Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=[O:20])=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:19](=[O:20])[CH2:18][C:15]2[CH:16]=[CH:17][C:12]([Br:11])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: COc1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(=O)Cc2ccc(Br)cc2)c(Cl)c1Cl
Reaction time: 17 h

Procedure:
To a stirred mixture of 2,3-dichloroanisole (73.5 g., 0.414 mole), 4-bromophenylacetyl chloride (105 g., 0.456 mole) and carbon disulfide (300 ml.) is added portionwise aluminum chloride (60.9 g., 0.456 mole) with cooling at 0°-5° C. The reaction mixture is left at 25° C. for 17 hours, then flushed with nitrogen, and the solid residue treated with crushed ice and 12N hydrochloric acid (80 ml.) to give 147.7 g. of 2,3-dichloro-4-(4-bromophenyl)acetylanisole which melts at 163°-164.5° C. after crystallization from benzene:hexane, 1:1.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:13])[CH2:11][NH2:12])[CH3:8].Br[CH2:15]/[CH:16]=[CH:17]/[CH2:18]Br.[ClH:20]>C1COCC1>[ClH:20].[CH2:7]([O:9][C:10]([C@:11]1([NH2:12])[CH2:18][C@@H:17]1[CH:16]=[CH2:15])=[O:13])[CH3:8]
Reactant: CCOC(=O)CN
Reactant: BrC/C=C/CBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: C=C[C@H]1C[C@@]1(N)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of potassium tert-butoxide (11.55 g, 102.9 mmol) in THF (450 mL) at −78° C. was added the commercially available N,N-dibenzyl imine of glycine ethyl ester (25.0 g, 93.53 mmol) in THF (112 mL). The reaction mixture was warmed to 0° C., stirred for 40 min, and was then cooled back to −78° C. To this solution was added trans-1,4-dibromo-2-butene (20.0 g, 93.50 mmol), the mixture stirred for 1 h at 0° C. and was cooled back to −78° C. Potassium tert-butoxide (11.55 g, 102.9 mmol) was added, the mixture immediately warmed to 0° C., and was stirred one more hour before concentrating in vacuo. The crude product was taken up in Et2O (530 mL), 1N aq. HCl solution (106 mL, 106 mmol) added and the resulting biphasic mixture stirred for 3.5 h at rt. The layers were separated and the aqueous layer was washed with Et2O (2×) and basified with a saturated aq. NaHCO3 solution. The desired amine was extracted with Et2O (3×) and the combined organic extract was washed with brine, dried (MgSO4), and concentrated in vacuo to obtain the free amine. This material was treated with a 4N HCl solution in dioxane (100 mL, 400 mmol) and concentrated to afford (1R,2S)/(1S,2R)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester hydrochloride as a brown semisolid (5.3 g, 34% yield) identical to the material obtained from procedure A, except for the presence of a small unidentified aromatic impurity (8%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18]([NH:20][C:21]1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH:38]1([CH:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)CN)[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18]([NH:20][CH2:21][CH:43]([CH:38]1[CH2:39][CH2:40][CH2:41][CH2:42]1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:19])(=[O:15])=[O:16])([CH3:2])[CH3:3]
Reactant: NCC(c1ccccc1)C1CCCC1
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Product: CC(C)c1cccc(C(C)C)c1NS(=O)(=O)CC(=O)NCC(c1ccccc1)C1CCCC1

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with 2-cyclopentyl-2-phenylethylamine, mp 168°-170° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][C@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[C@H:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([C:22]3[CH:23]=[C:18]([CH:19]=[CH:20][CH:21]=3)[NH2:17])=[CH:7][N:6]=1)[CH2:10]2
Reactant: Brc1cnc(O[C@@H]2CN3CCC2CC3)nc1
Reactant: Nc1cccc(B(O)O)c1
Product: Nc1cccc(-c2cnc(O[C@@H]3CN4CCC3CC4)nc2)c1

Procedure:
The product of Example 22A (284 mg, 1.0 mmol) was treated with 3-aminophenylboronic acid (Lancaster, 276 mg, 2.0 mmol) according to the procedure of Example 1B. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.1) as solid (285 mg, yield, 96%). 1H NMR (300 MHz, MeOH-d4) δ 1.48-1.62 (m, 1H), 1.61-1.91 (m, 2H), 2.01-2.16 (m, 1H), 2.22-2.30 (m, 1H), 2.74-3.05 (m, 5H), 3.36-3.47 (m, 1H), 5.12-5.20 (m, 1H), 6.75 (ddd, J=8.2, 2.1, 1.0 Hz, 1H), 6.89 (ddd, J=7.4, 1.7, 1.0 Hz, 1H), 6.93 (t, J=1.8 Hz, 1H), 7.20 (t, J=7.8 Hz, 1H), 8.74 (s, 2H) ppm. MS (DCl/NH3) m/z 297 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH:25]([CH3:27])[CH3:26])=[N:7][C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][C:9]=2[Cl:24])=[O:4].[CH:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)([CH3:30])[CH3:29]>>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:25]([CH3:27])[CH3:26])=[N:7][C:8]2[C:13]([C:14]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:28]([CH3:30])[CH3:29])[CH:36]=1)=[CH:12][C:11]([Cl:23])=[CH:10][C:9]=2[Cl:24])=[O:4]
Reactant: COC(=O)c1c(C(C)C)nc2c(Cl)cc(Cl)cc2c1OS(=O)(=O)C(F)(F)F
Reactant: CC(C)c1cccc(B(O)O)c1
Product: COC(=O)c1c(C(C)C)nc2c(Cl)cc(Cl)cc2c1-c1cccc(C(C)C)c1

Procedure:
The title compound was prepared in analogy to example 72 step C from 6,8-dichloro-2-isopropyl-4-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid methyl ester (prepared as described in example 72 step B) and 3-isopropylphenylboronic acid. Colorless semisolid. MS (ESI): 416.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[CH:4][N+:3]=1[O-].[OH-].[K+].O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:5]1[N:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[N:3][CH:4]=1
Reactant: Cc1ncc[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1ncc(Cl)nc1C
Reaction time: 2 h

Procedure:
2,3-Dimethyl-pyrazine 1-oxide (L2) (25 g, 0.2 mol) was dissolved in POCl3 (200 mL) under cooling. The mixture was gradually heated to reflux and stirred for 2 hrs. After cooling, the reaction mixture was poured onto ice, basified to pH 8 with a saturated KOH solution under cooling and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated. The residue was purified by column (P. E./EtOAc 100:1-60:1) to obtain 5-chloro-2,3-dimethylpyrazine (L3). 1HNMR (CDCl3, 300 MHz) δ 8.31 (s, 1H), 2.53 (s, 6H). MS (ESI) m/e (M+H+) 143.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1ccc2c(c1)C(C)NCC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: Cc1ccc2c(c1)C(C)N(C(=O)c1cc3ncc(Cl)cn3n1)CC2
Yield: 58 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,7-Dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:3].[CH:9]1[C:15]([NH2:16])=[N:14][C:12](=[O:13])[N:11]([C@@H:17]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([OH:24])[C:18]2([F:26])[F:25])[CH:10]=1.Cl>>[CH2:5]([O:4][C:2]([NH:16][C:15]1[CH:9]=[CH:10][N:11]([C@H:17]2[C:18]([F:26])([F:25])[C@H:19]([OH:24])[C@@H:20]([CH2:22][OH:23])[O:21]2)[C:12](=[O:13])[N:14]=1)=[O:3])[CH2:6][CH2:7][CH3:8]
Reactant: CCCCOC(=O)Cl
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Agent: Cl
Product: CCCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Yield: 91 %

Procedure:
Using Method A and butyl chloroformate, gemcitabine hydrochloride was converted to 15 (white solid, 91% yield): 1H NMR (200 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.23-8.27 (d, 1H), 7.11-7.15 (d, 1H), 6.37 (s, 1H), 6.16-6.23 (t, 1H), 5.33 (s, 1H), 4.12-4.18 (t, 2H), 3.65-3.95 (m, 4H), 1.44-1.66 (m, 2H), 1.33-1.40 (m, 2H), 0.93-0.97 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:27][CH2:26][CH2:25][C@:9]32[N:13]([CH3:14])[C:12](=[O:15])[N:11]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)[C:10]3=[O:24])=[CH:4][CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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:2]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:27][CH2:26][CH2:25][C@:9]32[N:13]([CH3:14])[C:12](=[O:15])[N:11]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)[C:10]3=[O:24])=[CH:4][CH:3]=1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(Br)cc1
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Yield: 25.3 %

Procedure:
A solution of (5R*,6S*)-6-(4-bromophenyl)-3-(3,5-dichlorophenyl)-1-methyl-1,3-diazaspiro[4.4]nonane-2,4-dione (80 mg, 0.17 mmol) (Example 1), phenylboronic acid (73 mg, 0.6 mmol), (Ph3P)4Pd (20 mg, 0.02 mmol) and K2CO3 (80 mg, 0.6 mmol) in a mixture of DME (1.5 ml) and water (50 μl) was heated at 80° C. for 12 h. The insoluble material was filtered off and the filtrate concentrated. After chromatography, (5R*,6S*)-6-biphenyl-4-yl-3-(3,5-dichlorophenyl)-1-methyl-1,3-diazaspiro[4.4]nonane-2,4-dione (20 mg) was obtained as a white solid. 1H NMR (CDCl3): 7.5-7.6 (4H, m), 7.3-7.5 (3H, m), 7.15-7.3 (3H, m), 6.64 (2H, m), 3.45 (1H, dd, J1=12.4 Hz, J2=6.1 Hz), 3.18 (3H, s), 2.5-2.75 (1H, m), 1.8-2.45 (5H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][CH2:10][C:11]#[CH:12]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:8][O:9][CH2:10][C:11]#[C:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C#CCOC
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: COCC#Cc1ccccn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of 2-bromopyridine (20 g) dissolved in diethylamine (100 mL) was added 3-methoxy-1-propyne (11.8 g), dichlorobis(triphenylphosphine)palladium(II) (888 mg) and copper iodide (121 mg), and the reaction mixture was stirred for 1 hour at 40° C. under a nitrogen stream. After the reaction mixture was filtered through celite to remove insoluble residue, the filtrate was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (16.8 g) was obtained as a light orange oil from the n-hexane:ethyl acetate (5:1) fraction.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]([CH3:10])[C:7](Cl)=[O:8])(=[O:3])[CH3:2].C(OC([C@@H](N[C@H](C([N:30]1[N:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[S:32][C@H:31]1[C:41]([OH:43])=[O:42])=O)C)CCC1C=CC=CC=1)=O)C>ClCCl>[C:1]([S:4][CH2:5][C@@H:6]([CH3:10])[C:7]([N:30]1[N:34]=[C:33]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[S:32][CH:31]1[C:41]([O:43][CH2:33][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:42])=[O:8])(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1N=C(c2ccccc2)S[C@H]1C(=O)O
Reactant: CC(=O)SC[C@H](C)C(=O)Cl
Solvent: ClCCl
Product: CC(=O)SC[C@@H](C)C(=O)N1N=C(c2ccccc2)SC1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3-Acetylthio-2-(S)-methylpropanoyl chloride (2.3 g) in dichloromethane (30 ml) was added over 5 minutes to a stirred mixture of the product of Example 1, step a) (3.6 g) and polyvinylpyridine (2.4 g) in dichloromethane (60 ml). The mixture was stirred at room temperature for 20 hours and 3-acetylthio-2-(S)-methylpropanoyl chloride (1.2 g) was then added. The mixture was stirred for a further 2 hours, filtered and the filtrate stirred with a saturated solution of sodium bicarbonate for 1 hour. The organic phase was separated, washed with water, dried and evaporated to a gum. The residue was purified by flash chromatography to give the sub-title product (4.4 g) as an oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:29])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[C:8]=1[CH2:27][CH3:28]>C1COCC1.CO>[CH2:27]([C:8]1[N:9]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=2)[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]=1[CH2:6][C:5]([OH:29])=[O:4])[CH3:28]
Reactant: CCc1c(CC(=O)OC)c2cccnc2n1Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1c(CC(=O)O)c2cccnc2n1Cc1ccc(C(F)(F)F)cc1

Procedure:
0.5 M Aqueous NaOH (1.0 ml) is added to a solution of [2-ethyl-1-(4-trifluoromethyl-benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (48 mg, 0.13 mmol) in 1:1 THF/MeOH (1 ml). After 3 hours the reaction is concentrated in vacuo, and the residue dissolved in water. The aqueous solution is cooled in an ice-bath and acidified to pH 2 using concentrated HCl. The resulting precipitate is filtered and dried under high vacuum at 50° C. to yield the titled compound as a white powder. (MH+ 363)
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21]CC)=[O:20]>CC(C)=O>[CH2:1]1[O:2][C:3]2[CH:9]=[CH:8][C:7]([O:10][CH2:18][C:19]([OH:21])=[O:20])=[CH:6][C:4]=2[O:5]1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)COc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
The mixture of sesamol (270 mg, 2.0 mmol), potassium carbonate (910 mg, 6.6 mmol), ethyl bromoacetate (2.55 ml, 22.9 mmol) and acetone (25 ml) was refluxed for 21 h. After cooling, the mixture was filtered to remove potassium carbonate. The filtrate was concentrated under reduced pressure. To this residue, 20 ml dioxane and 14 ml 5% sodium hydroxide solution were added. After the uiixture was stirred at room temperature overnight, it was acidified with concentrated hydrochloric acid to pH 2, and then extracted three times with ethyl acetate (20 ml each). Organic phases were combined, washed with water and brine, dried over magnesium sulfate, filtered, and then evaporated in vacuo. The residue was recrystallized from chloroform and acetone to give 45 mg 3,4-methylenedioxyphenoxyacetic acid as white crystals, mp 149-151° C.
Reaction SMILES: C([C:3]1[C:13]2[CH2:12][CH:11]([CH2:14][C:15]([OH:17])=[O:16])[C:10]3[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=3[CH2:8][C:7]=2[CH:6]=[C:5]([O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][CH2:32][CH3:33])[N:26]=2)[CH:4]=1)C.[OH-].[Na+]>CO>[CH2:32]([NH:31][C:27]1[N:26]=[C:25]([CH2:24][CH2:23][O:22][C:5]2[CH:4]=[CH:3][C:13]3[CH2:12][CH:11]([CH2:14][C:15]([OH:17])=[O:16])[C:10]4[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=4[CH2:8][C:7]=3[CH:6]=2)[CH:30]=[CH:29][CH:28]=1)[CH3:33]
Reactant: CCNc1cccc(CCOc2cc(CC)c3c(c2)Cc2ccccc2C(CC(=O)O)C3)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNc1cccc(CCOc2ccc3c(c2)Cc2ccccc2C(CC(=O)O)C3)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl (±)-10,11-dihydro-3-[2-[6-(ethylamino)-2-pyridyl]-1-ethoxy]-5H-dibenzo[a,d]cycloheptene-10-acetic acid (80 mg, 0.18 mmol) was dissolved in MeOH (3 mL), and 1.0 N NaOH (0.22 mL, 0.22 mmol) was added. The solution was stirred at RT overnight, then was concentrated in vacuum. The residue was dissolved in H2O (3 mL), and the solution was acidified with 20% TFA. Chromatography on C-18 Bond Elute (30% CH3CN/H2O containing 0.1% TFA) gave the title compound as a white solid: MS(ES) 417 (M+H)+. Anal. Calcd for C26H28N2O3.1.3 CF3CO2H: C, 60.83; H, 5.23; N, 4.96. Found: C, 60.64; H, 5.26; N, 4.26.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH:9](I)([CH3:11])[CH3:10]>>[CH:9]([S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])([CH3:11])[CH3:10]
Reactant: CC(C)I
Reactant: Oc1ccccc1S
Product: CC(C)Sc1ccccc1O
Yield: 51 %

Procedure:
This compound was prepared in 51% yield from 2-mercaptophenol and isopropyl iodide according to the procedure for 1p in Example VIII. Colorless Oil; 1H NMR (CDCl3): δ 1.25 (d, J=6.85 Hz, 6H), 3.09 (s-7, J=6.66 Hz, 1H), 6.85 (s, 1H), 6.87 (dd, J=1.10 Hz, J=7.45 Hz, 1H), 6.99 (dd, J=1.10 Hz, J=7.95 Hz, 1H), 7.27 (dd, J=1.65 Hz, J=7.95 Hz, 1H), 7.44 (dd, J=1.65 Hz, J=7.70 Hz, 1H);); 13C NMR (CDCl3): δ 23.36, 40.66, 114.71, 118.02, 120.61, 131.44, 137.00, 157.56; HRMS (FAB): 169.06872 calcd for C9H12OS [M+1]+. found 169.06956 (3.1 ppm, 0.5 mmu).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[O:18])=[CH:16][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:20]=1)=O.[C:21]1([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.CC(O)=O>[C:21]1([CH:27]2[CH2:31][CH2:30][N:29]([CH2:1][C:3]3[CH:4]=[CH:5][C:6]4[O:12][C:11]5[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[O:18])=[CH:16][C:10]=5[CH2:9][CH2:8][C:7]=4[CH:20]=3)[CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)c1ccc2c(c1)CCc1cc(C=O)ccc1O2
Reactant: c1ccc(C2CCNC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: NC(=O)c1ccc2c(c1)CCc1cc(CN3CCC(c4ccccc4)C3)ccc1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of aldehyde intermediate obtained in step 4, Example 1 (92 mg, 0.34 mmol) in THF/AcOH (6.5 mL/30 μL) add 3-phenylpyrrolidine (0.34 mmol). Stir the mixture at room temperature overnight. Add NaBH(OAc)3 (0.52 mmol) and stir at room temperature overnight. Eliminate the solvent and purify by ISCO chromatography (eluent: CHCl3/B 0-10%; B: EtOH/NH4OH 10%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]2.C1C(=O)N([Cl:27])C(=O)C1>C1COCC1>[Cl:27][C:15]1[C:16]2[C:11](=[CH:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=3[F:1])=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[OH:19]
Reactant: Oc1ccc(-c2ccc3cc(O)ccc3c2)c(F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Oc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)c(F)c1

Procedure:
The title compound was prepared by reacting 6-(2-fluoro-4-hydroxyphenyl)-2-naphthol (300 mg, 1.18 mmol) and NCS (191 mg, 1.43 mmol) in THF (30 mL) according to method C to yield 170 mg (50%) of yellowish solid: mp 179-180° C.; 1H NMR (DMSO-d6): δ 6.73 (1H, dd, J=12.69 Hz, J=2.44 Hz), 6.75 (1H, dd, J=8.30 Hz, J=2.44 Hz), 7.31 (1H, d, J=8.79 Hz), 7.45 (1H, t, J=9.28 Hz), 7.70-7.72 (1H, m), 7.83 (1H, d, J=8.79 Hz), 7.97 (1H, s), 8.06 (1H, d, J=7.79 Hz), 10.06 (1H, s), 10.48 (1H, s); MS (ESI) m/z287/289 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=3[CH3:24])[C:6]=2[CH:5]=[C:4]([N+:25]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.Cl>CO>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[C:15]=3[CH3:24])[C:6]=2[CH:5]=[C:4]([NH2:25])[CH:3]=1
Reactant: Cc1c(Cn2c(CF)nc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Cc1c(Cn2c(CF)nc3c(Br)cc(N)cc32)cccc1C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a solution of 4-bromo-2-(fluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-nitro-1H-benzo[d]imidazole (3.05 g, 6.84 mmol) in Methanol (40 mL) in a 250 ml round bottomed flask was added Tin(II)chloride dihydrate (9.25 g, 41.0 mmol) and HCl (1.869 mL, 61.5 mmol). The reaction mixture was left to stir at 50° C. for 1 h; reaction mostly complete with a very small amt of starting material and a very small amt of des-fluoro product. The solvent was removed and diluted with water (100 mL) and this solution was decanted into a 250 mL Erlenmeyer flask. This solution was neutralized with 6N NaOH to pH 9—a white solid was observed. The brown residue in the rb flask was dissolved in 100 mL of EtOAc and washed with 1N NaOH, brine, dried and evaporated to yield a brown oil. The water layer was extracted with EtOAc to which yielded an additional oil. The oils were combined and purified by reversed phase HPLC; eluted with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (25-70%) over 12 minutes. The fractions were collected and evaporated to yield the expected compound 4-bromo-2-(fluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-amine (2.3 g, 5.53 mmol, 81% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.54 (s, 3H) 5.39 (s, 2H) 5.51 (s, 1H) 5.63 (s, 1H) 6.32 (d, J=2.02 Hz, 1H) 6.56 (d, J=7.83 Hz, 1H) 6.96 (d, J=2.02 Hz, 1H) 7.16 (t, J=7.83 Hz, 1H) 7.61 (d, J=7.83 Hz, 1H); LC/MS: MS (ES+) m/e 417 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:24]=[C:23]3[C:18]([C:19](=[O:34])[C:20]([C:29]([O:31]CC)=[O:30])=[CH:21][N:22]3[CH2:25][CH2:26][C:27]#[N:28])=[CH:17][C:16]=2[F:35])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:24]=[C:23]3[C:18]([C:19](=[O:34])[C:20]([C:29]([OH:31])=[O:30])=[CH:21][N:22]3[CH2:25][CH2:26][C:27]#[N:28])=[CH:17][C:16]=2[F:35])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC(NC(=O)OC(C)(C)C)CC3)c(F)cc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3CCC#N)CC1
Reaction time: 3 h

Procedure:
A suspension of EXAMPLE 66A (0.71 g) in THF (100 mL) and methanol (50 mL) at reflux was treated with 1M LiOH (100 mL), stirred for 3 hours, concentrated to half volume, acidified with 10% citric acid, and filtered.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:19])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:4]1=[O:18].Cl[C:21]1[N:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:31])[CH:27]=2)[N:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:31][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([N:15]1[CH2:16][CH2:17][CH:12]([N:5]3[C:6]4=[N:7][CH:8]=[CH:9][N:10]=[C:11]4[C:3]([CH3:19])([CH3:2])[C:4]3=[O:18])[CH2:13][CH2:14]1)[N:30]=[CH:29]2
Reactant: Fc1ccc2nc(Cl)ncc2c1
Reactant: CC1(C)C(=O)N(C2CCNCC2)c2nccnc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)C(=O)N(C2CCN(c3ncc4cc(F)ccc4n3)CC2)c2nccnc21
Temperature: 110 °C
Yield: 35.2 %

Procedure:
A mixture of 7,7-dimethyl-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one hydrochloride (Intermediate 78) (0.088 g, 0.311 mmol), 2-chloro-6-fluoroquinazoline (0.063 g, 0.342 mmol), and potassium carbonate (0.129 g, 0.934 mmol) in DMSO (3 mL) was heated at 110° C. overnight. The mixture was cooled, H2O was added, and the solid was collected, dried, and purified by ISCO (40% EtOAc/Hexanes) to give the title compound (43 mg, 35%). MS (M+1): 393. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (1 H, s), 8.08 (1 H, d, J=3.1 Hz), 8.12 (1 H, d, J=3.1 Hz), 7.62-7.74 (2 H, m), 7.46-7.62 (1 H, m), 5.00 (2 H, d, J=13.5 Hz), 4.47-4.67 (1 H, m), 2.97-3.14 (2 H, m), 2.36-2.48 (2 H, m), 1.80 (2 H, d, J=9.6 Hz), 1.32 (6 H, s).