Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][S:11]([CH2:14][C:15]([OH:17])=O)(=[O:13])=[O:12].[OH:18][CH:19]([CH:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)[CH2:20][NH2:21].OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[OH:18][CH:19]([CH:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)[CH2:20][NH:21][C:15](=[O:17])[CH2:14][S:11](=[O:12])(=[O:13])[NH:10][C:3]1[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: CC1(C)OCC(C(O)CN)O1
Reactant: O=C(O)CS(=O)(=O)Nc1c(F)cc(F)cc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC1(C)OCC(C(O)CNC(=O)CS(=O)(=O)Nc2c(F)cc(F)cc2F)O1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
1.38 g (3.16 mmol) of 2-[N-(2,4,6-trifluorophenyl)sulfamoyl] acetic acid is dissolved in 20 ml of DMF with exclusion of moisture and under argon atmosphere, 509 mg (3.16 mmol) of 2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamine and 484 mg (3.16 mmol) of hydroxybenzotriazole are added and the solution is cooled to -10° C. 652 mg (3.16 mmol) of dicyclohexylcarbodiimide is added to the cooled solution, it is stirred for one hour at -10° C and for 12 more hours at room temperature. The turbid reaction solution is then filtered and the clear filtrate is evaporated to dryness in a vacuum. The residue is dissolved in 100 ml of ethyl acetate and the solution is shaken out five times with saturated sodium bicarbonate solution and twice with water. The ethyl acetate solution is dried on sodium sulfate, filtered and evaporated to dryness. The residue is chromatographed on silica gel 60 (Merck) with ethyl acetate/methylene chloride 8:2. The corresponding fractions together contain 0.62 g (1.42 mmol)=45% of the theoretical yield of product is obtained as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][O:6][CH3:7])[CH2:3][OH:4].[CH2:9]([Si:11](Cl)([CH3:13])[CH3:12])[CH3:10]>>[CH3:1][C:2]([CH3:8])([CH2:3][O:4][Si:11]([CH2:9][CH3:10])([CH3:13])[CH3:12])[CH2:5][O:6][CH3:7]
Reactant: COCC(C)(C)CO
Reactant: CC[Si](C)(C)Cl
Product: CC[Si](C)(C)OCC(C)(C)COC

Procedure:
According to the procedure as described in Example 1,2,2-dimethyl-1-methoxy-3-[(ethyldimethylsilyl)oxy]propane was prepared from intermediate 2,2-dimethyl-3-methoxy-1-propanol and reagent ethyldimethylsilyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:19][O:20][CH2:21][O:22][CH3:23])([CH2:14][O:15][CH2:16][O:17][CH3:18])[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:19][O:20][CH2:21][O:22][CH3:23])([CH2:14][O:15][CH2:16][O:17][CH3:18])[CH2:12][NH:11][CH2:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COCOCC1(COCOC)CN(C(=O)OC(C)(C)C)CC=C1c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCOCC1(COCOC)CNCC=C1c1ccc(F)cc1

Procedure:
To a dichloromethane solution (0.80 mL) of tert-butyl 4-(4-fluorophenyl)-5,5-bis[(methoxymethoxy)methyl]-5,6-dihydropyridine-1(2H)-carboxylate (40.0 mg, 0.0940 mmol) synthesized in Reference Synthesis Example 358, trifluoroacetic acid (40.0 μL, 0.538 mmol) was added at room temperature and the resultant mixture was stirred for 1 day. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product of the title compound.
Reaction SMILES: FC1C=C(C=CC=1S(C)=[N:21][C:22]#[N:23])CN1C(=O)C2C(=CC=CC=2)C1=O.[C:25]([O:29][C:30](=[O:42])[NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([S:39][CH3:40])=[CH:35][C:34]=1[F:41])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:42])[NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([CH3:40])=[N:23][C:22]#[N:21])=[CH:35][C:34]=1[F:41])([CH3:28])([CH3:26])[CH3:27]
Reactant: CS(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1F
Reactant: CSc1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Product: CS(=NC#N)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1

Procedure:
The title compound is prepared following the procedure described for preparation 15b, using (2-fluoro-4-methylsulfanyl-benzyl)-carbamic acid tert-butyl ester (preparation 18b) as starting material. ESI mass spectrum: [M+H]+=312; r.t. HPLC: 0.68 min (5-95AB).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH:13][CH3:14].[H][H]>C1COCC1.[Pd]>[NH2:10][C:6]1[C:5]([NH:13][CH3:14])=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([NH:2][CH3:1])=[O:15]
Reactant: CNC(=O)c1cccc([N+](=O)[O-])c1NC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(N)c1NC
Reaction time: 3 h

Procedure:
To a stirred solution of N-methyl-2-(methyl-amino)-3-nitrobenzamide (17; 0.22 g, 0.00104 mol) in THF (10 ml) was added 10% palladium on carbon (catalytic amount) portion wise at room temperature. The reaction mixture was allowed to stir under the atmosphere of hydrogen gas supplied by balloon at room temperature for 3 h. The reaction mixture was filtered through CELITE® and filtrate was concentrated to afford the desired product 3-amino-N-methyl-2-(methyl-amino) benzamide after drying and carry forward to next step by checking LCMS. LCMS (ES) m/e MS (M+1=180) Purity: 85.6%.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17](O)=[O:18].[NH2:20][C:21]1[S:25][CH:24]=[C:23]([C:26]#[N:27])[C:22]=1[N:28]1[N:32]=[CH:31][CH:30]=[N:29]1>>[C:26]([C:23]1[C:22]([N:28]2[N:32]=[CH:31][CH:30]=[N:29]2)=[C:21]([NH:20][C:17](=[O:18])[CH2:16][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:25][CH:24]=1)#[N:27]
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Reactant: N#Cc1csc(N)c1-n1nccn1
Product: N#Cc1csc(NC(=O)Cn2c(=O)ccc3cc(C(F)(F)F)ccc32)c1-n1nccn1

Procedure:
N-(4-cyano-3-(2H-1,2,3-triazol-2-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide was prepared from 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (0.15 g, 0.56 mmol) and 5-amino-4-(2H-1,2,3-triazol-2-yl)thiophene-3-carbonitrile (0.070 g, 0.37 mmol) according to protocol A. The crude product was purified by prep HPLC. Retention time (min)=6.5, method [7], MS(ESI) 467.1 (M+Na). 1H NMR (CDCl3) δ 11.50 (s, 1H), 7.93-7.85 (m, 4H), 7.83 (s, 1H), 7.64 (s, 1H), 7.60 (d, J=8.5 Hz, 1H), 6.95 (d, J=9.7 Hz, 1H), 5.29 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:14][O:15]CC3CCCCC3)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH2:35]([O:37][C:38]([C:40]1([O:44][C:45]2[CH:50]=[CH:49][C:48](O)=[CH:47][CH:46]=2)[CH2:43][CH2:42][CH2:41]1)=[O:39])[CH3:36].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:35]([O:37][C:38]([C:40]1([O:44][C:45]2[CH:50]=[CH:49][C:48]([O:15][CH2:14][CH:13]([N:12]3[C:11]4[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=4[N:9]=[C:8]3[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:47][CH:46]=2)[CH2:43][CH2:42][CH2:41]1)=[O:39])[CH3:36]
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Reactant: CCOC(=O)C1(Oc2ccc(O)cc2)CCC1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C1(Oc2ccc(OCC(C3CCCCC3)n3c(-c4ccc(Cl)cc4)nc4cc(F)c(F)cc43)cc2)CCC1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Example 1, intermediate c), 1-(4-hydroxy-phenoxy)-cyclobutanecarboxylic acid ethyl ester (CAS RN: 879094-83-4), tri-n-butylphosphin and N,N,N′,N′-tetramethylazodicarboxamide. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Light yellow foam (45%). MS (Turbo Spray): m/z=609.3 [M+H].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:15]([N:18]=[C:19]=[O:20])([CH3:17])[CH3:16]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:19]([NH:18][CH:15]([CH3:17])[CH3:16])=[O:20])[CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(I)cc(N)cc1C(C)(C)C
Reactant: CC(C)N=C=O
Product: COc1c(I)cc(NC(=O)NC(C)C)cc1C(C)(C)C

Procedure:
3-tert-Butyl-5-iodo-4-methoxyaniline (305 mg, 1 mmol) and isopropyl isocyanate were reacted in the same manner as Example 15 Part A to give the title compound
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=1Cl)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])([O-:10])=[O:9]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc(C(=O)c3ccccc3)cc2[N+](=O)[O-])CC1
Yield: 90 %

Procedure:
N-methyl-piperazine is reacted with 3-nitro-4-chloro-benzophenone as described in Example 7 or 8 to obtain 3-nitro-4-(N-methyl-piperazino)-benzophenone (compound B11, supra with a yield of 90%. The product melts at 94°C. Analysis for C18H19N3O3 : Calculated: C 66.44% H 5.89% N 12.92% Found: C 66.28% H 5.83% N 12.79%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>CC(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[S:20]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)(=[O:22])=[O:21]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Nc1ccc(OS(=O)(=O)c2c(Cl)cccc2Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.3 %

Procedure:
To a solution of 3.14 g of 4-amino-3-nitrophenol in 50 cm3 of acetone are added 5 g of 2,6-dichlorobenzenesulfonyl chloride. The reaction medium is stirred for five minutes and then placed in a bath of ice-water so as not to exceed 30° C. during the addition of 2.9 cm3 of triethylamine. The formation of a precipitate is observed, and the mixture is stirred for twenty-four hours at a temperature in the region of 20° C. 500 mg of 2,6-dichlorobenzenesulfonyl chloride are added and, after stirring for two hours, the insoluble material is filtered off, washed with three times 30 cm3 of acetone and set aside*. The filtrate is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in 1 L of dichloromethane and then washed with three times 40 cm3 of water. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2 kPa). 3.28 g of 4-amino-3-nitrophenyl 2,6-dichlorobenzenesulfonate are obtained in the form of orange crystals, the characteristics of which are as follows:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[CH:18]=[C:17]([CH2:19][CH3:20])[O:16][N:15]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:31])=[N:25][C:26]=2Cl)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:41]([CH:43]([NH2:46])[CH2:44][CH3:45])[CH3:42]>C(O)(C)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[CH:18]=[C:17]([CH2:19][CH3:20])[O:16][N:15]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:31])=[N:25][C:26]=2[NH:46][CH:43]([CH2:44][CH3:45])[CH2:41][CH3:42])(=[O:3])[CH3:2]
Reactant: CCC(N)CC
Reactant: CCc1cc([C@H]2O[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCc1cc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1
Temperature: 50 °C

Procedure:
(2R,3R,4 R,5R)-4-(acetyloxy)-2-(2,6-dichloro-9H-purin-9-yl)-5-(5-ethylisoxazol-3-yl)tetrahydrofuran-3-yl acetate (125 mg) was dissolved in isopropanol (5 ml) and the solution was treated with diisopropylethylamine (0.06 ml) followed by 1-ethylpropylamine (0.044 ml). The mixture was heated at 50° C. under nitrogen for 16 h. The solvent was removed in vacuo and the mixture partitioned between ethyl acetate and 1 M hydrochloric acid. The organic layers were washed with saturated sodium bicarbonate solution and brine, dried (MgSO4) and evaporated in vacuo. Purification by chromatography on silica gel (Varian Bondelut cartridge), eluting with (i) dichloromethane, (ii) ether and (iii) ethyl acetate, gave the title compound as a colourless oil (108 mg). TLC SiO2 (ether) Rf=0.26.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([N:16]2[CH2:17][CH2:18][N:13]([CH2:11][CH3:12])[CH2:14][CH2:15]2)=[O:9])[CH:3]=1
Reactant: CCN1CCNCC1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Product: CCN1CCN(C(=O)c2cc(Cl)ccn2)CC1

Procedure:
Using 4-chloropicolinic acid chloride and N-ethylpiperazine instead of N-Boc-piperazine, amidation was carried out in the same manner as Step A in Example 1-D-199, to obtain (4-chloro-pyridin-2-yl)-(4-ethyl-piperazin-1-yl)-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (232 mg, 0.430 mmol), and the obtained (4-chloro-pyridin-2-yl)-(4-ethyl-piperazin-1-yl)-methanone (120 mg, 0.473 mmol) instead of 4-chloropicolinic acid t-butylamide, amination was carried out in the same manner as Example 1-D-07, to obtain a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-(4-ethyl-piperazin-1-yl)-methanone as a yellow solid (225 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-201) as a yellow powder (85 mg, 57%).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)([CH3:10])[C:7]([OH:9])=[O:8].[Br:20][CH2:21][CH2:22]O>C(#N)C>[CH3:10][C:6]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)([CH3:5])[C:7]([O:9][CH2:22][CH2:21][Br:20])=[O:8]
Reactant: OCCBr
Reactant: CC(C)(C(=O)O)c1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CC(C)(C(=O)OCCBr)c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Yield: 65.5 %

Procedure:
Thionyl chloride (3 mL, 41 mmol) was added to 2-methyl-2-(4-nitrophenyl)-propionic acid (1 g, 4.78 mmol) and heated at 90° C. overnight. Excess thionyl chloride was evaporated to give a crude acid chloride which was dissolved in acetonitrile (8 mL). To this was added 2-bromoethanol (0.41 mL, 5.78 mmol) then the mixture was heated at reflux overnight. After concentration in vacuo, the residue was diluted with ethyl acetate and washed with sodium bicarbonate solution, then the organic layer was dried and evaporated to afford 2-methyl-2-(4-nitrophenyl)-propionic acid, 2-bromo-ethyl ester (0.99 g, 65.5%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2(O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]2=[O:31])=[C:4]([OH:33])[CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]2=[O:31])=[C:4]([OH:33])[CH:3]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc(F)c(F)cc1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2cc(F)c(F)cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 55.7 %

Procedure:
To a solution of 3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (11.72 g, 26.4 mmol) in trifluoroacetic acid (60 mL) under nitrogen was added triethylsilane (10.55 mL, 66.0 mmol), and the reaction mixture was stirred for 16 h. Following concentration in vacuo, the residue was purified by column chromatography (30% ethyl acetate in hexanes). Precipitation from diethyl ether/hexanes followed by filtration yielded 3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one (6.29 g, 56%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 9.27 (br s, 1H), 7.37-7.12 (m, 12H), 6.94 (s, 1H), 6.87 (dd, J=11.3, 7.1 Hz, 1H), 6.76 (dd, J=11.2, 8.9 Hz, 1H), 6.58-6.56 (m, 1H), 5.12 (s, 1H); MS (ES+) m/z 428.2 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[N+:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([O-:27])=[O:26]>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:31]4[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=4)=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc([N+](=O)[O-])cc1
Yield: 18 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 4-nitrophenylboronic acid (available from Combi-Blocks Inc.; 67 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-nitro-biphenyl-2-carboxylic acid (17 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ 13.35 (br s, 3H), 8.50 (s, 1H) 8.47 (s, 1H), 8.34 (s, 1H), 8.27-8.32 (m, 2H), 8.10 (d, J=8.5 Hz, 1H), 7.77 (d, J=6.8 Hz, 1H), 7.68 (d, J=7.0 Hz, 2H), 7.61 (d, J=6.5 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8](Cl)[N:7]([CH3:12])[C:6]=2[C:5]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1.[C:20]1([CH3:29])[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[NH2:28]>C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([NH:28][C:21]3[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=3[CH3:29])[N:7]([CH3:12])[C:6]=2[C:5]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCCN(CCC)c1ccc(Br)c2nc(Cl)n(C)c12
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CCOC(C)=O
Product: CCCN(CCC)c1ccc(Br)c2nc(Nc3c(C)cc(C)cc3C)n(C)c12
Temperature: 120 °C

Procedure:
A mixture of 4-bromo-2-chloro-1-methyl-N,N-dipropyl-1H-benzimidazol-7-amine (220 mg, 0.638 mmol) and mesityl amine (1.79 ml, 12.8 mmol) was heated at 120° C. for 60 h. The mixture was dissolved in ethyl acetate and washed with saturated sodium bicarbonate in water, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting 5% n-hexane/ethyl acetate to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.Cl[CH:33]([F:35])[F:34]>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=1)[C:10]([O:17][CH:33]([F:35])[F:34])=[N:11]2
Reactant: FC(F)Cl
Reactant: COC(=O)COc1ccc(F)c2[nH]c(=O)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Product: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(-n4cccn4)cc3)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 10c using [8-fluoro-4-methyl-2-oxo-3-(4-pyrazol-1-ylbenzyl)-1,2-dihydroquinolin-5-yloxy]acetic acid methyl ester and chlorodifluoromethane.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH3:7])[CH2:3][C:4]#[CH:5].[C:8]1([C:14](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1>O>[C:8]1([C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:1][CH:2]([CH2:6][CH3:7])[CH2:3][C:4]#[CH:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#CCC(O)CC
Solvent: O
Solvent: c1ccncc1
Product: C#CCC(CC)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A stirred solution of 9.81 g. (0.10 moles) of 4-hydroxy-1-hexyne and 33.5 g. (0.12 moles) of triphenylmethyl chloride in 100 ml. of dry pyridine is heated at reflux for 2 hours. The cooled mixture is treated with water and extracted with a hexane-ether mixture. The extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the residue on Florisil gives an oil, λ max. 3290 (acetylenic hydrogen), 1600, 1030 and 705 cm-1 (triphenylmethoxy group).
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[N:25]=2)[CH:17]([CH2:30][O:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:16]1)=O)(C)(C)C>CO>[ClH:1].[ClH:1].[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([O:31][CH2:30][CH:17]2[CH2:16][NH:15][CH2:20][CH2:19][N:18]2[C:21]2[S:22][CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[N:25]=2)[CH:33]=1
Reactant: COC(=O)c1csc(N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1csc(N2CCNCC2COc2cccnc2)n1
Reaction time: 8 h
Yield: 17 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of methyl 2-(4-(tert-butoxycarbonyl)-2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-4-carboxylate (32 mg, 0.074 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure. The material was dissolved in H2O (20 mL), and the pH was adjusted to ˜2 with concentrated HCl. This was washed with Et2O (3×5 mL, discarded). The aqueous layer was adjusted to pH ˜12 with 1 N NaOH and was extracted with EtOAc (3×20 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure, yielding 5.0 mg (17%) of the title compound. LC-MS: RT=3.41 min, (M+H)+=335.4.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][O:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([S:32]([N:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([CH2:45][C:46](O)=[O:47])[CH:43]=3)[CH2:38][CH2:37][CH2:36]2)(=[O:34])=[O:33])=[C:27]([CH3:49])[CH:26]=1.[CH2:50]1[C:54]2([CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:53][CH2:52][N:51]1[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH3:49])[C:28]([S:32]([N:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([CH2:45][C:46]([N:57]4[CH2:56][CH2:55][C:54]5([CH2:50][N:51]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:52][CH2:53]5)[CH2:59][CH2:58]4)=[O:47])[CH:43]=3)[CH2:38][CH2:37][CH2:36]2)(=[O:33])=[O:34])=[C:29]([CH3:31])[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCc3ccc(CC(=O)O)cc32)c(C)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: COc1cc(C)c(S(=O)(=O)N2CCCc3ccc(CC(=O)N4CCC5(CC4)CCN(C(=O)OC(C)(C)C)C5)cc32)c(C)c1
Yield: 53 %

Procedure:
The target compound was prepared according to general working procedure GWP X (TBTU coupling) from the starting materials 2-(1-(4-methoxy-2,6-dimethylphenyl-sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)acetic acid (E-10) and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (F-26). Yield: 53%