Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[OH-].[K+].[CH3:14][N:15]([CH3:19])[C:16](Cl)=[S:17]>>[CH3:14][N:15]([C:16]([O:9][C:4]1[C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=[CH:6][CH:5]=1)=[S:17])[CH3:19]
Reactant: CN(C)C(=S)Cl
Reactant: Oc1ccccc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Product: CN(C)C(=S)Oc1ccccc1C(F)(F)F
Yield: 89 %

Procedure:
If the procedure described in Preparation XI is followed starting from 3.95 g (24.3.10-3 mol) of 2-trifluoromethylphenol, 1.43 g (25.6.10-3 mol) of potassium hydroxide and 3.46 g (28.10-3 mol) of dimethylthiocarbamoyl chloride, 5.37 g (yield: 89%) of a yellow oil are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].OC1C=CC([N:17]2[C:21](=[O:22])[N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:29])[NH:18]2)=CC=1>>[OH:9][C:3]1[C:4]([CH3:8])=[CH:5][C:6]([N:17]2[C:21](=[O:22])[N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:29])[NH:18]2)=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cccc(C)c1O
Reactant: O=c1[nH]n(-c2ccc(O)cc2)c(=O)n1-c1ccccc1
Product: Cc1cc(-n2[nH]c(=O)n(-c3ccccc3)c2=O)cc(C)c1O

Procedure:
Compound 30 was prepared from 2,6-dimethylphenol in the same manner of compound 27, and was obtained as white solids (61%). 1H NMR (300 MHz, DMSO-d6): δ 11.32 (br s, 1H), 8.42 (s, 1H), 7.53-7.39 (m, 5H), 7.14 (d, J=1.8 Hz, 1H). 13C NMR (75 MHz, DMSO-d6): δ 152.07, 151.38, 129.58, 127.13, 125.61, 121.94, 121.48, 17.43. HRMS: calcd for C16H15N3O3 (MH+) 298.1186. found 298.1184.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][CH2:17]2)=[CH:13][C:12]=1[CH:20]=O.[CH:22]1([N+:27]#[C-:28])[CH2:26][CH2:25][CH2:24][CH2:23]1.Cl(O)(=O)(=O)=O>CO>[CH:22]1([NH:27][C:28]2[N:6]3[N:5]=[CH:4][C:3]([C:7]#[N:8])=[C:2]3[NH:1][C:20]=2[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:11]=2[O:10][CH3:9])[CH2:17][CH2:16][CH2:15]3)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1cc2c(cc1C=O)CCC2
Reactant: N#Cc1cn[nH]c1N
Reactant: [C-]#[N+]C1CCCC1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Product: COc1cc2c(cc1-c1[nH]c3c(C#N)cnn3c1NC1CCCC1)CCC2
Reaction time: 15 h
Yield: 8.5 %

Procedure:
To a mixture of 5-amino-1H-pyrazole-4-carbonitrile (193 mg, 1.79 mmol) and 6-methoxy-2,3-dihydro-1H-indene-5-carbaldehyde (315 mg, 1.79 mmol) in a vial under nitrogen atmosphere were added methanol (10 mL) followed by cyclopentyl isonitrile (172 mg, 200 μL, 1.79 mmol) and perchloric acid (35.9 mg, 32.1 μL, 0.358 mmol) at RT. Then, the resulting light yellow suspension was stirred for 15 h and the resulting solids were collected by filtration and washed with methanol. After air drying, 55 mg (8.5% yield) of 3-(cyclopentylamino)-2-(6-methoxy-2,3-dihydro-1H-inden-5-yl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile was isolated as an off-white solid. LC/MS calcd. for C21H23N5O (m/e) 361.44, obsd. 362.1 (M+H, ES+).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CI.CN(P(N(C)C)(N(C)C)=O)C.[Cl-].[NH4+]>C1COCC1>[CH3:1][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CC(C)NC(C)C
Reactant: CCCCCCCCC(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCCCCCC(C)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a solution of diisopropylamine (9.0 ml, 64.4 mmol) in 100 ml anhydrous THF was added dropwise n-butyl lithium (1.61N, 40.0 ml, 64.4 mmol) at -78° C. under argon atmosphere. The mixture was stirred at -78° C. for 30 minutes and ethyl nonanoate (10.00 g, 53.7 mmol) was added dropwise. After stirring the mixture at -78° C. for 30 minutes, a solution of methyl iodide (3.7 ml, 59.1 mmol) in HMPA (2.8 ml, 16.1 mmol) was added dropwise and the mixture was stirred at -78° C. for 3.5 hours. Saturated aqueous solution of ammonium chloride (20 ml) was added to the reaction mixture and the resulting mixture was then extracted with ether (50 ml×4). The ether layers were washed with water (50 ml) and with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated. Distillation gave yellow liquid, ethyl 2-methylnonanoate (9.6892 g, yield: 90.1%, b.p.: 63°-64° C./0.7 mmHg). The structure of this product was confirmed by the following data.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][C:7]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C@H:6]1O)=[O:4].C(N(CC)CC)C.CS(Cl)(=O)=O.O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH2:10][CH2:9][CH2:8][C:7]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=1)=[O:4]
Reactant: COC(=O)[C@@H]1CCCC2(CCCCC2)[C@H]1O
Agent: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C1=CC2(CCCCC2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of trans-1-hydroxy-spiro[5.5]undecane-2-carboxylic acid methyl ester (2.74 g) obtained in Step 3 in chloroform (20 mL) was added triethylamine (2.02 mL). To the reaction mixture was added dropwise a solution of methanesulfonyl chloride (1.03 mL) in chloroform (5 mL) under ice-cooling, followed by stirring the reaction mixture at room temperature overnight. Then, after addition of water, the reaction mixture was washed therewith. The separated organic layer was dried and concentrated. To the residue were added tetrahydrofuran (30 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.62 mL), followed by heating the reaction mixture at 60° C. for 3 hours. After cooling down to room temperature, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed successively with 1N aqueous hydrochloric acid solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:8) to give spiro[5.5]undec-1-ene-2-carboxylic acid methyl ester (2.075 g).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH:25][C:26]([C:33]1[S:37][C:36]([CH:38]=[O:39])=[N:35][CH:34]=1)([CH3:32])[CH:27]([O:30][CH3:31])[O:28][CH3:29].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:38]([C:36]3[S:37][C:33]([C:26]([OH:25])([CH3:32])[CH:27]([O:30][CH3:31])[O:28][CH3:29])=[CH:34][N:35]=3)=[O:39])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: COC(OC)C(C)(O)c1cnc(C=O)s1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(OC)C(C)(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Yield: 68.5 %

Procedure:
A mixture of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (1.00 g), 5-(1-hydroxy-2,2-dimethoxy-1-methylethyl)-1,3-thiazole-2-carbaldehyde (0.73 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (77 mg), triethylamine (0.16 mL), tetrahydrofuran (8 mL) and ethanol (8 mL) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, and the residue was subjected to basic silica gel column chromatography, and the title compound (1.14 g, yield 69%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 580 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7](Cl)[C:6]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4].[IH:21].[Na+].[I-]>CC(C)=O>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([I:21])[C:6]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)nc(Cl)c1Cc1ccc(I)cc1
Reactant: I
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCc1nc(C)nc(I)c1Cc1ccc(I)cc1
Temperature: 40 °C
Yield: 99.3 %

Procedure:
To a solution of 380 mg (0.947 mmol) 6-butyl-4-chloro-2-methyl-5-[(4-iodophenyl)methyl]-pyrimidine in 10 mL acetone were added 0.119 mL 57% HI (0.900 mmol) and 851 mg (5.68 mmol) NaI. The mixture was warmed to 40° C. for 2.5 hours. As the reaction proceeds, NaCl can be seen precipitating out of solution. The mixture was diluted with brine and saturated NaHCO3 solution. The mixture was extracted 3 times with ether. The combined organic material was dried over MgSO4 and decolorized with activated charcoal, was stripped of solvent in vacuo, then was medium pressure chromatographed on silica gel using 10% EtOAc/hexane to give 440 mg of 6-butyl-4-iodo-2-methyl-5-[(4-iodophenyl)methyl]pyrimidine, 947% yield.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:13]=[CH:12][C:6]2[O:7][CH2:8][C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.C1COCC1>[O-2].[O-2].[Mn+4].ClCCCl>[O:11]=[C:9]1[CH2:8][O:7][C:6]2[CH:12]=[N:13][C:3]([CH:2]=[O:1])=[CH:4][C:5]=2[NH:10]1
Reactant: O=C1COc2cnc(CO)cc2N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: O=Cc1cc2c(cn1)OCC(=O)N2
Temperature: 60 °C

Procedure:
A mixture of the hydroxymethyloxazinone (h) (584 mg), manganese dioxide (2.3 g), THF (50 ml) and 1,2-dichloroethane (50 ml) was heated at 60° C. under argon for 20 hours. Filtration through kieselguhr and evaporation of solvent gave a solid which was triturated under EtOAc/hexane 1:3, filtered off and dried (383 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][N:24]([CH3:30])[C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>>[CH3:23][N:24]([CH3:30])[C@@H:25]1[CH2:29][CH2:28][N:27]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:26]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CN(C)[C@@H]1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-N,N-dimethylpyrrolidin-3-amine (1.2 equiv) to give 210 (M+1 410.0)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:11])[CH3:10]
Reactant: CC(C)c1ccccc1S
Reactant: Cc1ccccc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Cc1ccccc1Sc1ccccc1C(C)C
Yield: 87.9 %

Procedure:
The general procedure in example 39 was followed. 2-Iodotoluene (218 mg, 1.0 mmol), 2-Isopropylbenzenethiol (90% purity, 168 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 2-tolyl 2-Isopropylphenyl sulfide (213 mg, 88% yield) as colorless liquid. Column chromatographic solvent (hexane). Rf=0.4 (hexane). 1H NMR (CDCl3, 300 MHz) δ 7.32 (d, 1 H, J=7.5 Hz), 7.18-7.26 (m, 2 H), 7.13 (dd, 1 H, J=1.5 Hz, 7.2 Hz), 7.09-7.11 (m, 1 H), 7.01-7.08 (m, 2 H), 7.00 (dd, 1 H, J=1.5 Hz, 7.2 Hz), 3.49 hept, 1 H, J=6.6 Hz), 2.37 (s, 3 H), 1.25 (s, 3 H), 1.22 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 149.6, 138.6, 135.5, 133.1, 132.2, 131.1, 130.6, 127.9, 127.0, 126.8, 126.7, 126.1, 30.9, 23.9, 20.9. IR (neat, cm−1) 3060, 3012, 2962, 2867. MS (EI) m/z (relative intensity) 242 (100), 225 (80). Anal. Cald. for C16H18S, Cald. C: 79.29, H: 7.49; Found C: 79.33, H: 7.62.
Reaction SMILES: C[S:2][CH2:3][CH2:4][C@@H:5]([OH:8])[CH2:6]O.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.CCCCCC.[SH+]1CCCC1>N1C=CC=CC=1.C(OCC)(=O)C>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([O:8][C@@H:5]2[CH2:4][CH2:3][S:2][CH2:6]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CSCC[C@@H](O)CO
Agent: C1CC[SH+]C1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CCSC2)cc1

Procedure:
(R)-4-(methylthio)1,2-butanediol (1.0 , 7.35 mmol) and p-toluenesulfonyl chloride (3.0 g, 15.8 mmol) were combined in 10 ml of pyridine at 0.5° C., then stirred at room temperature, at which time tlc (3:1 hexane:ethyl acetate) indicated no diol (Rf 0.1), appreciable of th ediol ditosylate (Rf 0.53), some intermediate thiolanium salt (Rf 0.03) and a trace of title product (Rf 0.72). The reaction mixture was then heated at 60° C. for 8 hours, at which time tlc (5:1 hexane:ethyl acetate) indicated an appreciable amount of the desired title product (Rf 0.45 ), only a trace of the ditosylate (Rf 0.22), some probable thiolanium salt (Rf 0.0), and other, generally less polar impurities. The cooled reaction mixture was diluted with an equal volume of water and two volumes of ethyl acetate. The organic layer was separated, washed with saturated NaCl, dired (MgSO4), stripped and the residue chromatographed on silica gel using 10:1 g less polar impurities (stench-) and 0.25 g of present, purified title product; tlc Rf 0.55 (4:1 hexane:ethylacetate); [alpha]D =+15.87 (c=0.6, CH3OH).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][C:12]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:24][C:25]([CH:27]1[C:32](=[O:33])[CH:31]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30][S:29][CH2:28]1)=[O:26])[CH:22]=[CH2:23]>C1CCCCC1.CCOC(C)=O>[CH2:21]([O:24][C:25]([C@@:27]1([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:20])=[C:12]([F:19])[CH:13]=2)[C:32](=[O:33])[CH:31]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30][S:29][CH2:28]1)=[O:26])[CH:22]=[CH2:23]
Reactant: O=C(Nc1ccc(CBr)cc1F)OCc1ccccc1
Reactant: C=CCOC(=O)C1CSCC(NC(=O)OC(C)(C)C)C1=O
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)[C@]1(Cc2ccc(NC(=O)OCc3ccccc3)c(F)c2)CSCC(NC(=O)OC(C)(C)C)C1=O

Procedure:
The title compound was prepared in analogous manner as described for example 1c from (4-bromomethyl-2-fluoro-phenyl)-carbamic acid benzyl ester (37 g, 109 mmol) and 5-tert-butoxycarbonylamino-4-oxo-tetrahydro-thiopyran-3-carboxylic acid allyl ester (33 g, 105 mmol, example 1b) to yield a diastereomeric mixture of a yellow solid: TLC (cyclohexane-EtOAc 1:1) Rf=0.77; ESIMS [M+NH4]+=590; LCMS [M+NH4]+=590, RtI=1.60 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5](I)=[CH:4][C:3]=1[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[Cl:18].[CH2:19]([Sn](CCCC)(CCCC)C=C)[CH2:20]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH:19]=[CH2:20])=[CH:4][C:3]=1[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[Cl:18]
Reactant: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1I
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(-c2cc(Cl)ccc2Cl)c(Cl)cc1OC
Yield: 34.1 %

Procedure:
A mixture of 2,2′,5′-trichloro-5-iodo-4-methoxy-1,1′-biphenyl (1.17 g, 2.9 mmol), tributyl(vinyl)stannane (1.1 g, 3.5 mmol), Pd(PPh3)4 (670 mg, 0.6 mmol) in toluene (30 mL) was stirred at reflux under argon for 6 h. The reaction mixture was quenched with KF aqueous solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/DCM=100:1) to afford the desired product (310 mg, 35% yield) as a white solid.
Reaction SMILES: [Br:1][C:2](Br)=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>O>[Br:1][C:2]#[C:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: Cc1ccc(C=C(Br)Br)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C#CBr)cn1
Temperature: 80 °C
Yield: 32.4 %

Procedure:
A mixture of 5-(2,2-dibromovinyl)-2-methylpyridine (0.10.9 g, 0.00393 mol), potassium tertbutoxide (0.88 g, 0.00787 mol) and toluene (13 mL) were heated at 80° C. for 4 h. After completion of reaction, the reaction mixture was cooled to RT, diluted with water (15 mL), and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduce pressure to obtain product as a yellow oil (0.25 g, 32.4%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:26])[C:9]2[CH:25]=[CH:24][C:12]3[N:13]([CH3:23])[C:14]([NH:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:27][S:28]([CH2:31][CH2:32][C:33]1[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=1)(=[O:30])=[O:29]>>[ClH:1].[CH:17]1([NH:16][C:14]2[N:13]([CH3:23])[C:12]3[CH:24]=[CH:25][C:9]([N:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:35]5[CH:36]=[CH:37][CH:38]=[C:33]([CH2:32][CH2:31][S:28]([CH3:27])(=[O:30])=[O:29])[CH:34]=5)[N:7]=4)[CH3:26])=[CH:10][C:11]=3[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CN(c1ccc2c(c1)nc(NC1CCCCC1)n2C)c1ccnc(Cl)n1
Reactant: CS(=O)(=O)CCc1cccc(N)c1
Product: CN(c1ccc2c(c1)nc(NC1CCCCC1)n2C)c1ccnc(Nc2cccc(CCS(C)(=O)=O)c2)n1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example 1 with N5-(2-Chloro-pyrimidin-4-yl)-N2-cyclohexyl-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (74 mg, 0.20 mmol) and 3-(2-methanesulfonyl-ethyl)-phenylamine (47 mg, 0.20 mmol) as a white solid (59 mg, 52%). 1H NMR (300 MHz, D6-DMSO) δ 9.07 (s, 1H), 7.76-7.78 (m, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.13-7.20 (m, 2H), 7.09 (d, J=1.8 Hz, 1H), 6.79-6.82 (m, 2H), 6.47 (d, J=7.8 Hz, 1H), 5.61 (d, J=6.0 Hz, 1H), 3.70 (m, 1H), 3.51 (s, 3H), 3.44 (s, 3H), 3.35-3.40 (m, 2H), 2.97 (s, 3H), 2.91-2.95 (m, 2H), 2.01 (m, 2H), 1.74 (M, 2H), 1.63 (m, 1H), 1.16-1.31 (m, 5H) ppm. MS (ESI) m/z=534 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6](Br)=[C:7]([CH2:15][CH2:16][O:17][CH3:18])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.C([Li])CCC.CCCCCC.[CH:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[C:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=1[CH:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[OH:38]
Reactant: O=Cc1ccccc1
Reactant: COCCc1cc(OCOC)cc(OCOC)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCCc1cc(OCOC)cc(OCOC)c1C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 51.7 %

Procedure:
3,5-Bis(methoxymethoxy)-2-bromo-1-(2-methoxyethyl)-benzene (5.3 g, 16 mmol) obtained in Example 1, Step 4 was dissolved in tetrahydrofuran (0.10 L). After the solution was cooled to −78° C., a 1.6 mol/L solution of n-butyllithium in hexane (30 mL, 48 mmol) was added thereto, followed by stirring for 5 minutes. Benzaldehyde (6.4 mL, 62 mmol) was added to the reaction mixture, followed by stirring for 1 hour. To the reaction mixture was added a saturated aqueous solution of ammonium chloride (30 mL), and the mixture was extracted with ethyl acetate (0.30 L). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/2) to obtain [2,4-bis(methoxymethoxy)-6-(2-methoxyethyl)phenyl]phenylmethanol (3.0 g, 53%). Then, [2,4-bis(methoxymethoxy)-6-(2-methoxyethyl)phenyl]phenylmethanol (3.0 g, 8.4 mmol) was dissolved in dichloromethane (50 mL), and Molecular Sieves 4 Å (7.9 g) and pyridinium dichromate (7.9 g, 21 mmol) were added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/2) to obtain 2,4-bis(methoxymethoxy)-6-(2-methoxyethyl)phenyl=phenyl=ketone (2.9 g, 96%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][N:18]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:32]I.O>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:29])[N:7]([CH3:32])[CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][N:18]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncnc3c2ncn3C2CCCCO2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ncnc3c2ncn3C2CCCCO2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 74.1 %

Procedure:
The {1-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (107.7 mg, 0.27 mmol) of Example 1A was dissolved in anhydrous dimethylformamide (1 ml) and the solution was cooled to 0° C. in an ice bath. Sodium hydride (13 mg, 60% suspension in oil, 0.33 mmol) was added in small portions. The suspension was stirred vigorously for an additional 20 minutes at 0° C. and then the methyl iodide (0.020 ml, 0.32 mmol) was added drop wise. After stirring the reaction mixture for 30 minutes at 0° C. this was brought to room temperature and left stirring additionally overnight. Water (1.2 ml), followed by ethyl acetate (5 ml) was added to the reaction mixture. The organic layer was separated, washed with water, 0.1M HCl, a saturated aqueous NaHCO3 solution, and brine before being dried and concentrated in vacuo. The crude product was purified by flash silica column chromatography eluting with 5% methanol in dichloromethane to afford the required compound as a white solid (83 mg, 0.2 mmol, 73%) LC-MS (LCT) Rt 7.07 [M+H]+ 417.
Reaction SMILES: [CH:1]1(C2C(OC3C=CC(C4C=CC=CC=4C4N=NNN=4)=CC=3)=C(C(OC(OC(=O)CC)C(C)C)=O)C3C(=CC=CC=3)N=2)C[CH2:2]1.[CH:44]1([C:47]2[C:56]([O:57][C:58]3[CH:63]=[CH:62][C:61]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=4[C:70]4[N:71]=[N:72][N:73]([C:75]([C:88]5[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=5)([C:82]5[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=5)[C:76]5[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=5)[N:74]=4)=[CH:60][CH:59]=3)=[C:55]([C:94]([OH:96])=[O:95])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[N:48]=2)[CH2:46][CH2:45]1.C(I)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH:44]1([C:47]2[C:56]([O:57][C:58]3[CH:59]=[CH:60][C:61]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=4[C:70]4[N:71]=[N:72][N:73]([C:75]([C:88]5[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=5)([C:76]5[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=5)[C:82]5[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=5)[N:74]=4)=[CH:62][CH:63]=3)=[C:55]([C:94]([O:96][CH2:1][CH3:2])=[O:95])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[N:48]=2)[CH2:45][CH2:46]1
Reactant: CCC(=O)OC(OC(=O)c1c(Oc2ccc(-c3ccccc3-c3nn[nH]n3)cc2)c(C2CC2)nc2ccccc12)C(C)C
Reactant: O=C(O)c1c(Oc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C2CC2)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCI
Product: CCOC(=O)c1c(Oc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C2CC2)nc2ccccc12
Temperature: 90 °C
Yield: 64 %

Procedure:
A mixture of the title A compound of Example 28, 2-cyclopropyl-3-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]oxy]-4-quinolinecarboxylic acid (372 mg, 0.517 mmol), ethyl iodide (0.13 mL, 254 mg, 1.62 mmol), and potassium carbonate (335 mg, 2.42 mmol) in dimethylformamide (2.5 mL) were heated at 90° C. for 90 minutes. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and rinsed with aq. 5% sodium bisulfite and brine, dried (magnesium sulfate), and concentrated in vacuo to give a crude product (580 mg). Flash chromatography on silica gel (40 g) eluted with 10:1, hexanes:ethyl acetate yielded the title compound (372 mg, 64%).