Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]4[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=4)[CH:16]=3)[S:11][C:10]([CH3:32])([CH3:31])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=4)[CH:16]=3)[S:11][C:10]([CH3:32])([CH3:31])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CC(C)(C)S3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(C)(C)Sc3ccc(CCc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a solution of ethyl 4-[[4-(4-methylphenyl)-2,2-dimethyl-(2H)thiochromen-6-yl]-ethynyl]-benzoate (Compound 226, 126.0 mg, 0.287 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (160.0 mg, 4.0 mmol, 2.0 mL of a 2M aqueous solution). The resulting solution was heated to 45° C. and stirred overnight. Upon cooling to room temperature the reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 85.0 mg (72%) of the title compound as a pale-yellow solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.00 (2H, d, J=8.3 Hz), 7.58 (2H, d, J=8.3 Hz), 7.45-7.38 (2H, m), 7.28-7.17 (5H, m), 5.92 (1H, s), 2.37 (3H, s), 1.47 (6H, s).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:13]3=[C:14]4[S:20][CH:19]=[CH:18][C:15]4=[N:16][CH:17]=[C:12]3[N:11]=[C:10]2[CH2:21][C:22]#[N:23])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>C(Cl)Cl>[C:22]([CH2:21][C:10]1[N:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([CH2:2][NH:1][C:31](=[O:34])[CH2:32][CH3:33])[CH2:4][CH2:5]2)[C:13]2=[C:14]3[S:20][CH:19]=[CH:18][C:15]3=[N:16][CH:17]=[C:12]2[N:11]=1)#[N:23]
Reactant: N#CCc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NC[C@H]1CC[C@H](n2c(CC#N)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}acetonitrile (9.5 mg, 0.029 mmol) and triethylamine (20. μL, 0.14 mmol) in methylene chloride (1 mL) was added propanoyl chloride (3.0 μL, 0.035 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (1.1 mg, 9.9%). LCMS calculated for C20H24N5OS (M+H)+: m/z=382.2. Found: 382.1.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([NH:11][CH:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][NH:21]3)=[CH:16][CH:15]=2)[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].[CH3:26][O:27][CH2:28][C:29](O)=O>>[CH3:26][O:27][CH2:28][CH2:29][N:21]1[C:22]2[C:17](=[CH:16][CH:15]=[C:14]([CH:12]([NH:11][C:9](=[O:10])[CH:8]=[CH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:13])[CH:23]=2)[CH2:18][CH2:19][CH2:20]1
Reactant: COCC(=O)O
Reactant: CC(NC(=O)C=Cc1ccccc1)c1ccc2c(c1)NCCC2
Agent: [BH4-]
Agent: [Na+]
Product: COCCN1CCCc2ccc(C(C)NC(=O)C=Cc3ccccc3)cc21
Temperature: 23 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a stirred solution of 3-phenyl-N-[1-(1,2,3,4-tetrahydro-quinolin-7-yl)ethyl]acrylamide (Example 233) (75 mg, 0.245 mmol) in methoxyacetic acid (5 ml) was added, in small portions, NaBH4 (232 mg) over 30 minutes. The mixture was stirred at 23° C. for an additional 2 hours and then the excess hydride destroyed by adding MeOH. That solution was diluted with EtOAc and washed several times with water. The organic phase was dried (MgSO4) and evaporated. The crude material was purified by chromatography (SiO2, 25% EtOAc in hexane) yielding 59 mg (66%) of the desired compound as a thick oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Br[C:10]1[N:15]2[C:16]([NH:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1.[O-]C1C=CC=CC=1.[Na+]>CN(C=O)C>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:15]2[C:16]=1[NH:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Oc1ccccc1
Reactant: Clc1ccccc1-c1nc2cccc(Br)n2c1NC1CCCCC1
Agent: [Na+]
Agent: [Na]
Agent: [O-]c1ccccc1
Solvent: CN(C)C=O
Product: Clc1ccccc1-c1nc2cccc(Oc3ccccc3)n2c1NC1CCCCC1
Temperature: 90 °C

Procedure:
Phenol (40.43 mg, 0.687 mmol) was dissolved in DMF (5 ml) and sodium metal (10.31 mg, 0.687 mmol) was added portion-wise. 5-Bromo-2-(2-chlorophenyl)-N-cyclohexylimidazo[1,2-a]pyridin-3-amine 42 (139.1 mg, 0.344 mmol) was added to this sodium phenoxide solution and heated at 90° C. for 4 h. The reaction was quenched with water and extracted into ethyl acetate. The product was purified by column chromatography, elution ethyl acetate:hexane.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O.[CH3:10][NH:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:11]([CH2:12][CH2:13][CH2:14][CH3:15])[CH3:10])=[O:9]
Reactant: CCCCNC
Reactant: O=C(O)CCCCCBr
Product: CCCCN(C)C(=O)CCCCCBr

Procedure:
Using the procedure of Step A of Example 3, 4.88 g of 6-bromohexanoic acid and 4.36 ml of N-methylbutylamine were reacted to obtain 7.0 g of the expected product which was used as is for the following step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH:21]=O)=[CH:20][C:15]=2[N:14]=[N:13]1>>[NH:12]1[C:16]2[CH:17]=[CH:18][C:19](/[CH:21]=[C:5]3/[C:6](=[O:11])[NH:7][C:8]4[C:4]/3=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=4)=[CH:20][C:15]=2[N:14]=[N:13]1
Reactant: O=Cc1ccc2[nH]nnc2c1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: O=C1Nc2ccc(Br)cc2/C1=C\c1ccc2[nH]nnc2c1

Procedure:
The title compound was synthesized according to the method described for Example A1, except reacting 5-bromooxindole (39 mg, 0.185 mmol) with 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (30 mg, 0.204 mmol) to obtain 32 mg, 51%. 1H NMR (400 MHz, d6-DMSO) δ 15.97 (s, 1H), 10.85 (s, 1H), 9.27 (s, 1H), 8.37 (d, J=9.2 Hz, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H); MS ESI 341.0 [M+H]+, calcd for [C15H9BrN4O+H]+ 341.00.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18]([NH:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[N:34]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[C:33]4[CH:43]=[CH:44][CH:45]=[CH:46][C:32]=4[N:31]=3)[CH2:25][CH2:24]2)=S)[CH:5]=[CH:6][C:7]=1[Cl:8].[S]>[Hg]=O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]=[C:18]2[NH:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[N:34]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[C:33]4[CH:43]=[CH:44][CH:45]=[CH:46][C:32]=4[N:31]=3)[CH2:25][CH2:24]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Fc1ccc(Cn2c(NC3CCN(CCNC(=S)Nc4ccccc4NCc4ccc(Cl)c(Cl)c4)CC3)nc3ccccc32)cc1
Agent: O=[Hg]
Agent: [S]
Solvent: CCO
Product: Fc1ccc(Cn2c(NC3CCN(CCNc4nc5ccccc5n4Cc4ccc(Cl)c(Cl)c4)CC3)nc3ccccc32)cc1
Yield: 45 %

Procedure:
A mixture of 40 parts of N-[2-[[(3,4-dichlorophenyl)methyl]amino]phenyl]-N'-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]thiourea, 60 parts of mercury(II)oxide, 0.1 parts of sulfur and 400 parts of ethanol was stirred and refluxed overnight. The reaction mixture was filtered over Hyflo and the filtrate was evaporated. The residue was crystallized from ethanol. The product was filtered off and dried, yielding 17 parts (45%) of 1-[(3,4-dichlorophenyl)methyl]-N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]1-piperidinyl]ethyl]-1H-benzimidazol-2-amine; mp. 113.2° C. (compound 83).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][CH:24]2[CH2:25][CH2:26][N:22]([CH3:21])[CH2:23]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN1CCC(N)C1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CN1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)C1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1-methylpyrrolidin-3-amine (10.0 mg, 0.1 mmol). The title compound was obtained as a solid (4.3 mg, 10% yield). MS m/z: 432.84, 434.84 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]([CH3:20])([O:16][CH2:17][C:18]#[CH:19])[CH3:15])=[CH:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:28](I)([CH3:30])[CH3:29]>C(C(C)=O)C>[CH:28]([O:5][C:4](=[O:6])[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:8][CH2:9][CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]([CH3:20])([O:16][CH2:17][C:18]#[CH:19])[CH3:15])([CH3:30])[CH3:29]
Reactant: CC(C)I
Reactant: C#CCOC(C)(C)CCCC(C)CC=CC(C)=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CCOC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C
Temperature: 0 °C

Procedure:
2.63 g. of 3,7,11-trimethyl-11-(2-propynyloxy)-2,4-dodecadienoic acid are dissolved in 40 ml. of methyl ethyl ketone and then treated with 2.45 g. of potassium carbonate and 6.1 g. of isopropyl iodide. The mixture is heated at reflux under a nitrogen atmosphere for 6 hours, then poured on to ice-water and extracted with ether. The extracts are washed with water and saturated sodium chloride solution, dried and evaporated. By chromatography on silica gel, there is obtained pure 3,7,11-trimethyl-11-(2-propynyloxy)-2,4-dodecadienoic acid isopropyl ester; boiling point (bulb-tube) = 122°C/0.023 mmHg; nD25 = 1.4940.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:36])[CH2:7][C:8]1[C:9](=[O:35])[N:10]=[C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=3)=[CH:19][CH:18]=2)[NH:12][CH:13]=1)(=O)[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][O:14][C:11]3[NH:12][CH:13]=[C:8]([CH2:7][C:6]4[O:36][C:1]([CH3:2])=[N:4][N:5]=4)[C:9](=[O:35])[N:10]=3)=[CH:22][CH:21]=2)=[CH:25][C:26]=1[C:31]([F:34])([F:32])[F:33]
Reactant: CC(=O)NNC(=O)Cc1c[nH]c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: Cc1nnc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)o1
Temperature: 130 °C
Yield: 39.5 %

Procedure:
To a solution of N′-acetyl-2-(2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl) ethyl]oxy}-4-oxo-1,4-dihydro-5-pyrimidinyl)acetohydrazide (26 mg, 0.050 mmol) in THF (5 mL) was added Burgess reagent (17.71 mg, 0.074 mmol). The mixture was heated with a microwave reactor at 130° C. for 0.5 h. Purification via MDAP then afforded the title compound (10 mg, 9.8% yield). LCMS: rt=3.38 min, [M+H+]=507
Reaction SMILES: [N:1]([CH:4]1[CH2:7][N:6]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5]1)=[N+]=[N-].[H][H]>C(OCC)(=O)C.[C].[Pd]>[NH2:1][CH:4]1[CH2:7][N:6]([CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:5]1
Reactant: [H][H]
Reactant: [N-]=[N+]=NC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NC1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 72.2 %

Procedure:
5% Palladium-carbon (200 mg) was added to 3-azido-1-benzhydrylazetidine (630 mg) obtained from Referential Example 104 in ethyl acetate (12 mL). The resultant mixture was subjected to catalytic reduction in a hydrogen atmosphere for 15 hours. The catalyst was filtered off. The solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as a solid (410 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[N:14]=[C:13]1[N:8]([CH2:9][CH2:10][CH2:11][O:12]1)[C:7]2=[O:16].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH:28]3[CH2:30][CH2:31][CH:25]2[CH2:26][NH:27]3)=[CH:20][CH:19]=1.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[NH:14][C:13](=[O:12])[N:8]([CH2:9][CH2:10][CH2:11][N:27]1[CH2:26][CH:25]3[CH2:31][CH2:30][CH:28]1[CH2:29][N:24]3[C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)[C:7]2=[O:16]
Reactant: Fc1ccc(N2CC3CCC2CN3)cc1
Reactant: O=c1c2cccc(Cl)c2nc2n1CCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c2c(Cl)cccc2c(=O)n1CCCN1CC2CCC1CN2c1ccc(F)cc1
Temperature: 120 °C
Yield: 32.8 %

Procedure:
8-Chloro-3,4-dihydro-2H-1-oxa-4a,9-diaza-anthracen-10-one (0.35, 1.49 mmol), 2-(4-Fluoro-phenyl)-2,5-diaza-bicyclo[2.2.2]octane (HCl salt) (0.30g, 1.24 mmol), triethylamine (0.21 ml, 1.49 mmol), p-toluene sulfonic acid (0.036 g, 0.187 mmol) were combined in dimethyl acetamide (2 ml) and heated at 120° C. for 15 hours. The reaction was cooled to room temperature, diluted with H2O (200 mL) and extracted with ethyl acetate (3×100 mL). The pooled organic layers were washed with water (3×200 mL),dried over magnesium sulfate, and concentrated to a brown semi-solid. Silica gel flash chromatography using 5% methanol/chloroform as the eluent yielded 8-Chloro-3-{3-[5-(4-fluoro-phenyl)-2,5-diaza-bicyclo[2.2.2]oct-2-yl]-propyl}-1H-quinazoline-2,4-dione (0.18 g, 32.7%) as an light brown solid Maleate salt was formed by dissolving the solid in hot ethyl acetate (5 ml) and maleic acid (0.57 g, 1.2 eq) in ethyl acetate (4 ml) was added. Upon cooling the white solid was filtered to yield the maleate salt (0.12 g) which had the following properties: Mp. 186-188° C.; 1H NMR DMSO-d6 δ: 11.04 (brds, 1H), 9.40 (brd s, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.20 (t, J=7.9 Hz, 1H), 6.68 (brds, 2H), 6.02 (s, 2H), 4.11 (brds, 1H), 4.02-3.92 (m, 2H), 3.80-3.52 (m, 3H), 3.44-3.17 (m, 4H), 2.18-1.65 9m, 6H). IR(KBr): Analysis calculated for C23H24ClFN4O2* C4H4O4: C, 56.40; H, 4.91; N, 9.74;
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH:8]2[CH2:16][CH2:15][CH2:14][C:13]3[NH:12][C:11]([CH:17]=O)=[CH:10][C:9]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[CH2:28][C:29](=[O:35])[NH:30]3)[CH:23]=[CH:24][CH:25]=1>N1CCCCC1.C(O)C>[F:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2/[C:28](=[CH:17]/[C:11]2[NH:12][C:13]4[CH2:14][CH2:15][CH2:16][CH:8]([CH2:7][CH2:6][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:9]=4[CH:10]=2)/[C:29](=[O:35])[NH:30]3)[CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1cc2c([nH]1)CCCC2CCN1CCCC1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cccc(-c3cccc(F)c3)c2/C1=C/c1cc2c([nH]1)CCCC2CCN1CCCC1

Procedure:
4-(2-Pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (0.2 was condensed with 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (0.2 mmol) and piperidine (2 drops) in ethanol at rt for overnight. The solvent was removed and the residue was purified on a silica gel column to give 25 mg of the titled compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([OH:17])[CH:10]=1>CCO>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([NH:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:10][C:11]=1[OH:17])#[N:14]
Reactant: Brc1ccccn1
Reactant: N#Cc1ccc(N)cc1O
Solvent: CCO
Product: N#Cc1ccc(Nc2ccccn2)cc1O
Temperature: 90 °C
Yield: 1 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-bromopyridine (0.21 mL, 2.2 mmol) and 4-amino-2-hydroxybenzonitrile (146 mg, 1.1 mmol) in 10% aqueous EtOH (5 mL) was heated at 90° C. for 18 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 1/1) in 1% yield (1.5 mg).
Reaction SMILES: COC(=O)O[CH2:5][C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:9]([O:12][CH:13]([F:15])[F:14])=[CH:10][CH:11]=1.[CH3:24][O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)CCCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].C(OCC)(=O)C.O.CN(C=O)C>[CH3:24][O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([CH2:5][C:6]2[CH:7]=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[C:9]([O:12][CH:13]([F:14])[F:15])=[CH:10][CH:11]=2)=[CH:30][N:29]=1)=[O:27]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)OCc1ccc(OC(F)F)c(-c2cccc(Cl)c2)c1
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cc2ccc(OC(F)F)c(-c3cccc(Cl)c3)c2)cn1
Temperature: 85 °C
Yield: 55.6 %

Procedure:
In a 40 mL vial equipped with a stir bar was placed carbonic acid 3′-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl ester methyl ester (I-151, 700 mg, 2.04 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylicacid methyl ester (590 mg, 2.24 mmol), potassium carbonate (846 mg, 6.12 mmol), 1,5-bis(diphenylphosphino)pentane (270 mg, 0.612 mmol) and DMF (10 mL). The reaction mixture was degassed for 15 minutes by bubbling nitrogen and then allylpalladium(II) chloride dimer (112 mg, 0.306 mmol) was added. The reaction mixture was heated to 85° C. for 4 hours. To the reaction mixture was added water (40 mL) and ethyl acetate (40 mL) and the mixture was filtered through Celite. The layers of the filtrate were separated and the aqueous portion was extracted with ethyl acetate (40 mL). The organic portions were combined, washed with brine (40 mL), dried (MgSO4) and concentrated. The crude material was purified by a 50 gram silica gel SNAP cartridge (Biotage SP4 Flash Chromatography instrument) utilizing gradient elution of 12-100% ethyl acetate/hexanes to produce 458 mg of I-152 as a viscous yellow solid in 56% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][C:15]([S:18]([N:20]=[C:21]1[CH2:24][O:23][CH2:22]1)=[O:19])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]2([NH:20][S:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])[CH2:24][O:23][CH2:22]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)S(=O)NC1(c2ccc(Br)cn2)COC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 31.3 %

Procedure:
To a toluene (20 ml) solution of 2,5-dibromopyridine (1.93 g, 8.16 mmol) that is cooled to −78° C. in an atmosphere of nitrogen is added n-butyllithium (2.5 M in hexanes, 3.6 ml, 8.98 mmol) dropwise via syringe over a period of five minutes. The reaction mixture is stirred at −78° C. for ten minutes more before 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (1.43 g, 8.16 mmol) is added all at once as a concentrated solution in toluene. The reaction is stirred for 30 minutes at −78° C. and for 20 minutes at 0° C. before it is quenched with saturated aqueous ammonium chloride (5 ml). The volatiles were removed by rotary evaporation at reduced pressure. The residual material is partitioned between water (20 ml) and methylene chloride (50 ml). The aqueous is extracted once more with methylene chloride (30 ml). The combined extracts were concentrated and the residual material is subjected to flash column chromatography using a gradient of acetone in hexanes (20% to 75% over 5 column volumes) to provide N-(3-(5-bromopyridin-2-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (850 mg): 1H NMR (400 MHz, CDCl3) 1.32 (s, 9H) 4.91-4.97 (m, 2H) 5.13 (d, 1H) 5.34 (d, 1H) 7.78 (d, 1H) 8.04 (m, 1H) 8.68 (d, 1H); m/z (Cl) 333, 335 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:11]1([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(-c2ccccc2)n1
Temperature: 110 °C
Yield: 17.6 %

Procedure:
A mixture of 6-bromopicolinic acid (2.02 g, 10 mmol), phenyboronic acid (1.22 g, 10 mmol), cesium carbonate (5.00 g) and PdCl2 [(t-Bu)2P(OH)]2 (70 mg, CombiPhos Catalysts, Inc. Princeton, N.J.) in DMF (20 mL) and water (3 mL) was purged with Ar-gas and heated at 110° C. for 24 h. The reaction was incomplete and did not progress further. To the reaction mixture were added EtOAc (200 mL) and 1 N aq. HCl (40 mL). The EtOAc layer was separated, and the aqueous layer was washed with EtOAc (150 mL). The combined EtOAc layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to afford the desired product (350 mg, 18%) as a white solid. 1H NMR (CDCl3) δ 10.45 (s, 1H), 8.18–7.96 (m, 5H), 7.51–7.53 (m, 3H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:43]=[C:42]([F:44])[C:15]([CH2:16][S:17][C:18]2[N:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:20]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][CH3:34])[CH:27]=3)([CH3:25])[CH3:24])=[CH:21][N:22]=2)=[C:14]([F:45])[CH:13]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]([C:20]2[N:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:18]([S:17][CH2:16][C:15]3[C:14]([F:45])=[CH:13][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:43][C:42]=3[F:44])=[N:22][CH:21]=2)([CH3:25])[CH3:24])=[CH:27][C:28]=1[O:33][CH3:34]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCO[Si](C)(C)C(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 16 h
Yield: 79.2 %

Procedure:
To a solution of 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-2,6-difluorobenzylthio)-5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (440 mg, 0.65 mmol, 1.0 eq) in anhyd DCM was added tetrabutylammonium fluoride (2.9 mL, 2.9 mmol, 4.4 eq, 1.0 M in THF). After stirring 16 h, the reaction was quenched with satd NaHCO3 and extracted with DCM. The combined extracts were washed with water and brine, dried, concentrated and purified (silica, 0 to 80% EtOAc/Hex) to yield 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethanol (290 mg, 79%) as a white foam: 1H NMR (400 MHz, CDCl3) δ 7.18 (d, J=7.8 Hz, 1H), 7.06 (d, J=8.2 Hz, 1H), 6.74-6.63 (m, 2H), 6.46-6.33 (m, 2H), 6.33-6.20 (m, 4H), 4.03 (s, H), 3.90 (dt, J=8.7, 4.1 Hz, 4H), 3.68 (s, 3H), 1.39 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:7][CH2:6][C:5]([CH2:17][OH:18])([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[N+:14]([O-:16])=[O:15])[CH2:4][O:3]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:1][C:2]1([CH3:19])[O:3][CH2:4][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[N+:14]([O-:16])=[O:15])([CH2:17][O:18][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:6][O:7]1
Reactant: CC1(C)OCC(CO)(Cn2ccnc2[N+](=O)[O-])CO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2(Cn3ccnc3[N+](=O)[O-])COC(C)(C)OC2)cc1

Procedure:
The obtained 2,2-dimethyl-5-hydroxymethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane is reacted with p-toluenesulfonyl chloride by for example a method of L. F. Fieser et al. (Reagents for Organic Synthesis, Vol. 1, Wiley, New York, p. 1179 (1967)) and purified, to give the desired 2,2-dimethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-5-(p-toluenesulfonyloxymethyl)-1,3-dioxane (FIG. 1, Step 5).