Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH2:27][CH2:28][CH2:29][OH:30]>CN1C(=O)CCC1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:27][CH2:28][CH2:29][OH:30])[CH:3]=1)=[O:15]
Reactant: NCCO
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(CNC(=O)c2cc(NCCO)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 1.5 h
Yield: 63 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol) and 2-aminoethanol (1 ml) in NMP (2 mL). The vessel was sealed and the reaction mixture was irradiated (microwave) at 130° C. for 1 h and then at 140° C. for 90 min. The mixture was evaporated under vacuum and the residue was purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated yellow oil was treated with EtOAc, sonicated, and treated with hexanes. The solids were filtered, dissolved in DMF (1 mL), and a few drops of water were added. The solution was allowed to stand at room temperature overnight, and then sonicated. The filtered solid was washed with Hexanes/EtOAc (1:1), and then dried to afford the title compound (55 mg, 63%) as a light yellow solid. LCMS E-S (M+H)=399.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (br. s., 1H) 8.44 (br. s., 1H) 7.84 (s, 1H) 7.20 (br. s., 1H) 6.68 (s, 1H) 5.89 (s, 1H) 4.95 (dt, J=13.01, 6.38 Hz, 1H) 4.72 (t, J=4.93 Hz, 1H) 4.32 (d, J=4.80 Hz, 2H) 3.58 (d, J=5.56 Hz, 2H) 3.38-3.46 (m, 2H) 2.21 (s, 3H) 2.12 (s, 3H) 1.43 (d, J=6.57 Hz, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([O-:12])([OH:11])=[O:10].[N:13]([O-])=O.[Na+]>O>[N+:9]([O-:12])([O-:11])=[O:10].[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N+:6]#[N:13])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(Cl)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccc(Cl)cc1
Product: O=[N+]([O-])[O-]
Reaction time: 0.5 h

Procedure:
This example illustrates the preparation of a graphite fiber product using a process of the present invention. Approximately 0.2 g of the graphite fibers of Example 4 were added to a stirring solution of 0.025 g 4-chloroaniline, 0.070 g 90% nitric acid and 70 g of water. A solution of 0.014 g NaNO2 in 2 g of water was added and the mixture was stirred for 30 minutes. 4-Chlorobenzenediazonium nitrate was formed in situ, which reacted with the graphite fibers. The fibers were removed from the solution, dried in an oven at 110° C., subjected to Soxhlet extraction overnight with THF, and dried. An ESCA analysis of the product gave a chlorine concentration of 0.4 atomic percent. No chlorine could be detected in the unreacted fibers by ESCA. This establishes that chlorophenyl groups are attached to the graphite fiber product.
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:35])[NH:15][C:16](=[O:34])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=4)[CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1>CO>[C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=5)[CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:34])[NH:15][C:14]2=[O:35])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: Cc1cccc(-c2ccc3[nH]cc(C4=C(c5cn6c7c(cccc57)CCC6)C(=O)NC4=O)c3c2)c1
Solvent: CO
Product: Cc1cccc(-c2ccc3[nH]cc([C@@H]4C(=O)NC(=O)[C@H]4c4cn5c6c(cccc46)CCC5)c3c2)c1

Procedure:
3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(5-(3-methylphenyl)-1H-indol-3-yl)pyrrole-2,5-dione, prepared as in Example 34, was reduced with Mg in methanol as described in Example 2, Procedure C, to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(5-(3-methylphenyl)-1H-indol-3-yl)pyrrolidine-2,5-dione. 1H NMR (CD3OD) δ: 1.98-2.18 (m, 2H), 2.34 (s, 3H), 2.85-3.00 (m, 2H), 3.90-3.98 (m, 1H), 3.98-4.09 (m, 1H), 4.35 (d, J=7.2 Hz, 1H), 4.64 (d, J=6.8 Hz, 1H), 6.88-6.99 (m, 2H), 7.00-7.10 (m, 3H), 7.13-7.26 (m, 5H), 7.36 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH3:19])[C:4]([N:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH3:7])=[O:5].[C:20]([C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]2[C:31]([CH:32]=O)=[CH:30][N:29]=[CH:28]2)=[CH:24][C:23]=1[F:36])#[N:21].C(N(CC)C(C)C)(C)C.[BH3-]C#N.[Na+]>CO.CC(O)=O>[C:20]([C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]2[C:31]([CH2:32][NH:2][C@H:3]([CH3:19])[C:4]([N:6]([C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=4)[CH:11]=[CH:10][CH:9]=3)[CH3:7])=[O:5])=[CH:30][N:29]=[CH:28]2)=[CH:24][C:23]=1[F:36])#[N:21]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Reactant: C[C@@H](N)C(=O)N(C)c1cccc2ccc(O)cc12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: C[C@@H](NCc1cncn1Cc1ccc(C#N)c(F)c1)C(=O)N(C)c1cccc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-2-Amino-N-(7-hydroxynaphthalen-1yl)-N-methylpropionamide hydrochloride, as described above in Step D, (109 mg, 0.39 mmol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde, as described in Example 4, Step G, (89 mg, 0.39 mmol), were stirred in MeOH (2 mL) and was neutralized with N,N-diisopropylethylamine. Acetic acid was then added dropwise to adjust the mixture to ca. pH 5, as judged by wetted pH paper. The mixture was stirred for 1 hr at ambient temperature, then NaCNBH3 (32 mg, 0.51 mmol) was added, the solution was readjusted to ca. pH 5 by addition of AcOH, and stirring was continued for 18 hrs. The reaction was quenched with saturated aqueous NaHCO3 (2 mL) and most of the MeOH was removed under reduced pressure. The residual solution was partitioned between saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted further with CH2Cl2 (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of 1% to 6% MeOH −0.1% to 0.6% NH4OH —CH2Cl2 to yield the titled product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH:7]1[CH3:14].[ClH:15].Cl.[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.[Na+].[I-]>C(#N)C>[ClH:15].[ClH:15].[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([N:32]3[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]4[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH:7]4[CH3:14])[CH2:34][CH2:33]3)=[CH:24]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1SC(C)(C)C(=O)N1CCCCBr
Reactant: c1ccc(-n2cc(N3CCNCC3)c3ccccc32)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1SC(C)(C)C(=O)N1CCCCN1CCN(c2cn(-c3ccccc3)c3ccccc23)CC1
Temperature: 75 °C
Yield: 45.8 %

Procedure:
A mixture of 3-(4-bromobutyl)-2,5,5-trimethyl-4-thiazolidinone (5.00 g), 1-(1-phenyl-1H-indol-3-yl)piperazine dihydrochloride (7.80 g), N,N-diisopropylethylamine (9.65 g), NaI (350 mg) in acetonitrile (250 ml) was heated at 75° C. for 17 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.80 g of crystals, m.p. 217-219° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:25]3[CH2:30][CH2:29][C@H:28]([C:31](N)=[O:32])[CH2:27][CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.C(OC1C=C(C2N=C(C3CCC(CO)CC3)N3C=CN=C(Cl)C=23)C=CC=1)C1C=CC=CC=1>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31][OH:32])[CH2:27][CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c1c(-c1cccc(OCc3ccccc3)c1)nc2[C@H]1CC[C@H](C(N)=O)CC1
Agent: OCC1CCC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)CC1
Product: Nc1nccn2c1c(-c1cccc(OCc3ccccc3)c1)nc2[C@H]1CC[C@@H](CO)CC1

Procedure:
cis-{4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexyl}-methanol (compound of Formula I-B where Z=cyclohexyl and Q1=Ph-(3-OBn)) was prepared according to the procedures described for the synthesis of trans-4-[8-amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide except for the substitution of cis-4-[1-(3-benzyloxyphenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]cyclohexane carboxylic acid methyl ester (compound of Formula II-A where Z=cyclohexyl, CO2A3=4-cis-CO2Me, and Q1=Ph-(3-OBn)) with {4-[1-(3-benzyloxy-phenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]-cyclohexyl}-methanol (compound of Formula II-B where Z=cyclohexyl and Q1=Ph-(3-OBn)); MS (ES) 429.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[CH3:15][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:10][C:2]=1[Br:1]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Br
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(F)(F)F)cc1Br
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of 2 g (7.434 mmol) 2-bromo-4-trifluoromethyl-benzoic acid (CAS: 328-89-2) in 20 ml DMF under nitrogen at room temperature, was added 1.13 g (8.177 mmol) potassium carbonate and 557 ul (8.921 mmol) methyl iodide. The mixture was stirred overnight under nitrogen. The mixture was poured into water (300 ml). The aqueous layer was extracted with ethyl acetate (2×80 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified on silica gel (eluent: heptane/ethyl acetate 0 to 10%) to provide 1.75 g (83%) of the title compound as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[NH2:33][CH2:34][CH2:35][C:36]1[C:37]([N:45]([CH3:47])[CH3:46])=[N:38][C:39]([CH:42]2[CH2:44][CH2:43]2)=[CH:40][CH:41]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:33][CH2:34][CH2:35][C:36]3[C:37]([N:45]([CH3:46])[CH3:47])=[N:38][C:39]([CH:42]4[CH2:43][CH2:44]4)=[CH:40][CH:41]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CN(C)c1nc(C2CC2)ccc1CCN
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C5CC5)nc4N(C)C)cc3)c(Cl)cc21
Reaction time: 0.25 h
Yield: 25.8 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation B; 200 mg, 0.531 mmol) was diluted with dichloromethane (2 mL) followed by the addition of oxalyl chloride in dichloromethane (2M) (292 μL, 0.584 mmol) and dimethylformamide (1 drop). After stirring for 15 minutes, 3-(2-aminoethyl)-6-cyclopropyl-N,N-dimethylpyridin-2-amine (109 mg, 0.531 mmol) and diisopropyl ethylamine (277 μL, 1.59 mmol) were added. After stirring for 2 hours, the reaction was loaded onto silica gel and eluted with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield ethyl 6-chloro-7-(4-(2-(6-cyclopropyl-2-(dimethylamino)pyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate (77 mg, 0.137 mmol, 25.7% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3=[C:16]([CH2:19][C:20]4([OH:27])[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]4)[CH:17]=[CH:18][N:14]3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[BH3-]C#[N:30].[Na+]>CO>[NH2:30][CH:23]1[CH2:24][CH2:25][C:20]([CH2:19][C:16]2[CH:17]=[CH:18][N:14]3[C:15]=2[C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)=[N:11][CH:12]=[N:13]3)([OH:27])[CH2:21][CH2:22]1
Reactant: [BH3-]C#N
Reactant: O=C1CCC(O)(Cc2ccn3ncnc(Nc4ccc(F)c(Cl)c4)c23)CC1
Agent: [Na+]
Solvent: CO
Product: NC1CCC(O)(Cc2ccn3ncnc(Nc4ccc(F)c(Cl)c4)c23)CC1
Reaction time: 12 h
Yield: 15 %

Procedure:
To a solution of 4-[4-(3-chloro-4-fluoro-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl]-4-hydroxy-cyclohexanone (24 mg, 0.06 mmole) in dry MeOH (0.5 mL) was added powdered 3A molecular sieves (24 mg), (10 eq) NH4OAc (48 mg, 0.06 mmole), and NaCNBH3 (4 mg, 0.06 mmole); the reaction stirred under nitrogen for 12 hr. The reaction mixture was filtered and a 15% NaOH solution was added. After 10 min, the mixture was diluted with DCM (50 mL) and washed with water. The organic phase was dried (Na2SO4) and the solvent was removed. The material was purified and separated by preparative HPLC to afford the title compound (3.5 mg, 15%) and the cis isomer (7.9 mg, 32%). The title compound: MS: 390 (M+H)+; HPLC Ret Time: 2.070 min (XTERRA 4.6×50 mm S5 column, 3 min gradient, 4 mL/min). The cis isomer: MS: 390 (M+H)+; HPLC Ret Time: 2.190 min (XTERRA 4.6×50 mm S5 column, 3 min gradient, 4 mL/min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:16]Br>O1CCCC1.C(OCC)C.[Cl-].[Al+3].[Cl-].[Cl-]>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([Br:16])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC1CCC(=O)C(Br)C1
Temperature: 2.5 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
A solution of (4-Oxo-cyclohexyl)-carbamic acid tert-butyl ester (10 grams, 46 mmol) and aluminum chloride (0.25 grams, 2 mmol) in tetrahydrofuran (30 mL) and diethyl ether (30 mL) was cooled to 0° C., then treated with bromine (2.4 mL, 46 mmol) over a period of 30 minutes. The reaction mass was stirred for 24 hours at 0-5° C. After completion of reaction, the obtained solids were filtered and lower filtrate was concentrated under vacuum. The obtained crude was triturated with diethyl ether and the resulted solids were filtered and dried under vacuum to obtain the title compound (9.0 grams).
Reaction SMILES: [F:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O[Li].O>CC(C)=O.O>[F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccc(O)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]O
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1cccc(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
A suspension of 2-fluoro-3-hydroxybenzoic acid (12.0 g, 76.9 mmol) and potassium carbonate (23.4 g, 169 mmol) in acetone (154 mL) was stirred at ambient temperature for 1 hour. To the mixture was added dimethyl sulfate (21.8 mL, 231 mmol) and the mixture stirred at ambient temperature for 30 minutes then heated at reflux for 4 hours. The mixture was cooled to ambient temperature, filtered and concentrated under reduced pressure. The residue was dissolved in anhydrous THF (154 mL) and the solution cooled to 0° C. in an ice bath. To this solution was added LiOH—H2O (12.9 g, 307 mmol) followed by water (30 mL) and the resulting mixture stirred at ambient temperature for 3 hours. The mixture was concentrated under reduced pressure and the residue partitioned between water and ethyl acetate and the layers separated. The aqueous layer was acidified with 1N HCl solution and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried (MgSO4), filtered and concentrated under reduced pressure to afford 2-fluoro-3-methoxybenzoic acid (12.31 g, 94%).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[N:20]1([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1>CC#N.CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:30][CH:29]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc(N2CCCC2)cc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(Nc2ccc(N3CCCC3)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 68.6 %

Procedure:
A mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.500 mmol), (4-pyrrolidin-1-ylphenyl)amine (0.081 g, 0.500 mmol) and TEA (0.070 ml, 0.500 mmol) in MeCN (2 ml) and DMF (1 ml) was heated in a microwave reactor at 120° C. for 45 mins. TEA (0.070 ml, 0.500 mmol) was added and the mixture was heated at 120° C. for 15 mins. The precipitate from the reaction mixture was isolated by filtration and washed with MeCN. The crude product was dissolved in MeOH and purified by silica gel column chromatography using 15-100% EtOAc in petroleum ether 40-60° C. as eluent, to give the title compound (0.146 g, 69%). 1H NMR (500 MHz, CDCl3): δ 7.22-7.02 (m, 5H), 6.55 (d, 2H), 6.14 (d, 2H), 3.15-3.10 (m, 4H), 1.99-1.92 (m, 4H), 1.77 (s, 9H); 13C NMR (125 MHz CDCl3): δ 160.8, 149.9, 131.6, 129.7, 128.5, 127.9, 125.5, 124.7, 123.9, 111.2, 108.8, 61.8, 47.9, 27.9, 25.6; Mass Spectrum: M+H+ 426.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5](I)=[CH:4][C:3]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1C=CC(P([C:40]2[CH:45]=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:46][Si:47]([C:50]#[CH:51])([CH3:49])[CH3:48]>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.N1CCCCC1>[CH3:46][Si:47]([C:50]#[C:51][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5]([C:40]#[C:45][Si:47]([CH3:49])([CH3:48])[CH3:46])=[CH:4][C:3]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH3:49])[CH3:48]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCCOc1cc(I)c(OCCCCCCCC)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCNCC1
Product: CCCCCCCCOc1cc(C#C[Si](C)(C)C)c(OCCCCCCCC)cc1C#C[Si](C)(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1,4-Diiodo-2,5-di-n-octyloxybenzene (4.01 g, 6.84×10−3 mol), Pd(PPh3)2Cl2 (0.248 g, 3.53×10−4 mol), PPh3 (0.179 g, 6.82×10−4 mol), CuI (0.072 g, 3.8×10−4 mol) and piperidine (40 ml) were added to a 100-ml round-bottom flask. Ar was bubbled into the reaction mixture for 5 min before trimethylsilylacetylene (3.0 ml, 2.1×10−2 mol) was added. The reaction mixture was stirred at 60° C. for 2 h under Ar. After cooling, the solvent was evaporated. CHCl3 was added to the residue, and the organic solution was washed with aqueous NH4Cl (3 times), water, and dried over Na2SO4. After the solvent was evaporated, the residue was chromatographed on silica gel with 2:1 hexane:CHCl3 as the eluent. Yield=3.455 g (96% based on 4.01 g of 1,4-diiodo-2,5-di-n-octyloxybenzene). 1H NMR (300 MHz, CDCl3): δ 6.88 (s, 2H, Ph-H), 3.94 (t, 4H, J=6.4 Hz, —OCH2), 1.78 (quint, 4H, J=6.9 Hz, —OCH2CH2—), 1.42-1.60 (m, 4H, —OCH2CH2CH2—), 1.16-1.42 (m, 16H, —CH2—), 0.88 (t, 6H, J=6.7 Hz, —CH3), 0.25 (s, 18H, —Si—CH3). CI MS m/z: 526.366 (M+) (calcd 526.366).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>CCOCC.C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:25][CH:22]1[CH2:24][CH2:23]1
Reactant: OCc1ccccc1Br
Reactant: NC1CC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Brc1ccccc1CNC1CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a THF solution (0.15 M) of 2-bromobenzyl alcohol (1 eq.) was added triethylamine (1.6 eq.). The reaction mixture was cooled to 0° C. before methanesulfonyl chloride (1.3 eq.) was added dropwise. The resulting solution was then allowed to warm slowly to RT. After 1.5 h, cyclopropylamine (5 eq.) was added to the now cloudy suspension. After another 18 h, the reaction mixture was diluted with ether and quenched with 1 N aq. NaOH. The organic extract was separated, washed with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 4:1 (v/v) Hex:EtOAc→1:4 (v/v) Hex:EtOAc) afforded the title compound as a light yellow oil.
Reaction SMILES: C(O)C.O.[Si:5]([O:22][CH2:23][CH2:24][C@H:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][C:37]([C:40]([O:42]C)=[O:41])=[C:36]([Cl:44])[CH:35]=1)[CH3:26])([C:18]([CH3:21])([CH3:20])[CH3:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>O1CCCC1>[Si:5]([O:22][CH2:23][CH2:24][C@H:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][C:37]([C:40]([OH:42])=[O:41])=[C:36]([Cl:44])[CH:35]=1)[CH3:26])([C:18]([CH3:20])([CH3:21])[CH3:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(-c2ccccc2O[C@H](C)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccccc1-c1ccc(C(=O)O)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution in tetrahydrofuran (5.0 ml), ethanol (5.0 ml) and water (5.0 ml) of methyl 2′-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-methylpropyl]oxy}-3-chlorobiphenyl-4-carboxylate (565 mg) was added 1 N aqueous sodium hydroxide solution (1.48 ml), followed by stirring at 60° C. for 8 hours. After the reaction solution was concentrated under reduced pressure, a 10% aqueous citric acid solution and dichloromethane were added to the residue, and the solution was separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 2′-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-methylpropyl]oxy}-3-chlorobiphenyl-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1c(C(=O)c2ccc(Br)cc2)[nH]c2cc(Cl)ccc12
Reactant: OB(O)c1cccnc1
Product: COC(=O)Cc1c(C(=O)c2ccc(-c3cccnc3)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 207 from methyl[6-chloro-2-(4-bromobenzoyl)-1H-indol-3-yl]acetate (Example 206) and pyridine-3-boronic acid.