Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH3:18][C:19]1([C:24]#[N:25])[CH2:22][C:21](=O)[CH2:20]1>O1CCCC1>[C:7]([CH:9]=[C:21]1[CH2:22][C:19]([CH3:18])([C:24]#[N:25])[CH2:20]1)#[N:8]
Reactant: CC1(C#N)CC(=O)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C#N)CC(=CC#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (52.9 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (8.98 mL, 0.0555 mol) in tetrahydrofuran (90 mL, 1 mol). The reaction was warmed to rt and then cooled at 0° C. again. To the reaction mixture was added a solution of 1-methyl-3-oxocyclobutanecarbonitrile (5.50 g, 0.0504 mol) in tetrahydrofuran (40 mL, 0.6 mol). The reaction was allowed to warm up to rt and stirred at rt overnight. After quenching with water, the mixture was extracted with ether. The combined organic layers were washed with water, brine, dried and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 60% EtOAc in hexane, to give the desired product (3.12 g, 46.84%). LCMS calculated for C8H9N2(M+H)+: 133.1. Found: 133.1.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:22][CH2:23][CH2:24][CH2:25]I.O>O1CCCC1>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:2][C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: ClCCCI
Reactant: CC(=O)c1ccc(C#N)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)CCCCCl)cc1
Reaction time: 0.5 h

Procedure:
1 g (6.9 mmol) of 4-acetylbenzonitrile was dissolved in 8 ml of tetrahydrofuran. 9 ml of lithium bis(trimethylsilyl)amide (1 M solution in hexane) was gradually added to the solution at −70° C. and they were stirred for 30 minutes. 1.43 g (7 mmol) of 1-chloro-3-iodopropane dissolved in 6 ml of tetrahydrofuran was added thereto, and the resultant mixture was stirred at room temperature overnight. The reaction liquid was poured into water. After the extraction with ethyl acetate, the extract was washed with 1 N hydrochloric acid and saturated aqueous common salt solution, and then dried over powdery magnesium sulfate. The solvent was evaporated, and the residue was purified by the silica gel chromatography to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][C:16]=1[Cl:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1ccc(Cl)cc1Cl)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 38.4 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 0.50 g, 3.4 mmol), 2,4-dichlorophenylboronic acid (Lancaster; 645 mg, 3.4 mmol), copper(II) acetate (621 mg, 3.4 mmol) and triethylamine (480 μL, 3.4 mmol) in 1,2-dichloroethane (15 mL) was heated in an oil bath at 50° C. for 2 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 10% ethyl acetate/hexanes, to give N′-(2,4-dichloro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (380 mg, 34%) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([S:18](Cl)(=[O:20])=[O:19])[CH3:17]>>[Br:15][C:12]1[CH:13]=[N:14][C:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[S:18]([CH2:16][CH3:17])(=[O:20])=[O:19])=[N:10][CH:11]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Brc1cnc(NCc2ccccc2)nc1
Product: CCS(=O)(=O)N(Cc1ccccc1)c1ncc(Br)cn1

Procedure:
The subtitle compound was prepared by the method of example 38 step (i) using benzyl-(5-bromo-pyrimidin-2-yl)-amine and ethanesulphonyl chloride, yield 0.31 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[C:10]([OH:11])=[CH:9][N:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=1)[CH3:2].[Br:17]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:6]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:9]([Br:17])[C:10]=1[OH:11])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)(C)C)ncc1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(C)(C)C)nc(Br)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a solution of the above isonicotinic acid ethyl ester (2.0 g, 9.47 mmol) in DMF (20 mL) was added N-bromosuccinimide (1.85 g, 10.4 mmol). The solution was stirred at room temperature for 0.5 h then poured into saturated aqueous NaHCO3. The aqueous layer was extracted with diethyl ether and the combined organic layers were washed with saturated aqueous NaHCO3, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 2-bromo-6-tert-butyl-3-hydroxy-isonicotinic acid ethyl ester (2.74 g, 96%) as a pale yellow oil which was utilized without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]([C:29](O)=[O:30])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:33][C:34]1([F:40])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.Cl.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]([C:29]([N:37]2[CH2:38][CH2:39][C:34]([F:40])([F:33])[CH2:35][CH2:36]2)=[O:30])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21
Reactant: FC1(F)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21

Procedure:
The title compound was synthesized in analogy to Example 1, from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid, 4,4-difluoropiperidine hydrochloride, triethylamine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as a yellow solid (70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[CH3:10][C:11](=[CH2:19])[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].S(=O)(=O)(O)O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:11]([CH3:19])([CH3:10])[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: C=C(C)CCCC(=O)OC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)CCCC(C)(C)c1cc(Cl)c(O)c(Cl)c1

Procedure:
12.8 Parts of 2,6-dichlorophenol, 14.2 parts of methyl 5-methyl-hex-5-enoate, 130 parts of 98% sulphuric acid, and 24 parts of methanol were stirred and heated on a steam-bath for 24 hours and the reaction mixture then worked up as in Example 25. Distillation gave methyl 5-(3,5-dichloro-4-hydroxyphenyl)-5-methyl-hexanoate b0.5 140°-60° C. and m.p. 101°-3° C., with the following percentage composition by weight.
Reaction SMILES: [ClH:1].C1(C(C2C=CC=CC=2)=[N:9][CH:10]([P:18]([CH:23]([N:31]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:22])[O:19][CH2:20][CH3:21])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)C=CC=CC=1>CCOCC>[ClH:1].[NH2:31][CH:23]([P:18]([CH:10]([NH2:9])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:22])[O:19][CH2:20][CH3:21])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOP(=O)(C(Cc1ccccc1)N=C(c1ccccc1)c1ccccc1)C(Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCOP(=O)(C(N)Cc1ccccc1)C(N)Cc1ccccc1
Yield: 97 %

Procedure:
Approximately 10% strength aqueous hydrochloric acid (30 ml) is added to a solution of the bis-alkylated phosphinate 5 (1161 mg; 1.76 mmol) in ether (30 ml) at room temperature with stirring. After 24 hours the organic phase is separated off and the aqueous phase is extracted with ethyl acetate (20 ml). The phosphinate hydrochloride 10 (690 mg, 97% of theory) is obtained after freeze-drying.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[C:11]3/[C:12](=[O:20])[NH:13][C:14]4[C:19]/3=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:8]=2)[CH:3]=[N:2]1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1C1C2C(=CC(C=O)=CC=2)NN=1>>[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:3]1[C:4]2[C:9](=[CH:8][C:7](/[CH:10]=[C:11]3/[C:12](=[O:20])[NH:13][C:14]4[C:19]/3=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2cn[nH]c2c1
Reactant: O=Cc1ccc2c(-c3cccs3)n[nH]c2c1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(-c3cccs3)n[nH]c2c1

Procedure:
According to the procedure for the synthesis of (E)-3-((1H-indazol-6-yl)methylene)indolin-2-one, except substituting 3-(thiophen-2-yl)-1H-indazole-6-carbaldehyde (29 m 0.13 mmol), the title compound was prepared as a yellow solid (19.7 mg, 45%). 1H NMR (400 MHz, d6-DMSO) δ 10.64 (br s, 1H), 8.22 (d, J=8.5 Hz, 1H), 7.92 (s, 1H), 7.79 (s, 2H), 7.61 (d, J=7.5 Hz, 1H), 7.59 (d, J=5.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.26-7.20 (m, 2H), 6.89 (d, J=7.5 Hz, 1H), 6.85 (t, J=7.5 Hz, 1H); MS ESI 344.1 [M+H]+, calcd for [C20H13N3OS+H]+ 344.08.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][CH2:19][OH:20]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[N:6]([CH2:18][CH2:19][OH:20])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: OCCBr
Reactant: Cc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc2ccccc2n1CCO
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-1H-benzimidazole (3.50 g, 25.95 mmol) in DMF (70.0 mL), Cs2CO3 (12.08 g, 36.33 mmol) and 2-bromoethanol (2.5 mL, 34.15 mmol) was added. After stirring at 150° C. for 1 h, the reaction mixture was allowed to reach rt and was diluted with EtOAc. The org. layer was separated and the aq. layer was extracted with EtOAc (5×). The combined org. layers were washed with brine, dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 2-(2-methyl-1H-benzoimidazol-1-yl)ethanol which was used in the next step without further purification. LC-MS conditions B: tR=0.25 min, [M+H]+=177.17.
Reaction SMILES: NCCC([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[C:20]([Cl:33])[CH:19]=1)=O.C(OC(=O)NCCC(=O)NC1C=C2C(=CC=1)N=CN=C2NC1C=CC(F)=C(Cl)C=1)(C)(C)C>>[Cl:33][C:20]1[CH:19]=[C:18]([NH:17][C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[C:7]([NH2:6])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1
Reactant: NCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Product: Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1

Procedure:
The procedure of (20-1) of Example 20 was repeated except for using 0.55 g of the compound obtained in Example 52 instead of the compound obtained in (1-4) of Example 1 to obtain the title compound (0.4 g, 93%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[NH:20][C:19](=[O:21])[C:18]2=[C:22]([CH3:28])[N:23]=[C:24]([CH2:25][CH2:26][CH3:27])[N:17]2[N:16]=1)[CH2:2][CH3:3].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30].CN1C(=O)C2=CN=C(CCC)N2N=C1C1C(OCCC)=CC=C(S(N)(=O)=O)C=1>ClCCl.CO>[CH2:29]([N:31]([CH2:32][CH3:33])[S:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[C:6]([C:15]2[NH:20][C:19](=[O:21])[C:18]3=[C:22]([CH3:28])[N:23]=[C:24]([CH2:25][CH2:26][CH3:27])[N:17]3[N:16]=2)[CH:7]=1)(=[O:13])=[O:12])[CH3:30]
Reactant: CCNCC
Reactant: CCCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(CCC)nc(C)c2c(=O)[nH]1
Agent: CCCOc1ccc(S(N)(=O)=O)cc1-c1nn2c(CCC)ncc2c(=O)n1C
Solvent: ClCCl
Solvent: CO
Product: CCCOc1ccc(S(=O)(=O)N(CC)CC)cc1-c1nn2c(CCC)nc(C)c2c(=O)[nH]1

Procedure:
By the same method, starting with 42 mg (0.1 mmol) of 4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 22 mg (0.6 mmol) of diethylamine, 42 mg (92%) of N,N-diethyl-3-(5-(methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide are obtained. Rf=0.64 (dichloromethane/methanol=9:1)
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]([Cl:21])([Cl:20])[C@@H:11]1[N:15]2[CH2:16][CH2:17][CH2:18][C@H:14]2[C:13](=[O:19])[O:12]1.[CH3:22][N+:23]([CH3:25])=[CH2:24].[I-].O>C1COCC1>[CH3:22][N:23]([CH2:25][C@@:14]12[CH2:18][CH2:17][CH2:16][N:15]1[C@@H:11]([C:10]([Cl:9])([Cl:20])[Cl:21])[O:12][C:13]2=[O:19])[CH3:24]
Reactant: C=[N+](C)C
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Agent: CC(C)[N-]C(C)C
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 1M of solution of lithium diisopropylamide in a 3:5 mixture of hexanes/THF (8.25 ml) is added dropwise to (3R,7aS)-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1-one (1.51 g, prepared as described by Wang and Germanas Synlett 1999, 33-36.) in THF (5 ml) at −78° C. After stirring 30 minutes at −78° C. Eschenmoser's salt (2.78 g) is added. The reaction mixture is then allowed to warm to −40° C. with vigorous stirring over 1 hour and maintained for 2 hours at −40° C. Water is then added and the aqueous layer extracted with dichloromethane, the combined organic layers dried over sodium sulphate and evaporated. The residue is then purified by mormal phase chromatography eluting with a gradient from dichloromethane to 20% ethyl acetate in dichloromethane to give the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][CH:8]=2)=[CH:5][CH:4]=[C:3]([C:16]([OH:18])=O)[CH:2]=1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]2[N:24]=[C:25]([Cl:27])[NH:26][C:22]=2[CH:21]=1>>[Cl:27][C:25]1[NH:24][C:23]2[CH:28]=[CH:29][C:20]([NH:19][C:13]([C:10]3[CH:9]=[CH:8][C:7]([C:6]4[CH:1]=[CH:2][C:3]([C:16]([NH:19][C:20]5[CH:29]=[CH:28][C:23]6[NH:24][C:25]([Cl:27])=[N:26][C:22]=6[CH:21]=5)=[O:18])=[CH:4][CH:5]=4)=[CH:12][CH:11]=3)=[O:15])=[CH:21][C:22]=2[N:26]=1
Reactant: O=C(O)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: Nc1ccc2nc(Cl)[nH]c2c1
Product: O=C(Nc1ccc2[nH]c(Cl)nc2c1)c1ccc(-c2ccc(C(=O)Nc3ccc4[nH]c(Cl)nc4c3)cc2)cc1

Procedure:
Compound 285 was prepared according to the procedure similar to that described in Scheme V from 4,4′-bisbenzoic acid and 5-amino-2-chlorobenzimidazole. [M+H]+ calcd for C28H18N6O2: 541.09; found: 541.91.
Reaction SMILES: [CH2:1]([Si:4]([CH2:18][CH:19]=[CH2:20])([CH3:17])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH:2]=[CH2:3].Br[C:22]1[C:35]2[C:26](=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30][CH:29]=[N:28]3)[N:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].O.CO>C1(C)C=CC=CC=1>[CH2:1]([Si:4]([CH2:18][CH:19]=[CH2:20])([CH3:17])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:22]2[C:35]3[C:26](=[C:27]4[C:32](=[CH:33][CH:34]=3)[C:31]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:30][CH:29]=[N:28]4)[N:25]=[CH:24][CH:23]=2)=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: Brc1ccnc2c1ccc1c(-c3ccccc3)ccnc12
Reactant: C=CC[Si](C)(CC=C)CCCc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: C=CC[Si](C)(CC=C)CCCc1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Temperature: 100 °C

Procedure:
4-{3-[diallyl(methyl)silyl]propyl}phenylboronic acid is made by the method of Casado and Stobart (Casado, M. A.; Stobart, S. R., Org. Lett., 2 (11), 2000, 1549-1552). 4-{3-[diallyl(methyl)silyl]propyl}phenylboronic acid (0.576 g) and a solution of Pd(Ph3)4 (58 mg) in 5 mL of degassed toluene is placed in a 50 mL Schlenk tube. The mixture is purged with nitrogen, after which a solution of 4-bromo-7-phenyl-1,10-phenanthroline (0.670 g) and Na2CO3 (428 mg, 4 mmol) in 5 mL of degassed 4:1 H2O/CH3OH is added. The mixture is heated under nitrogen at 100° C. with rapid stirring until TLC monitoring shows the reaction to be complete (ca 24 hrs). The reaction mixture is then added to a separatory funnel and washed with ether (3×50 mL). The combined organic fractions are dried over MgSO4 and concentrated by roto-evaporation. The desired product is purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([CH2:5][OH:6])=[CH:9][CH:10]=[C:11]([CH3:13])[N:12]=1
Reactant: COC(=O)c1ccc(C)nc1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(C)ccc1CO
Yield: 99.3 %

Procedure:
A solution of methyl 2-methoxy-6-methylnicotinate (5.60 g, 30.9 mmol) in dry tetrahydrofuran (155 mL, 30.9 mmol) under an atmosphere of nitrogen was cooled in an ice bath. Lithium aluminum hydride (1.23 g, 30.9 mmol) was added as a slurry in tetrahydrofuran and the mixture was stirred with cooling in an ice bath for 75 minutes. The reaction mixture was diluted with tetrahydrofuran (30 mL). Some Celite® was added followed by sodium sulfate decahydrate to quench. The mixture was filtered and concentrated under vacuum to give (2-methoxy-6-methylpyridin-3-yl)methanol (4.7 g) which was used without purification.
Reaction SMILES: C(OC(C1C=C(OC2C=CC(NC)=C(N)C=2)C=CN=1)=O)(C)(C)C.NC(N)=S.IC.C([O:34][C:35]([C:37]1[CH:42]=[C:41]([O:43][C:44]2[CH:62]=[CH:61][C:47]3[N:48]([CH3:60])[C:49]([NH:51][C:52]4[CH:57]=[CH:56][C:55]([Br:58])=[C:54]([CH3:59])[CH:53]=4)=[N:50][C:46]=3[CH:45]=2)[CH:40]=[CH:39][N:38]=1)=[O:36])(C)(C)C.FC(F)(F)C(O)=O>CO.C(Cl)Cl>[Br:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:49]2[N:48]([CH3:60])[C:47]3[CH:61]=[CH:62][C:44]([O:43][C:41]4[CH:40]=[CH:39][N:38]=[C:37]([C:35]([OH:36])=[O:34])[CH:42]=4)=[CH:45][C:46]=3[N:50]=2)=[CH:53][C:54]=1[CH3:59]
Reactant: Cc1cc(Nc2nc3cc(Oc4ccnc(C(=O)OC(C)(C)C)c4)ccc3n2C)ccc1Br
Agent: CNc1ccc(Oc2ccnc(C(=O)OC(C)(C)C)c2)cc1N
Agent: NC(N)=S
Solvent: O=C(O)C(F)(F)F
Solvent: CI
Solvent: ClCCl
Product: Cc1cc(Nc2nc3cc(Oc4ccnc(C(=O)O)c4)ccc3n2C)ccc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 4-bromo-3-methylbenzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl4-(2-{[4-bromo-3-methylphenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluoroacetic acid and stirred at ambient temperature overnight. Resulting 4-(2-{[4-bromo-3-methylphenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH+=452
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:9]([C:10]2[S:11][CH:12]=[C:13]([Br:15])[CH:14]=2)[CH2:8][N:7]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:6]1)=[O:4].C1NCC2C1CC1C(C#N)=CSC=12>>[Br:15][C:13]1[CH:14]=[C:10]([CH:9]2[CH2:8][N:7]([CH:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[CH2:6][CH:5]2[C:3]([OH:4])=[O:2])[S:11][CH:12]=1
Reactant: COC(=O)C1CN(C(C)c2ccccc2)CC1c1cc(Br)cs1
Agent: N#Cc1csc2c1CC1CNCC21
Product: CC(c1ccccc1)N1CC(C(=O)O)C(c2cc(Br)cs2)C1
Yield: 100 %

Procedure:
The product of step b), diastereomer 1 (15 g, 0.038 mol) was treated by the method outlined in Example 34, step c) to afford the subtitle compound (14.7 g, yield: 100%). MS calculated for C17H18BrNO2S+H: 380, observed 380 and 383.
Reaction SMILES: [C:1]1([C:7]2[S:30][C:10]3[CH2:11][CH2:12][C:13]4[CH:14]=[N:15][C:16]([NH:19][C:20]5[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=5)=[N:17][C:18]=4[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[C:1]1([C:7]2[S:30][C:10]3=[CH:11][CH:12]=[C:13]4[C:18]([N:17]=[C:16]([NH:19][C:20]5[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=5)[N:15]=[CH:14]4)=[C:9]3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1cccc(Nc2ncc3c(n2)-c2cc(-c4ccccc4)sc2CC3)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cccc(Nc2ncc3ccc4sc(-c5ccccc5)cc4c3n2)c1
Yield: 38.5 %

Procedure:
To a dark solution of 3-(8-Phenyl-5,6-dihydro-thieno[2,3-h]quinazolin-2-ylamino)-benzenesulfonamide (130 mg, 0.30 mmol) in anhydrous 1,4-dioxane (7 mL) was added DDQ (75 mg, 0.33 mmol) and the mixture was refluxed under nitrogen for 2-3 hours. The reaction mixture was concentrated in vacuo and the resulting crude residue was triturated in a mixture of 2M NaOH (25 mL) and DCM (25 mL). The resulting solid was filtered and washed with DCM and water to afford 50 mg (39% yield) of the title compound as a pale yellow/green powder. MS (ES+) 433, (ES−) 431. δH (d6 DMSO) 7.39 (2H, br s), 7.41 (1H, m), 7.51 (4H, br m), 7.72 (1H, d), 7.83 (1H, d), 7.96 (3H, m), 8.68 (1H, s), 9.40 (1H, s), 9.61 (1H, br s) and 10.41 (1H, s).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](Cl)=[O:5].N1C=CC=CC=1.[OH:13][C:14]1[CH2:19][CH:18]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[CH2:17][C:16](=[O:29])[CH:15]=1.ClCCl>O>[C:4]([C:15]1[C:14](=[O:13])[CH2:19][CH:18]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[CH2:17][C:16]=1[OH:29])(=[O:5])[CH2:3][CH2:2][CH3:1]
Reactant: Cc1cc(C)c(C2CC(=O)C=C(O)C2)c(C)c1
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
n-Butyryl chloride (2.3 g; 21.7 mmole) and then pyridine (1.7 g; 21.7 mmole) were added to a stirred mixture of 3-hydroxy-5-mesitylcyclohex-2-en-1-one (5.0 g; 21.7 mmole) and dichloromethane (50 ml) under a nitrogen atmosphere. The mixture was stirred at room temperature for a period of two hours and then poured into slightly acidic water. The organic phase was separated and the aqueous phase was thoroughly extracted with dichloromethane. The combined organic phase and extracts were washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by evaporation under reduced pressure using a rotary evaporator. The residue was dissolved in 1,2-dichloroethane (50 ml), stannic chloride (5.7 g; 22 mmole) was added and the mixture was heated under reflux for a period of 8 hours. The mixture was cooled and poured into water and the aqueous mixture was extracted several times with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate and the solvent was removed by evaporation under reduced pressure using a rotary evaporator. The residue was purified by chromatography over silica gel (eluant dichloromethane) to give 2-butyryl-3-hydroxy-5-mesitylcyclohex-2-en-1-one (2.4 g). Proton nuclear magnetic resonance spectrum (CDCl3 : δ in ppm): 1.01 (3H, t); 1.30-1.60 (2H, m); 2.23 (3H, s); 2.37 (6H, s); 2.40-3.45 (7H, m); 6.83 (2H, s); 18.24 (1H, s).