Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[C:9]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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:24]1([C:2]2[C:14]([C:15]([CH3:17])([CH3:18])[CH3:16])=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][C:8]([C:2]5[CH:14]=[CH:13][CH:12]=[CH:4][CH:3]=5)=[C:9]([C:19]([CH3:20])([CH3:22])[CH3:21])[CH:10]=4)[CH2:5][C:4]=3[CH:3]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)c1cc2c(cc1Br)Cc1cc(Br)c(C(C)(C)C)cc1-2
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc2c(cc1-c1ccccc1)Cc1cc(-c3ccccc3)c(C(C)(C)C)cc1-2
Reaction time: 6 h
Yield: 179.4 %

Procedure:
To a mixture of 2,7-dibromo-3,6-di-t-butylfluorene (0.96 g, 2.20 mmol) and Pd(PPh3)4 (260 mg, 0.22 mmol) in toluene (50 ml) was added a solution of phenylboronic acid (0.81 g, 6.63 mmol) in EtOH (10 ml) and a solution of Na2CO3 (1.5 g) in water (10 ml). The reaction mixture was stirred for 6 hours under reflux. The reaction mixture was quenched with water, extracted with ether, dried over MgSO4, and evaporated under vacuum to afford the residue which was purified by column chromatography (silica gel, hexane/CH2Cl2=5/1) to produce 2,7-diphenyl-3,6-di-t-butyl-fluorene (0.85 g, ˜90%). 1H NMR (CDCl3): δ 7.96 and 7.15 (each s, 2H, 1,8- and 4,5-H (Flu), 7.33 (m, 10H, Ph), 3.77 (s, 2H, H9), 1.27 (s, 18H, t-Bu).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=1)=[O:19])=[C:13]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[OH:42])[CH:12]=[CH:11]2>C1COCC1>[OH:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[CH2:35][C:13]1[C:14]([CH:18]([OH:19])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:22][CH:21]=2)=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:7])[CH:17]=[CH:16]2
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(Cc2ccccc2O)ccc2cc(O)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(Cc3ccccc3O)ccc2c1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Add LAH solution (0.3 mL, 1M/THF) to a solution of [6-hydroxy-2-(2-hydroxy-benzyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (150 mg, 0.31 mmol) in THF (3 mL) at r.t. Stir for 30 min and quench with aq. NaHCO3. Dilute with CH2Cl2, wash with water and brine, dry over MgSO4, filter and concentrate. Purify the crude product by flash chromatography (0–5% (2M NH3 in MeOH)/CH2Cl2) to afford 6-(2-hydroxy-benzyl)-5-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-naphthalen-2-ol (123 mg, 82%).
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:28])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccccc1F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccccc1F

Procedure:
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): δ 0.69-0.82 (m, 3 H), 1.09-1.40 (m, 14 H), 1.90 (m, 2 H), 3.20-3.45 (m, 2 H), 4.40 (m, 2 H), 5.25-5.45 (m, 1 H), 6.08 (m, 1H), 7.08-7.41 (m, 5 H). Rf=0.24 (10% ethyl acetate/n-hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:14])[CH3:13])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-methyl-3-nitroaniline (3.60 g, 23.7 mmol) in acetic anhydride (28 mL) was allowed to stir at room temperature. After 16 h, the reaction mixture was concentrated in vacuo, diluted with ethyl acetate (25 mL), washed with saturated sodium bicarbonate (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give 4.20 g (Y: 99%) of the title compound; 1H-NMR (CDCl3): δ8.10 (d, J=1.7 Hz, 1H), 7.75 (dd, J=8.5, 1.7 Hz, 1H), 7.38 (bs, 1H), 7.29 (d, J=8.5 Hz, 1H), 2.56 (s, 3H), 2.21 (s, 3H); MS (DCI) m/e: 195 (MH+).
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].C([Li])CCC.C(#N)C.[Br:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>O1CCCC1.O>[NH2:22][C:21]([C:20]1[CH:23]=[CH:24][C:17]([Br:16])=[CH:18][CH:19]=1)=[CH:2][C:1]#[N:4]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: N#CC=C(N)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92.7 %

Procedure:
An oven dried flask was charged with 300 mL of tetrahydrofuran and diisopropylamine (31.4 mL, 223 mmol) and cooled to 0° C. under nitrogen. To the reaction mixture was then added butyl lithium (2.5 M in hexanes) (79.1 mL, 198 mmol) slowly by syringe over 10 minutes. The reaction mixture was then allowed to stir at 0° C. for 20 minutes. The reaction mixture was then cooled to −78° C. and acetonitrile (10.8 mL, 206 mmol) was added slowly over 5 minutes. The reaction mixture was allowed to stir for 10 minutes before 4-bromobenzonitrile (30.0 g, 165 mmol) was added as a solution in 100 mL of tetrahydrofuran over 10 minutes. The reaction mixture was allowed to proceed at −78° C. for an additional 10 minutes before being allowed to slowly warm to ambient temperature and proceed overnight. The reaction mixture was cooled to 0° C. and 200 mL of water was slowly added. The reaction mixture was stirred for 10 minutes and the solids were collected by means of vacuum filtration and dried under high vacuum. The solids were suspended in dichloromethane and the resulting solids were collected by means of vacuum filtration to obtain 3-amino-3-(4-bromophenyl)acrylonitrile (34.2 g, 153 mmol, 93.0% yield). MS (apci) m/z=222.0 (M−H).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:24])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19](SC)[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:25][O:26]C1C2N=C(C3N(C)C=NC=3C3C=CC=CC=3)SC=2N=CN=1.CN1C(C2SC3N=CN=C(SC)C=3N=2)=C(C2C=CC=CC=2)N=C1>>[Br:1][C:2]1[N:3]([CH3:24])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([O:26][CH3:25])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: CSc1ncnc2sc(-c3c(-c4ccccc4)nc(Br)n3C)nc12
Reactant: COc1ncnc2sc(-c3c(-c4ccccc4)ncn3C)nc12
Agent: CSc1ncnc2sc(-c3c(-c4ccccc4)ncn3C)nc12
Product: COc1ncnc2sc(-c3c(-c4ccccc4)nc(Br)n3C)nc12

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 37 but using 7-Methoxy-2-(1-methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidine (Example 33) in place of 2-(1-methyl-4-phenyl-1H-imidazol-5-yl)-7-(methylthio)[1,3]thiazolo[5,4-d]pyrimidine (Intermediate 42). Light brown solid (0.47 g, 45%);
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16](OCCN4CCCC4)=[CH:15][CH:14]=3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][N:28]([CH2:30]C1C=C(NC(N)=S)C=CC=1)[CH3:29]>C(Cl)Cl.CO>[CH3:27][N:28]([CH2:30][C:17]1[CH:18]=[C:13]([NH:12][C:10]2[S:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][N:9]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:29]
Reactant: CN(C)Cc1cccc(NC(N)=S)c1
Reactant: c1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1
Solvent: CO
Solvent: ClCCl
Product: CN(C)Cc1cccc(Nc2ncc(-c3ccccc3)s2)c1

Procedure:
The title compound is prepared as described in Example 1 for (5-phenyl-thiazol-2-yl)-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-amine but using (3-dimethylaminomethyl-phenyl)-thiourea. Title compound: ES-MS: 310.1 [M+H]+; single peak at tR=6.65 min (System 1); Rf=0.63 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][C:10]2[S:11][C:12]([CH3:15])=[CH:13][N:14]=2)=[O:8])[CH2:3]1.ClC1C=C2C(N=CC=C2)=C2C=1C=CC=N2.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40](Br)[CH:39]=1.[OH-].[NH4+].O>CN1CCCC1=O>[Br:37][C:38]1[CH:39]=[C:40]([N:14]2[CH:13]=[C:12]([CH3:15])[S:11]/[C:10]/2=[N:9]\[C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([F:1])[CH2:3]2)=[O:8])[CH:41]=[CH:42][CH:43]=1
Reactant: Brc1cccc(Br)c1
Reactant: Cc1cnc(NC(=O)N2CC[C@@H](F)C2)s1
Agent: Clc1cc2cccnc2c2ncccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cn(-c2cccc(Br)c2)/c(=N/C(=O)N2CC[C@@H](F)C2)s1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
In a 4 mL vial charged with a stir bar, (3R)-3-fluoro-N-(5-methyl-1,3-thiazol-2-yl)pyrrolidine-1-carboxamide (40 mg, 0.17 mmol, Example 34A) was added, followed by copper(I) trifluoromethanesulfonate benzene complex (17 mg, 0.03 mmol), 5-chloro-1,10-phenanthroline (15 mg, 0.07 mmol) and cesium carbonate (61 mg, 0.19 mmol). A loose cap with septum was placed on the vial and then the vial was placed under vacuum in a vacuum oven for 30 minutes. The mixture was purged with nitrogen gas a couple of times. 1,3-Dibromobenzene (47 mg, 0.2 mmol) dissolved in 1-methyl-2-pyrrolidinone (1.0 mL) was added to the mixture. The vial was capped and placed on a heater/stirrer and heated to 120° C. overnight. Then 1 mL of a solution of concentrated ammonium hydroxide/water (1:2) was added. The reaction was filtered and concentrated to dryness. The residue was purified by reverse phase HPLC (C8, gradient 10-100% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound.
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:44]1[CH:45]=[CH:46][CH:47]=[C:48]2[C:53]=1[CH:52]=[N:51][C:50]([NH:54][C:55]1[N:56]=[CH:57][C:58]([C:61]#[N:62])=[N:59][CH:60]=1)=[CH:49]2.C(=[NH:76])(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C1(C)C=CC=CC=1.CN(C=O)C.C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:76][C:44]1[CH:45]=[CH:46][CH:47]=[C:48]2[C:53]=1[CH:52]=[N:51][C:50]([NH:54][C:55]1[N:56]=[CH:57][C:58]([C:61]#[N:62])=[N:59][CH:60]=1)=[CH:49]2
Reactant: N#Cc1cnc(Nc2cc3cccc(Br)c3cn2)cn1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1cnc(Nc2cc3cccc(N)c3cn2)cn1
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 11 %

Procedure:
A mixture of tris(dibenzylideneacetone)dipalladium (0) (18 mg, 0.020 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (23 mg, 0.040 mmol) in toluene (1 mL) and DMF (1 mL) was degassed under a stream of nitrogen gas with stirring for 15 minutes. 5-(8-Bromoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (65 mg, 0.20 mmol), benzophenone imine (36 mg, 0.20 mmol) and caesium carbonate (130 mg, 0.40 mmol) were added and the mixture was degassed for a further 5 minutes, then heated at 140° C. for 40 minutes in a microwave reactor. Upon cooling the reaction mixture was diluted with ethyl acetate and filtered through celite, washed sequentially with water and brine then dried (Na2SO4) and concentrated to dryness to afford a brown oil. The residue was dissolved in THF (2 mL) and treated with aqueous hydrogen chloride (2 mL, 2M) for 30 minutes and then concentrated to dryness. Preparative HPLC gave the title compound (5.64 mg, 0.022 mmol, 11%). 1H NMR (d6-DMSO, 400 MHz) δ 10.90 (br s, 1H), 9.35 (s, 1H), 8.80 (s, 1H), 8.70 (s, 1H), 8.25 (s, 1H), 7.40 (t, 1H, J=7.8, 6.8 Hz), 6.95 (d, 1H, J=7.8 Hz), 6.60 (d, 1H, J=6.8 Hz), 6.25 (s, 1H). LC-MS (2) Rt=2.32 min; m/z (ESI+) 263 (M+H).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[CH2:13](O)[C@@H:14](O)[C@H:15]1[O:20][C:18](=O)[C:17](O)=[C:16]1O>>[C:18]([O:12][CH2:11][C@H:9]([OH:10])[C@H:7]1[O:8][C:2](=[O:1])[C:3]([OH:4])=[C:5]1[OH:6])(=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:2][CH2:3][CH2:5][CH2:7][CH2:9][CH3:11]
Reactant: O=C1O[C@H]([C@H](O)CO)C(O)=C1O
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: CCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O
Yield: 70 %

Procedure:
Repetition of the preparation substituting ascorbic acid for the erythorbic acid resulted in the isolation of 26.35 g of a white waxy solid assaying 95.1% ascorbic acid 6-laurate (0.070 mole, 70% yield).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1>>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH:12]=[CH:11][CH:10]=1
Reactant: c1cn[nH]c1
Reactant: COc1cccc(Br)c1
Product: COc1cccc(-n2cccn2)c1

Procedure:
Following General Procedure A (125° C., 24 hours), 1H-pyrazole (102 mg, 1.5 mmol) is coupled with 1-bromo-3-methoxybenzene (126 μL, 1.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=40/60) to provide 150 mg (86% isolated yield) of the desired product as an uncolored oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1>O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:18][CH2:17][CH:14]1[CH2:16][CH2:15]1
Reactant: NCC1CC1
Reactant: CCS(=O)(=O)c1ccc(F)c(Br)c1
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(NCC2CC2)c(Br)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of Example 84b (0.534 g, 2.00 mmol) and cyclopropylmethanamine (0.427 g, 6.00 mmol) in dioxane (5 mL) was heated at 100° C. for overnight. The reaction mixture was cooled to ambient temperature and filtered to remove the solid. The filtrate was concentrated. The residue was purified by flash chromatography (silica gel, 40% ethyl acetate in hexanes) to afford the title compound (0.63 g, 99%).
Reaction SMILES: [S:1]1[C:5]([CH2:6][C:7]2[C:8](Cl)=[N:9][C:10]3[C:15]([C:16]=2[Cl:17])=[CH:14][C:13]([Br:18])=[CH:12][CH:11]=3)=[CH:4][C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]1=2.[CH3:24][O-:25].[Na+].C1(C)C=CC=CC=1>C(Cl)Cl>[S:1]1[C:5]([CH2:6][C:7]2[C:8]([O:25][CH3:24])=[N:9][C:10]3[C:15]([C:16]=2[Cl:17])=[CH:14][C:13]([Br:18])=[CH:12][CH:11]=3)=[CH:4][C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]1=2
Reactant: C[O-]
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1cc2ccccc2s1
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc2ccc(Br)cc2c(Cl)c1Cc1cc2ccccc2s1

Procedure:
A heterogeneous mixture of 3-(benzo[b]thiophen-2-ylmethyl)-6-bromo-2,4-dichloroquinoline (7.5 g, 17.73 mmol, Intermediate 51: step a), sodium methoxide (4.79 g, 88.62 mmol), and toluene (25 mL) was heated at 110° C. in a sealed tube for 6 hours. The resulting black tar was diluted with DCM, then filtered through Celite®, rinsing with dichloromethane. The filtrate was concentrated and the crude product purified by chromatography (heptanes/DCM, gradient) to provide the title compound as a tan solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][C:10]([C:12]([O:14]C)=O)=[CH:11][C:4]=12.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH4+].[Cl-]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CCOC(C)=O>[CH3:1][S:2][C:3]1[C:4]2[CH:11]=[C:10]3[N:9]([C:5]=2[N:6]=[CH:7][CH:8]=1)[CH2:19][CH2:20][CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12]3=[O:14]
Reactant: COC(=O)c1cc2c(SC)ccnc2[nH]1
Reactant: CCOC(=O)CCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCn2c(cc3c(SC)ccnc32)C1=O
Reaction time: 0.08 h

Procedure:
To a solution of the compound of Step 4 (0.35 g, 1.6 mmol) in DMF (20 mL) at 0° C. was added NaH (1.2 eq.). After a period of 5 min., were added nBu4NI (0.10 g) and ethyl 4-bromobutyrate (0.40 mL). After a period of 1 h at room temperature, the reaction mixture was poured over saturated NH4Cl and EtOAc. The organic phase was separated, washed with H2O and dried over NaSO4. After evaporation the crude product was purified by flash chromatography. The bis ester was then dissolved in THF (7.0 mL) and a 1.06 M of THF solution of potassium tert-butoxide (2.2 mL) was added at 0° C. After a period of 1 h at room temperature, the reaction mixture was then poured over saturated NH4Cl and EtOAc. The organic phase was separated, dried over Na2SO4 and evaporated under reduced pressure to provide the title compound as a mixture of ethyl and methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].ClC1C=CC(C([NH:19][C:20]2[CH:21]=[N:22][C:23]([OH:26])=[CH:24][CH:25]=2)=O)=CC=1>>[OH:26][C:23]1[N:22]=[CH:21][C:20]([NH:19][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:25][CH:24]=1
Reactant: O=C(Nc1ccc(O)nc1)c1ccc(Cl)cc1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)Nc2ccc(O)nc2)c1

Procedure:
Starting from 3-methoxybenzoyl chloride (1.71 g, 10.0 mmol) and using the procedure as described for the preparation of 4-Chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide yielded the title compound, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH:34](=O)[CH:35]([CH3:37])[CH3:36].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH3:34][CH:35]([CH3:37])[CH2:36][NH:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)CNc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.8 %

Procedure:
The 3-[(3-aminophenyl )[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (50 mg, 0.12 mmol) was dissolved in 1 mL of dichloroethane. Acetic acid (8 μL, 0.14 mmol) followed by isobutyraldehyde (11.7 μL, 0.13 mmol) and solid NaBH(OAc)3 (37.3 mg, 0.18 mmol) were added. The solution was stirred at room temperature for 18 hours. The reaction was filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 16.1 mg (29%) of the desired 3-[[3-[(2-methylpropyl)amino]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C22H26F7N2O2: 483.1883 [M+H]+, found: 483.1932. 1H NMR (CDCl3) δ1.0 (m, 6H), 2.0 (m, 1H), 3.0 (m, 2H), 3.6 (dd, 1H), 3.8 (dd, 1H), 4.3 (m, 1H), 4.6 (m, 2H), 5.9 (tt, 1H), 6.6 (d, 1H), 6.7 (d, 1H), 6.9-7.4 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([CH3:12])[O:7][CH2:8][CH2:9][CH2:10]I)[CH3:2].[Cl:14]CCCO.C(OC(=O)/C=C/C)C.[H-].[Na+]>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([CH3:12])[O:7][CH2:8][CH2:9][CH2:10][Cl:14])[CH3:2]
Reactant: OCCCCl
Reactant: CCOC(=O)CC(C)OCCCI
Agent: C/C=C/C(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(C)OCCCCl

Procedure:
The 7-iodo-3-methyl-4-oxaheptanoic acid ethyl ester was obtained in the following manner: The 3-chloropropanol was added to the crotonic acid ethyl ester in the presence of sodium hydride to obtain the 7-chloro-3-methyl-4-oxaheptanoic acid ethyl ester (boiling point1 : 74° - 82° C). Then the 7-iodo-3-methyl-4-oxaheptanoic acid ethyl ester (boiling point0.05 : 62° - 65° C) was obtained in acetone with sodium iodide according to Finkelstein.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].OC1C=CC([N:19]2[C:23](=[O:24])[N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21](=[O:31])[NH:20]2)=CC=1>>[OH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[N:19]1[C:23](=[O:24])[N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21](=[O:31])[NH:20]1
Reactant: Oc1ccc2ccccc2c1
Reactant: O=c1[nH]n(-c2ccc(O)cc2)c(=O)n1-c1ccccc1
Product: O=c1[nH]n(-c2c(O)ccc3ccccc23)c(=O)n1-c1ccccc1

Procedure:
Compound 35 was prepared from 2-naphthol in the same manner of compound 27, and was obtained as white solids (89%). 1H NMR (300 MHz, DMSO-d6): δ 10.94 (br s, 1H), 7.95 (d, J=9.0 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.58-7.50 (m, 5H), 7.44-7.35 (m, 2H), 7.27 (dd, J=2.4, 9.0 Hz, 1H). 13C NMR (75 MHz, DMSO-d6): δ 154.39, 152.93, 152.16, 133.29, 132.99, 132.18, 129.59, 128.77, 128.58, 128.45, 128.29, 126.88, 124.19, 121.90, 119.38, 114.74. HRMS: calcd for C18H13N3O3 (MH+) 320.103. found 320.1032.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([C:14]([O:16]C)=[O:15])[CH2:12][CH2:11][N:10]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([C:14]([OH:16])=[O:15])[CH2:12][CH2:11][N:10]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CCN(CCc2ccccc2)C[C@H]1c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCN(CCc2ccccc2)C[C@H]1c1ccc(F)cc1
Temperature: 60 °C

Procedure:
The product from step B (750 mg, 2.197 mmol) in THF (15 ml) was treated at rt with 1 M aqueous lithium hydroxide (4.83 ml, 4.83 mmol). The mixture was heated at 60° C. for approximately 12 h, then cooled to rt and concentrated. The resulting residue was treated with 2M aq HCl (4.40 mL) and lyophilized twice from water (5 mL) to afford the title compound. HPLC/MS: 328.2 (M+1); Rt=0.95 min (LC-2 HPLC conditions).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([OH:19])=[O:18])=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:27][C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29].CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O.CO.CCOC(C)=O>[CH2:31]([N:30]([CH2:33][CH3:34])[C:28]([CH2:27][O:18][C:17]([C:9]1[NH:10][C:11]2[C:16]([C:8]=1[NH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:19])=[O:29])[CH3:32]
Reactant: CCN(CC)C(=O)CCl
Reactant: O=C(O)c1[nH]c2ccccc2c1Nc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)COC(=O)c1[nH]c2ccccc2c1Nc1ccncc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 96.1 %

Procedure:
Stir at 50° C. for 10 min. a mixture of 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid (2.0 g, 8 mmol), KI (10 mg) and Cs2CO3 (2.8 g, 8.6 mmol) in DMF (125 mL). Allow to cool to ambient temperature and then cool in an ice bath. Add 2-chloro-N,N-diethylacetamide (1.077 g, 0.9 mmol) and allow to warm to ambient temperature. Add a brine solution to the reaction and extract with EtOAc (3×). Wash the extract with brine and water, dry (MgSO4), filter and concentrate under vacuum to give a semi-solid. Flash chromatograph over silica gel eluting first with EtOAc and 10% MeOH/EtOAc and obtain 0.317 g the title compound as a solid: MS 367(M+H); HPLC: Rt=4.75 min. (95/5/0.1 (A) 5/95/0.1 (B) Water/CAN/Formic Acid YMC ODS-A 2×50 mm 1 mL/min Gradient Composition: 100% A for 0.1 min Linear Gradient to 100% B at 2 min Hold until 3.5 min).