Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[N:10]=[C:9](Br)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6])C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][N:10]=1
Reactant: CCc1nc(Br)ccc1C#N
Reactant: COc1ccccc1B(O)O
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: CN(C)C=O
Solvent: O
Product: COc1ccccc1-c1ccc(C#N)cn1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of ethyl 6-bromonicotinonitrile (1.81 g, 10 mmol) described in the Journal of Organic Chemistry 2001, 66, 1500-1502, 2-methoxyphenylboronic acid (1.22 g, 10 mmol), Pd(PPh3)4 (5% mol), K2CO3 (5 g) in DMF/water (3/1) is stirred at 50° C. for 12 hours. The reaction mixture is then pored on water (150 mL). The aqueous phase is extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water (3×200 mL). The organic phase is dried over magnesium sulfate and evaporated under vacuum to afford the title compound.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8](OC2C=C3C(=CC=2)N=C(C)C=C3C(F)(F)F)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[C:33]([OH:38])[CH:32]=[CH:31]2.O=O>>[Br:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[C:33]([O:38][CH:8]1[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]1)[CH:32]=[CH:31]2
Reactant: Oc1ccc2cc(Br)ccc2n1
Reactant: Cc1cc(C(F)(F)F)c2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Agent: O=O
Product: CC(C)(C)C1CCC(Oc2ccc3cc(Br)ccc3n2)CC1

Procedure:
Synthesized as per 6-(trans-4-tert-Butyl-cyclohexyloxy)-2-methyl-4-trifluoromethyl-quinoline using 6-Bromo-quinolin-2-ol as starting material. Alkylation was confirmed to be on the oxygen by 2D NMR (HMQC) of the subsequent intermediate. ESI-MS(M+H+): 362.1/364.10).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH:19]1([C:22]2[O:23][C:24]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:25]([C:27](O)=[O:28])[N:26]=2)[CH2:21][CH2:20]1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:27]([C:25]3[N:26]=[C:22]([CH:19]4[CH2:20][CH2:21]4)[O:23][C:24]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:28])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)s2)OCCO1
Reactant: O=C(O)c1nc(C2CC2)oc1-c1ccccc1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C4CC4)oc3-c3ccccc3)cn2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-cyclopropyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.77 min; [M+H]+=433.25.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[CH3:21])(O)[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1.O=S(Cl)[Cl:29]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([Cl:29])([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[CH3:21])[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cnccc1C(C)(O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Product: Cc1cnccc1C(C)(Cl)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(3-methylpyridin-4-yl)propan-2-ol (300 mg, 0.813 mmol) in SOCl2 (4 mL) was stirred at RT for 1 h. Excess SOCl2 was removed under vacuum to obtain 8-chloro-5-[2-chloro-2-(3-methyl-pyridin-4-yl)-propyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (305 mg, 0.78 mmol) which was dissolved in NMP (3 mL). Powdered KOH (308.14 mg, 5.50 mmol) was added and the contents heated at 80° C. for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was poured on ice cold water. The aqueous phase was extracted with EtOAc (500 mL). The organic layer was washed with water (100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product, which was subjected to reverse phase HPLC to yield 5 mg of the desired product. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.84 (s, 1H), 8.78 (d, 1H), 8.18 (d, 1H), 7.60 (s, 1H), 7.38 (d, 1H), 7.30 (d, 1H), 6.98 (s, 1H), 4.78 (d, 1H), 4.40 (d, 1H), 3.90 (m, 1H), 3.62 (m, 1H), 3.22 (m, 2H), 3.16 (s, 3H), 2.70 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([C:14]([S:17]([CH3:20])(=[O:19])=[O:18])([CH3:16])[CH3:15])[N:11]=[C:10]([C:21]2[S:25][C:24]([NH2:26])=[N:23][CH:22]=2)[N:9]=1.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29].C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([C:14]([S:17]([CH3:20])(=[O:19])=[O:18])([CH3:15])[CH3:16])[N:11]=[C:10]([C:21]2[S:25][C:24]([NH:26][C:28](=[O:29])[O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:23][CH:22]=2)[N:9]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(-c2cnc(N)s2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(-c2cnc(NC(=O)Oc3ccccc3)s2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
A mixture of 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidin-2-yl]-1,3-thiazol-2-amine (1.05 g, 2.6 mmol), phenyl chloroformate (618 mg, 3.9 mmol) and sodium hydrogen carbonate (311 mg, 3.9 mmol) in dioxane (10 mL) was stirred at RT for 2 hours then diluted with ethyl acetate and washed with water (150 mL) and brine (100 mL). The organics were dried over magnesium sulphate and concentrated in vacuo. The residue was recrystallised from diethyl ether and hexane to give the desired product as a beige solid (1 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].O[C@@H:13]1[CH2:17][CH2:16][O:15][CH2:14]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@H:13]1[CH2:17][CH2:16][O:15][CH2:14]1)[N:6]=[C:5]2[I:11]
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: O[C@@H]1CCOC1
Product: Fc1ccc2c(c1)c(I)nn2[C@H]1CCOC1
Yield: 56 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and (R)-3-hydroxytetrahydrofuran in 56% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 2.47-2.52 (2H, m), 3.95-4.00 (1H, m), 4.12-4.19 (2H, m), 4.19-4.28 (1H, m), 5.24-5.30 (1H, m), 7.12 (1H, dd, J=2.0, 8.4 Hz), 7.21 (1H, td, J=1.6, 8.8 Hz), 7.45 (1H, dd, J=4.0, 9.2 Hz).
Reaction SMILES: C([NH:4][C@H:5]([C:23]([O:25]C)=[O:24])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])(=O)C.Cl>C(O)(=O)C>[O:16]([C:13]1[CH:14]=[CH:15][C:10]([S:7]([CH2:6][C@@H:5]([C:23]([OH:25])=[O:24])[NH2:4])(=[O:9])=[O:8])=[CH:11][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)NC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: N[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)O
Yield: 109.2 %

Procedure:
A solution of the titled compound of Example 9d (3.27 g, 8.66 mmol) in glacial acetic acid (18.5 mL) was heated until all solids dissolved and then concentrated HCl (18.5 mL) was added. The solution was heated at reflux for 4 hours. The mixture was concentrated to an off white solid. The solid was treated with toluene, concentrated, and triturated with diethyl ether afforded the title amino acid as a white solid (3.04 g, 98%). Elemental Anal. Calcd. for C15H16NO5SCl: C, 50.35; H, 4.51; N, 3.91; S, 8.96. Found: C, 50.21; H, 4.43; N, 3.92; S, 9.04.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=O)[CH:9]=2)=[CH:4][CH:3]=1.C([NH:31][CH2:32][CH:33]([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])C1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:35]([O:34][CH:33]([O:37][CH2:38][CH3:39])[CH2:32][NH:31][C:21]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:11]=1)=[O:23])[CH3:36]
Reactant: CCOC(CNCc1ccccc1)OCC
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CNC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1)OCC
Reaction time: 23 h
Yield: 46 %

Procedure:
To a stirred solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid (prepared according to the methods described by Barth, et al. in U.S. Pat. No. 5,624,941); 740 mg, 2.01 mmol) and N-benzyl-N-(2,2-diethoxyethyl)amine (450 mg, 2.01 mmol) in methylene chloride (6.5 ml) at room temperature was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (464 mg, 2.42 mmol) and then diisopropylethylamine (0.42 ml, 2.2 mmol), dropwise. After stirring for 23 hr, the reaction was concentrated, in vacuo, and then extracted from saturated aqueous sodium bicarbonate with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), a concentrated, in vacuo. The crude material (1.05 g) was purified on a Biotage™ Flash 40S column using 0-20% ethyl acetate in hexanes as eluant to afford I-1A-1a as a foam (534 mg, 46%): +ES MS (M+1) 572.1; 1H NMR (500 MHz, CD2Cl2) 1:1 mixture of rotamers, δ 7.51 (br s, 0.5H), 7.47 (d, J=2.1 Hz, 0.5H), 7.38-7.34 (m, 2H), 7.38-7.23 (m, 9H), 7.18-7.11 (m, 2H), 7.03 (s, 0.5H), 6.95 (s, 0.5H), 5.22 (s, 1H), 4.91 (s, 1H), 4.83-4.79 (m, 1H), 3.56-3.07 (m, 6H), 1.20 (t, J=7.0 Hz, 3H). 1.07 (t, J=7.0 Hz, 3H).
Reaction SMILES: C(=O)(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)OCC(F)(F)C(F)(F)C(F)(F)C(F)F.FC(F)(C(F)(F)C(F)(F)C(F)F)C[NH:34][C:35](=[O:62])[O:36][CH2:37][CH:38]1[CH:43]=[CH:42][CH2:41][CH:40]([CH2:44][O:45][C:46](=[O:61])[NH:47]CC(F)(F)C(F)(F)C(F)(F)C(F)F)[CH2:39]1>>[C:46](=[O:61])([O:45][CH2:44][CH:40]1[CH:41]=[CH:42][CH2:43][CH:38]([CH2:37][O:36][C:35](=[O:62])[NH2:34])[CH2:39]1)[NH2:47]
Reactant: O=C(NCC(F)(F)C(F)(F)C(F)(F)C(F)F)OCC1C=CCC(COC(=O)NCC(F)(F)C(F)(F)C(F)(F)C(F)F)C1
Agent: O=C(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Product: NC(=O)OCC1C=CCC(COC(N)=O)C1
Yield: 98 %

Procedure:
The reaction was carried out in the same manner as Example 7 except for using 80.5 g (0.1642 mol) of bis(2,2,3,3,4,4,5,5-octafluoropentyl) carbonate (to be referred to as “BOFC” hereinafter) synthesized in the above Synthesis Example 4 in place of BTFC, and it Was confirmed that tetrahydro-m-xylylene bis(2,2,3,3,4,4,5,5-octafluoropentyl carbamate) (to be referred to as H-XDC-4 hereinafter) was generated as the main product (H-XDA base yield 98.0%). Structural assignment of the product H-XDC-4 was carried out by 19F-NMR and GC-Mass analyses as well as 1H-NMR. Analytical Results of mass fragments of H-XDC-4, 1H-NMR and 19F-NMR were shown in the following.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]=[N+:12]=[N-:13])=[N:8][C:7]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)=[O:5])C.O1CCCC1.O.[OH-].[Li+]>O.C(OCC)C>[N:11]([C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[N:8]=1)=[N+:12]=[N-:13]
Reactant: CCOC(=O)c1sc(N=[N+]=[N-])nc1-c1cccc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: [N-]=[N+]=Nc1nc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
To a mixture of 3.0 g (8.76 mmole) of 2-azido-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester, 54 mL of tetrahydrofuran was added 3.71 g (88.3 mmole) of lithium hydroxide monohydrate in 36 mL of water. The mixture was stirred at room temperature for 3 hours, and then diluted with 350 mL of diethyl ether. The mixture was extracted three times with 100 mL of water. The combined aqueous layers were acidified by addition of 1M hydrochloric acid, and extracted three times with 100 mL of ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2.20 g of 2-azido-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid as a yellow-orange solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CO.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][C:8]=1[S:16](Cl)(=[O:18])=[O:17]>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][C:8]=1[S:16](=[O:17])(=[O:18])[N:2]([CH3:3])[CH3:1]
Reactant: CNC
Reactant: CC(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: O
Solvent: CO
Product: CC(=O)c1ccc(Cl)c(S(=O)(=O)N(C)C)c1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 10 ml of 40% dimethyl amine solution and 60 ml of methanol, there were added, portionswise, 5.1 g of 4'-chloro-3'-chlorosulfonylacetophenone, so that the reaction temperature did not exceed 30° C. The reaction mixture was stirred for 3 hours at room temperature and 15 minutes at 60° C. After cooling, the reaction mixture was poured into 200 ml of water and the crystals were filtered off. Melting point: 108° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH2:16][C:17](O)=[O:18])([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].O[N:22]1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.N>ClCCl.C(#N)C>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH2:16][C:17](=[O:18])[NH2:22])([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: O=C1CCC(=O)N1O
Reactant: CCOC(=O)C(CC(=O)O)(C(=O)OCC)n1cccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)C(CC(N)=O)(C(=O)OCC)n1cccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
A mixture of 2-carboxymethyl-2-(pyrrol-1-yl)-malonic acid diethyl ester (36.0 g), N-hydroxysuccinimide (16.1 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (29.2 g) in dichloromethane (200 ml) was stirred at 25° C. for 1 hour, followed by addition of 7.8% (w/w) ammonia in acetonitrile (110 ml). The resulting mixture was stirred at 25° C. for 1 hour and concentrated under reduced pressure at the same temperature. The residue was dissolved in ethyl acetate. The solution was washed with 5% hydrochloric acid and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (29.0 g, 80.8%) as colorless crystals, mp 94°-95° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([O:15][CH3:16])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH2:18]([O:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[N:32]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][C:41]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:34][CH2:33]1)[CH3:19]>>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([O:15][CH3:16])=[CH:7][C:3]=1[C:4]([N:43]1[CH2:44][CH2:45][C:41]([CH2:40][CH2:39][N:35]2[CH2:36][CH2:37][CH2:38][N:32]([C:24]3[N:23]([CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=3)[CH2:33][CH2:34]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:6]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1cc(C(=O)O)c(Cl)c(OC)c1OC
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4Cl)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-chloro-3,4,5-trimethoxybenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2ccc(F)cc2F)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(CC(c1ccc(Br)cc1)c1ccc(F)cc1F)c1ccc(=O)[nH]c1
Temperature: 100 °C

Procedure:
To a solution of 3-(4-bromophenyl)-3-(2,4-difluorophenyl)-1-(6-methoxypyridin-3-yl)propan-1-one (0.245 g, 567 μmol) in dioxane (6 mL) was added 37% hydrochloric acid (1.23 g, 1.04 mL, 12.5 mmol) and the resulting mixture was heated at 100° C. for 1½ h. After cooling to room temperature, the reaction mixture was poured on water and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated. Off-white solid (0.227 g, 95%). MS (ESI−): m/z=418.0 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[N:12]=[C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[S:14][CH:15]=1.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1>[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[S:33]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[N:12]=[C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[S:14][CH:15]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: CC(C)(C)OC(=O)Nc1nc(CSc2ccc(Cl)cc2N)cs1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1nc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)cs1
Yield: 40 %

Procedure:
Following General Procedure B, the title compound (380 mg, 54%) was prepared from tert-butyl (4-{[(2-amino-4-chlorophenyl)thio]methyl}-1,3-thiazol-2-yl)carbamate (640 mg, 1.72 mmol) and 1-benzofuran-2-sulfonyl chloride (372 mg, 1.72 mmol) in pyridine (5 ml).
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@@H:4]([C:18]([O-:20])=O)[CH2:3]1.[Li+].Cl.[NH2:23][C@H:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)[CH3:25]>>[F:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[C@@H:4]([C:18]([NH:23][C@H:24]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)[CH3:25])=[O:20])[CH2:3]1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C([O-])[C@H]1C[C@H](F)CN1Cc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2C[C@H](F)CN2Cc2cccc(C(F)(F)F)c2)cc1
Yield: 73.8 %

Procedure:
The title compound (D36) (67.3 mg) was prepared according to the general procedure for amides preparation starting from lithium (2R,4S)-4-fluoro-1-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D16) (60 mg) and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (43.5 mg).
Reaction SMILES: [CH:1]([Si:4]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[SH:5])([CH3:3])[CH3:2].[H-].[Na+].[CH2:14]([O:16][C:17](=[O:28])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21](Br)[CH:20]=1)[CH3:15]>C1COCC1.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>[CH2:14]([O:16][C:17](=[O:28])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([S:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:6]([CH3:8])[CH3:7])[CH:9]([CH3:11])[CH3:10])[CH:20]=1)[CH3:15]
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Reactant: CCOC(=O)Cc1ccc(OC)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(OC)c(S[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 25 °C

Procedure:
Triisopropylsilanethiol (6.7 mL, 31.2 mmol) was dissolved in THF (75 mL) at 0° C. and sodium hydride (1.25 g, 60% dispersion in mineral oil, 31.3 mmol) was added, then the solution was allowed to warm to room temperature. Meanwhile, (3-bromo-4-methoxy-phenyl)-acetic acid ethyl ester (6.38 g, 23.4 mmol) was dissolved in THF (75 mL) and sparged with N2 (g). The first solution was added to the second and tetrakis(triphenylphosphine)palladium(0) (1.3 g, 1.1 mmol) was also added. The reaction was heated to reflux overnight then treated to standard aqueous workup. The residue was purified by silica gel chromatography (0-10% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:15]=[C:16]([Br:21])[CH:17]=[C:18]([F:20])[CH:19]=1.[C:22](=[O:24])=[O:23]>C1COCC1>[Br:21][C:16]1[CH:15]=[C:14]([F:13])[C:19]([C:22]([OH:24])=[O:23])=[C:18]([F:20])[CH:17]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1c(F)cc(Br)cc1F
Temperature: -50 °C
Yield: 38 %

Procedure:
n-BuLi (220 mL, 550 mmol, 2.5 M) was added dropwise to a solution of diisopropylamine (61 g) in THF (500 mL) with stirring at −50° C. under N2. After the addition, the reaction mixture was stirred at −50° C. for 15 minutes, and then warmed to 0° C. for 1 hour. The reaction was cooled to −50° C. and then a solution of 3,5-difluorobromobenzene (96 g, 0.5 mole) in THF (500 mL) was added dropwise. After the addition, the reaction mixture was stirred at −50° C. for 2 hours and then dry ice (about 200 g) was added portion-wise. The resulting mixture was warmed gradually to room temperature and stirred overnight. The mixture was concentrated under reduced pressure, and the resulting residue was partitioned between CH2Cl2 (1 L) and water (1 L). An aqueous NaOH solution was added to adjust the pH of the mixture to 10. The organic layer was discarded and the water phase was adjust the pH to 2 with HCl solution. The mixture was extracted with CH2Cl2 (3×400 mL), and the extracts were combined, dried over MgSO4, filtered and evaporated under vacuum to provide the title compound (45 g) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@H:27]([O:29][Si](C(C)(C)C)(C)C)[CH3:28])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[ClH:37]>CO>[ClH:37].[ClH:37].[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:29])[CH3:28])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(OC[C@@H](C)O[Si](C)(C)C(C)(C)C)cc3)cc3ccccc23)CC1
Agent: Cl
Solvent: CO
Product: CCN1CCN(c2nc(-c3ccc(OCC(C)O)cc3)cc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To the resulting 1-(4-ethylpiperazin-1-yl)-3-{4-[2-(R)-(tert-butyldimethylsilyloxy)propoxy]phenyl}isoquinoline (0.43 g) were added methanol (10 ml) and 2N hydrochloric acid (50 ml) and dissolved, and the resulting mixture was stirred at room temperature for 4.5 hr. The solvent was evaporated, and the resulting residue was adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, which was then extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.22 g of the free compound of the title compound as a colorless amorphous.