Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[K+].C(O)(C)(C)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.O1CCCCC1.Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36].[Br-].Cl>CCCCCC.CN(C=O)C.O>[OH:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: OCCCCCCBr
Agent: Cl
Agent: [Br-]
Agent: [H-]
Solvent: CCCCCC
Solvent: O
Solvent: CC(C)(C)O
Product: N#Cc1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
At room temperature, potassium hydride (2.5 g, 35 wt % oil dispersion, 0.88 g KH, 22 mmol) was washed twice with hexane and suspended in DMF (30 mL), followed by addition of t-butyl alcohol (2.1 mL, 1.63 g, 22 mmol). 4'-Hydroxy-4-cyanobiphenyl (3.9 g, 20 mmol) was added as a solid all at once to give a deep yellow solution. The mixture was stirred 5 min at room temperature and the tetrahydropyran of 6-bromohexanol (5.8 g, 22 mmol) was added all at once with a mild exotherm. After 2 h, more bromide (1.0 g) was added and the reaction mixture was stirred for 1 h. The mixture was diluted with water, acidified with 5 N hydrochloric acid and extracted with ether-dichloromethane (4:1). An insoluble white solid had to be removed by filtration through glass fiber to obtain good separation of phases. The extracts were washed with water, dried (MgSO4) and concentrated to a solid (7.7 g). The solid was stirred with tetrahydrofuran-2.5 N hydrochloric acid (4:1, 50 mL) overnight at room temperature and then heated to reflux for 2.0 h. The ethanol was removed and the aqueous phase was extracted with ether-dichloromethane (4:1). The extracts were washed with water, dried (MgSO4) and concentrated to a solid that was recrystallized from ethanol-ether to give 4'-(6-hydroxyhexyloxy)-4-cyanobiphenyl: (3.25 g, 55%): mp 87-89° C., nematic phase 89-106° C.; 1H NMR (CDCl3) 7.63(s, 4H), 7.46 and 6.90(2d, 4H), 3.97(t, 2H), 3.62(t, 2H), 1.9-1.3(m, 8H); IR (KBr) 3300, 2225, 1601, 1580, 1525 cm-1.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:15]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)[C:16]([OH:18])=[O:17])[CH3:14].CI>CN(C=O)C.C1COCC1>[CH2:13]([C:15]([C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1)([CH3:1])[C:16]([OH:18])=[O:17])[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CCC(C(=O)O)c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CN(C)C=O
Product: CCC(C)(C(=O)O)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To dry THF at -78° C. was added diisopropylamine (5.05 g 48 mmol, 7 mL) and then n-butyl lithium. The reaction mixture was stirred for 0.5 h and then ethyl 4-pyridyl acetic acid (7.85g, 46 mmol) was added, and after stirring for 0.5 h at that -78° C. the reaction temperature was raised to room temperature. DMF (20 mL was added and the reaction mixture cooled to -78° C. again. Methyl iodide (7.07 g, 50.2 mmol, 3.15 mL) was added and the reaction mixture stirred at that temperature for 1 h and then at room temperature overnight. All the volatiles were then stripped off and the reaction mixture was partitioned between water-CH2 Cl2. The aqueous phase was washed twice with CH2Cl2. The combined CH2Cl2 phases were dried and evaporated. The crude product was chromatographed on silica gel eluting with 80% EtOAc hexane to give the title compound (7.88g, MH+ 179).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[S:15]([OH:18])(=[O:17])=[O:16]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: Brc1ccc(-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1ccccc1-c1ccc(Br)cc1
Reaction time: 4 h

Procedure:
4′-Bromobiphenyl (14 g) was dissolved in chloroform (140 mL) at room temperature. Chlorosulfonic acid (8.4 g) was added dropwise and a precipitate appeared soon after addition was complete. Stirring was continued for a further 4 hours, after which the solid was collected by filtration. Further crops of crystals were collected from the filtrate. The solid was washed with cold chloroform and the washings also allowed to crystallise, to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:32].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][C:16]([Cl:32])=[C:10]2[CH:9]1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2COc1ccc(C(F)(F)F)cc1
Reactant: ClCCl
Solvent: CO
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2COc1ccc(C(F)(F)F)cc1

Procedure:
Subsequent chlorination (70° C.; 3 h) of 3-ethyl-8-(4-trifluoromethyl-phenoxymethyl)-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (0.664 g; 1.561 mmol), and purification by FC (DCM/MeOH=80/1) afforded 1-chloro-3-ethyl-8-(4-trifluoromethyl-phenoxymethyl)-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (0.381 g; 53%). LC-MS: tR=1.04 min.; [M+H]+=460.23 g/mol.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:43])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]4[CH3:42])[C:16]4[CH2:21][N:20]([CH2:22][CH:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)[CH2:19][C:17]=4[N:18]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl.CO>O1CCOCC1>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:14]=[C:15]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]4[CH3:42])[C:16]4[CH2:21][N:20]([CH2:22][CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[CH2:19][C:17]=4[N:18]=3)=[CH:11][CH:12]=2)=[O:43])[CH2:3][CH2:2]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CN(CC1CCNCC1)C2
Yield: 22.5 %

Procedure:
(S)-tert-butyl 4-((2-(4-(3-cyclopropylureido)phenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)methyl)piperidine-1-carboxylate (example 128) (24 mg, 0.04 mmol) was stirred in a solution of 4M HCl in dioxane (1 mL), and methanol (0.5 mL) until analysis by LCMS indicated reaction was complete. Reaction mixture was then purified by TsOH cartridge (loaded in MeOH eluted with 2M methanolic ammonia) to afford an orange brown solid (4.9 mg, 0.009 mmol, 25%).
Reaction SMILES: [Na+].[O:2]([CH2:9][C:10]([O:12][CH2:13][C:14]([F:20])([F:19])[S:15]([O-:18])(=[O:17])=[O:16])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Na].FC(F)(F)S([O-])(=O)=O.[C:30]1([CH:36]([SH+:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:37]1([CH:36]([SH+:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1.[F:20][C:14]([F:19])([S:15]([OH:18])(=[O:17])=[O:16])[CH2:13][O:12][C:10](=[O:11])[CH2:9][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(COc1ccccc1)OCC(F)(F)S(=O)(=O)[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Agent: [Na]
Product: O=C(COc1ccccc1)OCC(F)(F)S(=O)(=O)O
Yield: 92.5 %

Procedure:
<2> The reaction described in <3> of Synthesis Example 1 was performed under the same conditions, except that the phenoxyacetyloxymethyl difluoromethanesulfonic acid sodium salt (3.66 g) produced in <1> of Synthesis Example 5 above was used instead of the benzoyloxymethyldifluorosulfonic acid sodium salt in the reaction with diphenylmethylphenylsulfonium trifluoromethanesulfonic acid sodium salt, and thus 4.35 g (yield 92.5%) of phenoxyacetic acid 2,2-difluoro-2-sulfoethyl ester diphenylmethylphenylsulfonium salt as shown in the following reaction scheme 11 was obtained. The structure of the product was confirmed by 1H-NMR (see FIG. 10).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:28])[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]([OH:28])[C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)=[CH:21][CH:22]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2]
Reactant: N#Cc1cc(C(=O)c2ccc(-n3ccnc3)cc2)n2c1ccc1ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(C(O)c2ccc(-n3ccnc3)cc2)n2c1ccc1ccccc12
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of 3-cyano-1-(4-imidazol-1-yl-benzoyl)-pyrrolo[1,2-a]quinoline (40 mg, 0.11 mmol) in 1:1 methanol/chloroform (10 mL) was added sodium borohydride portion-wise over 1 h and the reaction mixture was stirred overnight. It was worked up as described in Example 22 and the crude was purified by chromatography (5% methanol/chloroform) to yield the title compound (38.4 mg, 95%). 1H NMR (CDCl3/MeOH-d4): 8.80 (d, J=8.7 Hz, 1H), 7.93 (s, 1H), 7.80 (dd, J=7.8, 1.5 Hz, 1H), 7.53 (m, 8H), 7.38 (t, J=1.2 Hz, 1H), 7.12 (s, 1H), 6.57 (s, broad, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(OCC)C.Cl.[N:25]([O-])=[O:26].[Na+]>O>[N:25]([N:8]([CH2:7][C:6]1[CH:17]=[CH:18][C:3]([Cl:2])=[CH:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:26]
Reactant: O=N[O-]
Reactant: COc1ccc(NCc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(N(Cc2ccc(Cl)cc2)N=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of N-(4-chlorobenzyl)-4-methoxyaniline hydrochloride salt (141.4 g; 497.5 mmol), prepared as above, in 1500 mL water, 750 mL diethyl ether, and 525 mL aqueous 1N HCl was treated with a solution of sodium nitrite (37.7 g; 547 mmol) in 150 mL water. After stirring for 2 hours at ambient temperature the reaction mixture was extracted twice with diethyl ether. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated to give N-nitroso-N-(4-chlorobenzyl)-4-methoxyaniline as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[C:16]1([S:22]N2C(=O)CCC2=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.B(F)(F)F.CCOCC>C(Cl)Cl.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[C:16]1([S:22][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: O=C1CCC(=O)N1Sc1ccccc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1Sc1ccccc1
Reaction time: 2 h

Procedure:
To a partial suspension of ethyl 5-chloroindole-2-carboxylate (698 mg, 3.1 mmol) and N-(phenylthio)succinimide (683 mg, 3.3 mmol) in anhydrous methylene chloride (20 mL) at ambient temperature under an inert gas atmosphere was added boron trifluoride etherate (0.12 mL, 1.0 mmol). The reaction was monitored by tlc (thin layer chromatography) until complete. After 2 hours, the reaction was diluted with chloroform and neutralized with aq. NaHCO3. The organic layer was dried (Na2SO4), filtered through a pad of charcoal, and the solvents evaporated. The residue was triturated with hexanes as the product crystallized out to yield the title product, mp 160°-162° C. [see Table II, mp 163°-164° C⟧ This material was used as is.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[CH2:10]([S:12]([NH2:15])(=[O:14])=[O:13])[CH3:11].C1(C)C=CC=CC=1.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O.CO>[Br:1][C:2]1[CH:9]=[C:6]([CH2:7][NH:15][S:12]([CH2:10][CH3:11])(=[O:14])=[O:13])[CH:5]=[N:4][CH:3]=1
Reactant: CCS(N)(=O)=O
Reactant: O=Cc1cncc(Br)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)NCc1cncc(Br)c1
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
A flask was charged with 5-bromonicotinaldehyde (2.55 g, 13.7 mmol), ethanesulfonamide (2.99 g, 27.4 mmol) and toluene (250 mL), then titanium isopropoxide (5.84 g, 20.6 mmol) was added dropwise. The reaction mixture was heated to 115° C. over night and then concentrated in vacuo. The residue was taken up in DCM (200 mL) and MeOH (200 mL) and NaBH4 (1.04 g, 27.4 mmol) was added portionwise at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then poured into water (100 mL) and the resulting suspension was filtered through a pad of Dicalite and washed with DCM (3×100 mL). The aqueous layer was separated and extracted with DCM (2×200 mL). Combined organics were dried over Na2SO4, filtered and preadsorbed on silica gel. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (3.01 g, 79%) as an orange solid. MS: 279.0, 281.0 (M+H+).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:16]=1)[CH3:14])(C)(C)C.C1(C2C=CC(N(CCCCOCC(O)=O)C)=NC=2C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+:64]>>[Na+:64].[C:21]1([C:18]2[CH:19]=[CH:20][C:15]([N:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][C:6]([O-:33])=[O:5])[CH3:14])=[N:16][C:17]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CN(CCCCOCC(=O)OC(C)(C)C)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Agent: CN(CCCCOCC(=O)O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Product: CN(CCCCOCC(=O)[O-])c1ccc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
After 2-{4-[N-(5,6-diphenylpyridin-2-yl)-N-methylamino]butyloxy}acetic acid tert-butyl ester was hydrolyzed in the same manner as in Example 42, the resulting 2-{4-[N-(5,6-diphenylpyridin-2-yl)-N-methylamino]butyloxy}acetic acid was treated with the same amount of 1N sodium hydroxide solution to obtain the desired compound as a pale brown amorphous.
Reaction SMILES: C(OC(=O)CCNC(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:36])[CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH:15]=1)C1C=CC=CC=1.C([O:46][C:47](NCCCC(O)=O)=[O:48])C1C=CC=CC=1.NC1C=C(C=CC=1)C(O)=O>C(O)C>[CH2:29]([O:28][C:26]([NH:25][CH2:24][CH2:23][CH2:22][C:21]([NH:20][C:16]1[CH:15]=[CH:14][CH:19]=[CH:18][C:17]=1[C:47]([OH:48])=[O:46])=[O:36])=[O:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(CCCNC(=O)OCc1ccccc1)Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1
Reactant: O=C(O)CCCNC(=O)OCc1ccccc1
Agent: Nc1cccc(C(=O)O)c1
Solvent: CCO
Product: O=C(CCCNC(=O)OCc1ccccc1)Nc1ccccc1C(=O)O

Procedure:
For the preparation of the ester starting material, m.p. 119°-120° C. (from ethanol), 4-[1-(benzyloxy)formamido]butyric acid is reacted with m-aminobenzoic acid to give m-[4-[1-(benzyloxy)formamido]butyramidobenzoic acid and the latter is reacted with β-alanine benzyl ester.
Reaction SMILES: [H-].[Na+].[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)([CH3:6])([CH3:5])[CH3:4].[C:20]([O:24][C:25](=[O:28])[CH2:26]Br)([CH3:23])([CH3:22])[CH3:21].Cl>CN(C)C=O>[C:20]([O:24][C:25](=[O:28])[CH2:26][N:13]1[C:14]2[C:10](=[C:9]([O:8][Si:7]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:19])[CH3:18])[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]ccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccc2c(O[Si](C)(C)C(C)(C)C)cccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 68 %

Procedure:
A dispersion of sodium hydride in mineral oil (55%, 61 mg, 1.4 mmol) was added to a solution of 4-(tert-butyl-dimethyl-silanyloxy)-1H-indole [251 mg, 1 mmol; Eur. Pat. Appl. (1986), EP 206225 A2] and bromo-acetic acid tert-butyl ester (160 μl. 1, 1.1 mmol) in N,N-dimethylformamide (10 ml) at 0° C. under an argon atmosphere. The reaction mixture was naturally warmed to ambient temperature, stirred for 14 h and cooled to 0° C. Ice water (10 ml) and concentrated HCl (2 ml) were added and the mixture was extracted three times with dichloromethane. The combined extracts were washed with brine and water and dried over sodium sulfate. The solvent was removed under reduced pressure to give a yellow liquid which was purified by column chromatography (silica gel, heptane/AcOEt) to give 246 mg (0.68 mmol, 67%) of the title compound as light yellow oil.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1>>[C:1]1([C:7]2[N:12]=[C:11]([O:13][CH2:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)[CH:10]=[C:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: O=C(O)c1ccc(COc2cc(-c3ccccc3)nc(-c3ccccc3)n2)cc1

Procedure:
The title compound was prepared from 2,6-diphenyl-pyrimidin-4-ol (which was obtained in Intermediate 4) and methyl 4-(bromomethyl)benzoate according to Method A and Method B; 1H NMR (DMSO-d6, 300 MHz) δ 5.62 (s, 2H), 7.25 (t, J=8.9 Hz, 2H), 7.49 (s, 1H), 7.50-7.70 (m, 12H); LC retention time 3.59 min; MS: m/z (ESI) 381 (M−H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:26]=[C:25]([I:27])[CH:24]=[CH:23][C:21]=1[NH2:22].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:22][C:21]1[CH:23]=[CH:24][C:25]([I:27])=[CH:26][C:20]=1[F:19])[CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)Nc1ccc(I)cc1F
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid (1.1 g, 4.06 mmol) and 2-fluoro-4-iodoaniline (800 mg, 3.38 mmol) in pyridine (15 mL) at −10° C. was slowly added phosphorus oxychloride (0.35 mL, 3.72 mmol) under an atmosphere of dry nitrogen. The mixture was stirred for 2 hours at −10° C. After removal of the solvent and the excess reagent by rotary evaporator, ice water was added. The mixture was extracted with dichloromethane and the organic layer washed with 1 M aqueous citric acid, brine, saturated aqueous sodium carbonate, brine and dried over sodium sulfate. The solvents were removed to give [(S)-1-(2-fluoro-4-iodo-phenylcarbamoyl)-2-thiophen-2-yl-ethyl]-carbamic acid tert-butyl ester as a yellow viscous oil for use in the next step (1.52 g, 92%).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24])[C:10](=[O:16])[N:11]1[CH2:15][CH2:14][S:13][CH2:12]1)(C)(C)C>C(OCC)(=O)C>[ClH:1].[NH2:8][CH:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24])[C:10]([N:11]1[CH2:15][CH2:14][S:13][CH2:12]1)=[O:16]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1F)C(=O)N1CCSC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(Cc1ccccc1F)C(=O)N1CCSC1

Procedure:
HCl was bubbled into a solution of [1-(2-fluoro-benzyl)-2-oxo-2-thiazolidin-3-yl-ethyl]-carbamic acid tert-butyl ester (0.39 g, 1.1 mmol) in ethyl acetate (15 mL). The solution was concentrated, the residue was triturated in ether, the solid was filtered and dried (0.27 g, 84%, mp 217-218° C.).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[S:22]([CH3:25])(=[O:24])=[O:23])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=O)C.[CH3:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[CH3:35])[CH2:30][NH2:31]>>[CH3:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[CH3:35])[CH2:30][NH:31][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[S:22]([CH3:25])(=[O:24])=[O:23])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:3]
Reactant: CCOC(=O)c1nc(-c2ccc(F)cc2S(C)(=O)=O)n(C)c(=O)c1O
Reactant: Cc1ccc(CN)cc1C
Product: Cc1ccc(CNC(=O)c2nc(-c3ccc(F)cc3S(C)(=O)=O)n(C)c(=O)c2O)cc1C

Procedure:
Prepared according to the procedure described for example 2 from 2-(4-fluoro-2-methanesulfonyl-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (55.56 mg, 0.15 mmol) and 3,4-dimethylbenzylamine (102 mg, 0.75 mmol). The title product was obtained as a pink solid (59.8 mg, 87% yield). 1HNMR (500 MHz, CDCl3) δ: 12.25 (1H, s), 7.86 (1H, dd, J=7.63, 2.44 Hz), 7.49–7.44 (2H, m), 7.41 (1H, dd, J=8.54, 4.88 Hz), 7.07 (1H, d, J=7.63 Hz), 7.01 (1H, s), 6.97 (1H, d, J=7.63 Hz), 4.53 (1H, dd, J=14.65, 6.41 Hz), 4.43 (1H, dd, J=14.96, 5.49 Hz), 3.26 (3H, s), 3.01 (3H, s), 2.22 (6H, s). HRMS (ESI) calcd for C22H23FN3O5S (M+H): 460.1343; found: 460.1337.
Reaction SMILES: [C:1]([Si:5]([CH3:37])([CH3:36])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22](OS(C(F)(F)F)(=O)=O)=[CH:21][C:20]=3[Cl:34])[C:14]2=[O:35])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[N:40]1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(COC)OC>[C:1]([Si:5]([CH3:37])([CH3:36])[O:6][C@@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22]([C:42]4[CH:41]=[N:40][N:39]([CH3:38])[CH:43]=4)=[CH:21][C:20]=3[Cl:34])[C:14]2=[O:35])[CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2cc(Cl)c(CC3CCN([C@H]4CC[C@@H](O[Si](C)(C)C(C)(C)C)CC4)C3=O)c(Cl)c2)cn1

Procedure:
Using the method of Example 81 and trifluoro-methanesulfonic acid 4-{1-[cis-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-2-oxo-pyrrolidin-3-yl methyl}-3,5-dichloro-phenyl ester (Preparation 74) (0.400 g, 0.658 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.411, 1.97 mmol), tetrakis(triphenylphosphine)palladium (0.076 g, 0.0658 mmol), dimethoxyethane (5 mL) and sodium carbonate (2M, 1.8 mL) gives the title compound. Purify the crude material over silica gel (3/1 hexane in ethyl acetate to ethyl acetate) to yield 0.301 g (85%) of the title compound: mass spectrum (m/z): 538(M+1).