoro-5′-(5-methyl-4-oxo-4,5-dihydroimidazo[4,5-c]pyridin-1-yl)biphenyl-2-carbonitrile as an off-white solid (360 mg, 55%): δH (400 MHz, d6-DMSO) 3.54 (3H, s), 6.67 (1H, d, J 7), 7.61 (1H, d, J 7), 7.69 (1H, t, J 9), 7.75-7.87 (4H, m), 8.09 (1H, dd, J 9 and 3), 8.38 (1H, s); m/z (ES+, 363 [MH+].
Reaction SMILES: [N:1]1[C:9](N)=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[CH3:18][Si:19]([CH3:26])([CH3:25])[NH:20][Si:21]([CH3:24])([CH3:23])[CH3:22]>>[CH3:18][Si:19]([N:20]([Si:21]([CH3:24])([CH3:23])[CH3:22])[C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[N:5]2)([CH3:26])[CH3:25]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: C[Si](C)(C)N(c1ncnc2nc[nH]c12)[Si](C)(C)C

Procedure:
Bis-trimethylsilyladenine was prepared by combining 7 g of adenine and 109 ml of hexamethyldisilazane with 250 mg of ammonium sulfate and heating the mixture at 110°-115° C. for 8 hours. The solution was refluxed for an additional 30 minutes and the excess hexamethyldisilazane subsequently removed and 14.5 g of the bis-trimethylsilyladenine were reconstituted in 3 ml of anisole. 1.58 g of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-α-methanesulfonate were reacted with the bis-trimethylsilyladenine solution at 105° C.-110° C. for 24 hours. HPLC analysis confirmed completion of the reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:15](=[O:25])[C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:15](=[O:25])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2Cc2cc(Cl)ccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)N2Cc3ccccc3Cc3cc(Cl)ccc32)cc1
Yield: 73.9 %

Procedure:
A solution of 2.1 g of 2-chloro-5-(4-nitrobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 400 ml of ethyl acetate-ethanol (1:1) and 0.25 g of palladium-on-carbon is hydrogenated in a Parr hydrogenator under 38 pounds per square inch of hydrogen. The mixture is filtered through diatomaceous earth and the filtrate concentrated to dryness. The solid (1.94 g) is dissolved in dichloromethane and the solution filtered through a thin pad of hydrous magnesium silicate. The filter pad is washed with dichloromethane and the filtrate concentrated. The residue is crystallized from dichloromethane-hexane to give 1.43 g of crystals, m.p. 211°-214° C.
Reaction SMILES: [C:1]1([C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:14]=[C:15]1[C:20]2[S:21][CH:22]=[C:23]([S:24](Cl)(=[O:26])=[O:25])[C:19]=2[CH2:18][CH2:17][CH2:16]1>>[OH:13][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH2:11][N:10]([S:24]([C:23]2[C:19]3[CH2:18][CH2:17][CH2:16][C:15](=[O:14])[C:20]=3[S:21][CH:22]=2)(=[O:25])=[O:26])[CH2:9][CH2:8]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Product: O=C1CCCc2c(S(=O)(=O)N3CCC(O)(c4ccccc4)CC3)csc21

Procedure:
From 4-phenyl-piperidine-4-ol (36 mg) and 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7) (50 mg), the title compound (72 mg) was obtained as a colorless amorphous substance, in the same way as Preparation Example 41.
Reaction SMILES: [C:1]1([P:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][CH:15]([C:18]2[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:34]O>C(Cl)Cl>[C:28]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][CH:15]([C:18]2[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13]3)=[O:34])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: OO
Reactant: C1=CC(c2cccc3ccccc23)Nc2c1cccc2P(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=P(c1ccccc1)(c1ccccc1)c1cccc2c1NC(c1cccc3ccccc13)C=C2
Yield: 90.7 %

Procedure:
Following the procedure described for the synthesis of compound 5,8-diphenylphosphino-2-naphthale-1-yl-1,2-dihydroquinoline (11) (8.8 g, 20 mmol) in CH2Cl2 (60 mL) was oxidised with H2O2 (4.15 mL, 30% w/w in H2O, 40 mmol) to give compound 12 (8.3 g) in 91% yield. 1H NMR (400.13 MHz, CDCl3) δ 8.00 (d, 1H, J=8.4 Hz, C5′—H), 7.83 (dd, 1H, J=7.6, 2.0 Hz, C8′—H), 7.7-7.6 (m, 3H, C2′—H/Ph-H), 7.6-7.5 (m, 3H, Ph-H), 7.5-7.4 (m, 5H, C6′/7′—H/Ph-H), 7.4-7.3 (m, 2H, Ph-H), 7.29 (d, 1H, J=8.0 Hz, C4′—H), 7.19 (t, 1H, J=8.0 Hz, C3′—H), 6.96 (d, 1H, J=7.2 Hz, C5—H), 6.64 (ddd, 1H, J=13.6, 7.6, 1.2 Hz, C7—H), 6.44 (td, 1H, J=7.2, 2.8 Hz, C6—H), 6.34 (dt, 1H, J=10.0, 1.6 Hz, C4—H), 6.32 (t, 1H, J=1.6 Hz, C2—H), 5.78 (dd, 1H, J=10.0, 4.0 Hz, C3—H) ppm; 13C NMR (100.61 MHz, CDCl3) δ 148.3, 148.2, 139.2, 132.9, 131.9 (d, J=11.1 Hz), 131.8 (d, J=12.1 Hz), 131.2 (d, J=10.1 Hz), 130.9 (d, J=9.1 Hz), 130.7, 129.8, 128.4, 127.8, 127.5 (d, J 12.1), 127.3 (d J 12.1), 126.6, 125.3, 124.7, 124.5, 123.8, 123.7, 123.4, 121.5, 121.5, 118.9, 114.2, 114.0, 108.9, 107.8, 52.6 ppm; 31P NMR (161.97 MHz, CDCl3) δ +35.2 ppm.