Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:33]=[N:34][CH:35]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2cncc(F)c2)c1

Procedure:
(S)-5-Bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1, 60 mg, 0.13 mmol), (5-fluoropyridin-3-yl)boronic acid (60.8 mg, 0.261 mmol), Pd(PPh3)2Cl2 (9.15 mg, 0.013 mmol) and Na2CO3 (41.5 mg, 0.391 mmol) were added to a MW vial. The vial was sealed, evacuated/purged with argon, and DME (553 μL), water (158 μL) and EtOH (79 μL) were added. The RM was subjected to MW irradiation at 120° C. for 15 min. The RM was diluted with DME (2 mL), treated with Si-Thiol (Silicycle, 1.27 mmol/g, 103 mg, 0.130 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 12, 15% to 45% in 14 min) to yield the title compound as a yellow solid. UPLC-MS (condition 1) tR=1.90 min, m/z=487.0 [M+H]+, m/z=485.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.27 (t, J=7.58 Hz, 3H) 1.50-1.62 (m, 1H) 1.77-1.89 (m, 1H) 2.15-2.28 (m, 1H) 2.82 (q, J=7.58 Hz, 2H) 2.99 (dd, J=11.00, 6.60 Hz, 1H) 3.08-3.20 (m, 2H) 3.21-3.30 (m, 2H) 3.29-3.38 (m, 1H) 4.60 (br. s, 1H) 7.34 (d, J=8.80 Hz, 2H) 7.38 (d, J=8.07 Hz, 1H) 7.75 (dd, J=7.82, 1.96 Hz, 1H) 7.86 (d, J=9.05 Hz, 2H) 8.02 (d, J=2.20 Hz, 1H) 8.55 (d, J=1.96 Hz, 1H) 8.75 (d, J=2.20 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=2)=[O:16])=[N:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([N:6]2[CH:7]=[C:3]3[CH2:2][N:17]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=4)[C:15](=[O:16])[C:4]3=[N:5]2)=[CH:9][CH:10]=1
Reactant: COc1cc(NC(=O)c2nn(-c3ccc(Cl)cc3)cc2CCl)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N2Cc3cn(-c4ccc(Cl)cc4)nc3C2=O)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
A mixture of 4-(chloromethyl)-1-(4-chlorophenyl)-N-(4-hydroxy-3-methoxyphenyl)-1H-pyrazole-3-carboxamide (29.9 mg, 0.076 mmol) and potassium carbonate (42 mg, 0.304 mmol) in DMF (0.5 mL) was stirred at room temperature overnight. The mixture was diluted with H2O (4.5 mL). The pH of the resulting mixture was adjusted to 8 by adding 1N aq. HCl. The solid was collected via filtration to give a product as pink color solid (15 mg, 56% yield). The product was used for next step without further purification. LCMS (ES): m/z 356.4 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[N:6][N:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:23]>ClCCl>[CH3:1][S:2]([C:3]1[S:4][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[N:6][N:7]=1)=[O:23]
Reactant: CSc1nnc(-c2ccc3ccccc3c2)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nnc(-c2ccc3ccccc3c2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methylsulfanyl-5-naphthalen-2yl-[1,3,4]thiadiazole (1.3 g, 5.03 mmol) in dichloromethane (50 ml) was added 50% moisten 3-chloro peroxybenzoic acid (1.9 g, 5.53 mmol) at 0° C. After stirred for 1 h at 0° C. the reaction was diluted with dichloromethane (50 ml) and quenched with addition of saturated aqueous sodium hydrogen carbonate (50 ml). The organic phase was separated and washed with water (50 ml), dried (MgSO4), filtered and evaporated in vacuo. The residue (1.4 g) was purified by column chromatography on silicagel (400 ml) using a mixture of ethyl acetate and heptane (1:1) as eluent. This afforded after drying in vacuo at 50° C. 0.9 g (65%) of the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(COC)OC.C(=O)([O-])[O-].[Cs+].[Cs+]>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.O>[F:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OB(O)c1cccc(F)c1F
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Oc1ccc(-c2cccc(F)c2F)cc1
Yield: 74.9 %

Procedure:
First, 34.6 g of 4-bromphenol, 37.9 g of 2,3-difluorophenylboronic acid, 380 ml of dimethoxyethane, 380 ml of water, 97.8 g of cesium carbonate, and 7 g of tetrakis(triphenylphosphine)palladium were placed in a 1 L flask. The mixture was stirred under reflux for 20 hours. The reaction mixture was poured into water and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=9/1) and recrvstallized from hexane to obtain 30.9 g of 2,3-difluoro-4'-hydroxybiphenyl (Y: 75%). The compound thus obtained had a purity of 99.8% by GC and an m.p. of 132° C. to 134.4° C.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([OH:20])[CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)([O-])=O.[H][H]>[Ni]>[NH2:1][CH2:4][CH:5]([OH:20])[CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1
Reactant: O=[N+]([O-])CC(O)C(c1ccccc1)c1cccc(Cl)c1
Reactant: [H][H]
Agent: [Ni]
Product: NCC(O)C(c1ccccc1)c1cccc(Cl)c1

Procedure:
reducing the 3-nitro-1-phenyl-1-(m-chlorophenyl)propan-2-ol with hydrogen in the presence of Raney nickel to yield 3-amino-1-phenyl-1-(m-chlorophenyl)propan-2-ol or its salt and (c) dimethylating the 3-amino-1-phenyl-1(m-chlorophenyl)propan-2-ol or its salt to yield 3-dimethylamino-1-phenyl-1-(m-chlorophenyl)propan-2-ol or its salt.
Reaction SMILES: [OH-].[K+].[CH3:3][S:4]([CH2:6]Cl)=[O:5].[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([S:14][CH2:6][S:4]([CH3:3])=[O:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Sc1ccccc1
Reactant: CS(=O)CCl
Agent: [K+]
Agent: [OH-]
Product: CS(=O)CSc1ccccc1
Temperature: 60 °C
Yield: 87.6 %

Procedure:
Potassium hydroxide (460 mg) was added in an atmosphere of nitrogen to a mixture of 560 mg of chloromethyl methyl sulfoxide and 616 mg of thiophenol, and then the mixture was heated at 60° C. for 13.5 hours. With addition of 3 ml. of water, the mixture was extracted with chloroform. The extract was dried using anhydrous sodium sulfate, and then subjected to column-chromatography [silica gel, chloroform-ethyl acetate (9:1 )] to yield 812 mg of methyl phenylthiomethyl sulfoxide having a boiling point of 148° C./0.5 mmHg and an nD25 of 1.6053 as a colorless liquid in a yield of 87.3%.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:20]=1[CH:21]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(#N)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:3]2[C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=[C:2]2[NH:1][CH2:21][C:20]2[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:19]=2[F:18])=[CH:12][CH:13]=1
Reactant: O=Cc1c(F)ccc(F)c1F
Reactant: COC(=O)c1cnc(N)n1-c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)c1cnc(NCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
Methyl 2-amino-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (67) (200 mg, 0.85 mmol), 2,3,6-trifluorobenzaldehyde (163 mg, 1.02 mmol), sodium triacetoxyborohydride (450 mg, 2.13 mmol) and catalytic amounts of acetic acid in acetonitrile (5 mL) was heated under microwave radiation for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to afford methyl 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)amino)-1H-imidazole-5-carboxylate (68).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:27]=[N:26][CH:25]=[CH:24][N:23]=2)[CH2:21][O:20]1.O>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:18][C:19]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)([OH:20])[CH3:21])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC1(c2cnccn2)CO1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cnccn2)CCN(C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
To a stirred solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido(4,3-b)indole (350 mg, 1.75 mmol) in DMF (4 mL) was added sodium hydride (210 mg, 5.25 mmol) followed by dropwise addition of 2-(2-methyl oxiranyl)pyrazine (310 mg, 2.275 mmol) at 10° C. and the reaction mixture was further stirred at RT for 16 h. After completion, the reaction mixture was poured into ice cooled water, extracted with EtOAc (3×75 mL). The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated yielding crude product, which was re-crystallized in ether and hexane to yield a yellow solid product (350 mg). 1H NMR (DMSO, Oxalate salt) d (ppm): 8.65 (s, 1H), 8.55 (s, 1H), 8.50 (d, 1H), 7.10 (s, 1H), 6.90 (d, 1H), 6.78 (d, 1H), 4.30 (m, 4H), 3.20 (m, 2H), 3.0 (m, 2H), 2.90 (s, 3H), 2.30 (s, 3H), 1.50 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH:9]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][C:12]([CH:9]([CH3:11])[CH3:10])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: Brc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)c1ccc(-c2cncc(Br)c2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 51.7 %

Procedure:
Part A. A solution of 3,5-dibromopyridine (1.0 g, 4.2 mmol) and 4-isopropylbenzeneboronic acid (346 mg, 2.1 mmol) in a mixture of ethanol-toluene-water (10 mL/5 mL/3 mL) is treated with sodium carbonate (450 mg). The mixture is degassed twice, treated with a catalytic amount of tetrakis(triphenylphosphine)palladium, and heated with stirring to 80° C. for 12 h. The mixture is cooled, filtered and evaporated. The residue is partitioned between water and ethyl acetate, and the organic phase is washed with brine, dried over sodium sulfate, filtered and evaporated. The residue is separated by column chromatography to afford 3-bromo-5-(4-isopropyl-phenyl)-pyridine (300 mg, 55%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][C:3]=1[CH3:10].[Li]C(C)(C)C.[B:16](OC)([O:19]C)[O:17]C.Cl>C(OCC)C>[CH3:10][C:3]1[CH:4]=[C:5]([S:8][CH3:9])[CH:6]=[CH:7][C:2]=1[B:16]([OH:19])[OH:17]
Reactant: COB(OC)OC
Reactant: CSc1ccc(Br)c(C)c1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CSc1ccc(B(O)O)c(C)c1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 52.4 %

Procedure:
Add 1-bromo-2-methyl-4-methylsulfanyl-benzene (608 mg, 2.80 mmol) to diethyl ether (60 mL) and cool to −78° C. under a nitrogen blanket. Add t-BuLi (3.4 mL, 5.78 mmol) over a 15 minute period, stir for 2 minutes, add trimethyl borate ((MeO)3B, 340 μL, 2.99 mmol) over 2 minutes, stir for 15 minutes at −78° C. and then let warm to room temperature. Quench the reaction with saturated aqueous NH4Cl (7 mL), stir for 15 minutes, add 1M aqueous HCl (6 mL), stir for another 2 minutes and separate. Dry with Na2SO4, filter (wash the drying agent with ethyl acetate (3×20 mL)), and concentrate. Chromatograph the crude material on a SiO2 column with 20% ethyl acetate in hexanes to 5% methanol in ethyl acetate to give 267 mg of the title compound (52%).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC1(C)[N:18](C(OC(C)(C)C)=O)[C@@:17]([CH3:50])([C:26]2[S:27][C:28]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[C:33]([C:46]([F:49])([F:48])[F:47])[CH:32]=3)=[N:29][N:30]=2)[CH2:16][O:15]1>CO>[NH2:18][C@@:17]([C:26]1[S:27][C:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[C:33]([C:46]([F:47])([F:49])[F:48])[CH:32]=2)=[N:29][N:30]=1)([CH3:50])[CH2:16][OH:15]
Reactant: CCCCCCCCOc1ccc(-c2nnc([C@@]3(C)COC(C)(C)N3C(=O)OC(C)(C)C)s2)cc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CCCCCCCCOc1ccc(-c2nnc([C@@](C)(N)CO)s2)cc1C(F)(F)F
Temperature: 20.5 °C
Reaction time: 1.5 h

Procedure:
A 5 L round bottom flask was inerted and charged with p-toluene sulfonic acid monohydrate (208 g, 1.09 mol, 5 equiv) and a solution of (R)-tert-Butyl 2,2,4-trimethyl-4-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)oxazolidine-3-carboxylate (125 g, 0.22 mol) in methanol (2.5 L), and heated to reflux. After 1.5 h HPLC indicated reaction complete. The heat was turned off and the mixture was allowed to cool to room temperature (18 to 23° C.) and stirred for 12 hours. The mixture was concentrated under vacuum to a residue to provide the title product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH2:13])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([Cl:27])=[C:22]([CH:26]=1)[C:23](O)=[O:24])(=[O:17])=[O:16].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[NH2:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([Cl:27])=[C:22]([CH:26]=1)[C:23]([NH:13][C:11]1[S:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9][N:10]=1)=[O:24])(=[O:17])=[O:16]
Reactant: Nc1nnc(-c2ccc(F)cc2)s1
Reactant: NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Product: NS(=O)(=O)c1ccc(Cl)c(C(=O)Nc2nnc(-c3ccc(F)cc3)s2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 ml scintillation vial containing a Teflon covered magnetic stir-bar was added commercially available 5-(4-fluorophenyl)-1,3,4-thiadiazol-2-amine (25 mg, 0.128 mmol) and 5-(aminosulfonyl)-2-chlorobenzoic acid (22.3 mg, 0.128 mmol). To this mixture was added EDC (25 mg, 0.128 mmol) and HOAt (18 mg, 0.128 mmol) followed by 3 ml of DCM. The resulting mixture was stirred at room temperature overnight. The product precipitated and was collected by vacuum filtration, washed with 3 ml of MeOH and air-dried under vacuum. Yield of 5-(aminosulfonyl)-2-chloro-N-[5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl]benzamide was (7 mg) as a white powder.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1Br)[CH3:7].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1(C)C=CC=CC=1.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>[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:7]
Reactant: CCOC(=O)c1cccc(OC)c1Br
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
Product: CCOC(=O)c1cccc(OC)c1-c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
2M Aqueous sodium bicarbonate (10 mL) was added to a suspension of 2-bromo-3-methoxybenzoic acid ethyl ester (2.06 g, 7.7 mmol), benzeneboronic acid (1.11 g), and tetrakis(triphenylphosphine)palladium(0) (0.30 g) in toluene (35 mL) under a nitrogen atmosphere. The mixture was stirred at 80° C. for 2 hours, poured into water, and extracted with diethyl ether. The organic layer was evaporated, and the residue was chromatographed, eluting with hexane/acetone (3:1) to give a semisolid oil. Recrystallization from diethyl ether/hexane gave 3-methoxy-2-phenylbenzoic acid ethyl ester as colorless crystals (0.69 g, 34%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=2)[CH:9]=[N:8]1.[OH-].[Na+].CN([CH:25]=[O:26])C>>[CH:25]([C:9]1[C:10]2[C:15](=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)[N:7]([CH3:6])[N:8]=1)=[O:26]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc2cnn(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(C=O)nn(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a dry flask under nitrogen is added dry DMF (1.6 mL) and the solution cooled to −5 C in an ice/ethanol bath. Phosphorous oxychloride (530 uL, 5.7 mmol) is added via syringe and the solution is allowed to stir for 30 minutes in the bath. Methyl 1-methyl-1H-indazole-6-carboxylate, (500 mg, 2.84 mmol, prepared as in Jadhav et al, U.S. Pat. No. 5,760,028) dissolved in DMF (3 mL) is added slowly to the cold solution. The reaction is then warmed to 35 C, stirred for four hours, and then poured onto crushed ice. The resulting slurry is neutralized with 1N NaOH to pH=7, heated rapidly to boiling for 1 minute, cooled quickly to room temperature, and the solution extracted with ethyl acetate. The combined organics are washed with water and brine, dried, filtered and concentrated. The resulting oil is purified by flash chromatography to afford the product.
Reaction SMILES: ClC(OC(Cl)=O)C.C([N:15]([CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:16][CH2:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=2)=[CH:20][CH:19]=1)C1C=CC=CC=1.ClCCCl.N>CO>[C:37]1([CH2:36][CH2:35][CH2:34][NH:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=3)=[CH:32][CH:33]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: NC(=O)c1ccc(Oc2ccc(CCN(CCCc3ccccc3)Cc3ccccc3)cc2)nc1
Agent: CC(Cl)OC(=O)Cl
Agent: N
Solvent: CO
Solvent: ClCCCl
Product: NC(=O)c1ccc(Oc2ccc(CCNCCCc3ccccc3)cc2)nc1
Yield: 66.9 %

Procedure:
Add 1-chloroethylchloroformate (0.056 mL, 0.52 mmol) to a stirred solution of 6-(4-{2-[benzyl-(3-phenyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide (0.1211 g, 0.2603 mmol) (Example 3) and 1,2-dichloroethane (5 mL). Beat the reaction to reflux under nitrogen for 1.5 h. Add methanol (7 mL) and heat at reflux under nitrogen for 1 h. Cool the reaction to room temperature and add 2 M ammonia in methanol (5 mL). Concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 1% concentrated ammonium hydroxide/10% ethanol/chloroform to yield 0.0654 g (67%) of 6-{4-[2-(3-phenyl-propylamino)-ethyl]-phenoxy}-nicotinamide: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 7.48 minutes, Purity: 99.2%; mass spectrum (ion spray): m/z=376.2 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:53])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22]2[N:30]=[C:29]([NH:31][C@H:32]4[CH2:37][CH2:36][C@H:35]([NH:38]C(OC(C)(C)C)=O)[CH2:34][CH2:33]4)[N:28]=[C:27]4[C:23]=2[N:24]=[CH:25][N:26]4C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[O:11])=[CH:5][CH:4]=1.Cl>CO>[NH2:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([NH:31][C:29]2[N:28]=[C:27]3[C:23]([N:24]=[CH:25][NH:26]3)=[C:22]([N:18]3[C:19]4[C:15](=[CH:14][C:13]([NH:12][C:10]([NH:9][C:6]5[CH:7]=[CH:8][C:3]([N:2]([CH3:53])[CH3:1])=[CH:4][CH:5]=5)=[O:11])=[CH:21][CH:20]=4)[CH2:16][CH2:17]3)[N:30]=2)[CH2:37][CH2:36]1
Reactant: CN(C)c1ccc(NC(=O)Nc2ccc3c(c2)CCN3c2nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc3c2ncn3C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CO
Product: CN(C)c1ccc(NC(=O)Nc2ccc3c(c2)CCN3c2nc(N[C@H]3CC[C@H](N)CC3)nc3[nH]cnc23)cc1
Reaction time: 48 h

Procedure:
The product obtained in stage 1 is dissolved in 5 ml of methanol. 5 ml of a 2N solution of hydrochloric acid in methanol are added. Stirring is carried out for 48 hours at ambient temperature, followed by evaporation to dryness. The residue is chromatographed on an Xterra LCMSprep column, eluting with aceto-nitrile/ammonium hydrogen carbonate buffer at 0.2% as a gradient. 42 mg of expected product, example 45, are thus obtained.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][O:31][CH2:30][C@H:29]1[CH2:34][C:35](O)=[O:36]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][C@@H:29]5[CH2:30][O:31][CH2:32][CH2:33][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)C[C@@H]1COCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(C[C@@H]1COCCO1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (52 mg, 71%), MS (ISP) m/z=459.5 [(M+H)+], mp 181° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) (R)-2-(1,4-dioxan-2-yl)acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[CH:5]2.Br[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:14]=1)=[CH:5]2
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(Oc2cnc3ccc(Cl)cc3c2)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(Oc2cnc3ccc(Cl)cc3c2)cc1

Procedure:
Ethyl 2-{4-[(6-chloroquinolin-3-yl)oxy]phenoxy}-2-methylpropionate (13) was prepared from 4-[(6-chloroquinolin-3-yl)oxy]phenol and ethyl 2-bromo-2-methylpropionate following essentially the same procedure as that described in Example 1 part (c). The product, a pale yellow oil, was characterised by mass spectrometry. Mass spectrum (m/e, %): 387 (M+, 13); 385 (M+, 35), 271 (100).