Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:23]1([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:21][O:20][C:11]1[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:10]=1[C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([O:31][CH2:30][CH2:29][N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[CH:33][CH:34]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc(OCCN4CCOCC4)cc3)nc12

Procedure:
[8-(2-methoxy-5-trifloromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.150 g, 0.5 mmol), and 4-(morpholin-4-yl-ethoxy)-phenylamine (0.130 g, 0.58 mmol) in a manner analogous to Example 2d. Product was isolated as a foam (0.19 g, 81%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (d, J=6.8 Hz, 1H), 7.96 (s, 1H), 7.68 (d, J=8.9 Hz, 1H), 7.55 (d, J=5.7 Hz, 1H), 7.51-7.46 (m, 2H), 7.12 (d, J=7.9 Hz, 1H), 6.94-6.89 (m, 1H), 6.77 (d, J=6.8 Hz, 1H) 6.71 (s, 1H) 6.65 (d, J=7.9 Hz, 1H), 4.15-4.03 (m, 2H), 3.89 (s, 3H), 3.78-3.71 (m, 4H), 2.86-2.76 (m, 2H), 2.64-2.56 (m, 4H). MS=514 (MH)+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCCN1CCOCC1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(CCN3CCOCC3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 83.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.72 g) and 4-(2-chloroethyl)morpholine hydrochloride (0.33 g) as starting materials, 5-benzyloxy-N-{[1-(2-morpholinoethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.69 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-{[1-(2-morpholinoethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.34 g) was obtained.
Reaction SMILES: [NH2:1][CH:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([O-:13])=[O:12])=[C:6]([CH2:9]I)[CH2:7][S:8][C@H:3]12.[CH:16]1[C:17]2[N:18]([CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:20][N:21]=1.O>C(#N)C>[NH2:1][CH:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([O-:13])=[O:12])=[C:6]([CH2:9][N+:21]3[CH:20]=[CH:19][N:18]4[CH:22]=[CH:23][CH:24]=[C:17]4[CH:16]=3)[CH2:7][S:8][C@H:3]12
Reactant: c1cc2cnccn2c1
Reactant: NC1C(=O)N2C(C(=O)[O-])=C(CI)CS[C@H]12
Solvent: CC#N
Solvent: O
Product: NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccn4cccc4c3)CS[C@H]12
Temperature: 0 °C
Yield: 93 %

Procedure:
2.5 g of 7-amino-3-iodomethyl-3-cephem-4-carboxylate was suspended in 30 ml of acetonitrile; and 2 ml bistrimethyl-silylacetamide was added thereto. To the mixture was added 2 g of pyrrolo[1,2-a]pyrazine prepared in Preparation Example 1. The reaction mixture was reacted at 10° C. for 1 hour and then cooled to 0° C. To this solution was added 0.6 ml of water; and the resulting mixture was filtered and then washed with 30 ml of cold acetonitrile to obtain 2.4 g of light yellow title compound (yield: 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH2:15][CH3:16])[N:5]2S(C1C=CC(O)=C(C)C=1)(=O)=O.[CH3:28][O:29][C:30]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH2:15][CH3:16])[N:5]2[C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[CH:38][C:30]=1[O:29][CH3:28]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: CCC1c2cccn2-c2ccc(Cl)cc2N1S(=O)(=O)c1ccc(O)c(C)c1
Product: CCC1c2cccn2-c2ccc(Cl)cc2N1C(=O)c1ccc(OC)cc1OC

Procedure:
7-Chloro-5-(2,4-dimethoxybenzoyl)-4-ethyl-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from the intermediate of Example 68A and 2,4-dimethoxy benzoyl chloride according to the procedure of Example 106, Step 2 mp 70-74° C. MS (ESI) m/z 397; Anal. Calcd for C22H21ClN2O3: C, 66.58; H, 5.33; N, 7.06. Found: C, 66.34; H, 5.59; N, 6.85.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:19][N:18]=2)=[CH:11][CH:10]=1)(=O)=O.[CH:30]1([CH2:33][NH2:34])[CH2:32][CH2:31]1>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:16]#[C:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][NH:34][CH2:33][CH:30]4[CH2:32][CH2:31]4)=[CH:10][CH:11]=3)=[N:18][CH:19]=2)=[CH:24][CH:25]=1
Reactant: NCC1CC1
Reactant: CS(=O)(=O)OCCOc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCNCC4CC4)cc3)nc2)cc1

Procedure:
The product was obtained analogously to Example 4.1f starting from 2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl methanesulfonate (Example 4.1e) and C-cyclopropylmethylamine. Yield: 700 mg (43% of theoretical); C25H23ClN2O (M=402.916); calc.: molpeak (M+H)+: 403/405 (Cl); found: molpeak (M+H)+: 403/405 (Cl); HPLC-MS: 5.08 minutes (method B).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:12][CH3:13])[C:9]([OH:11])=O.[NH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:12][CH3:13])[C:9]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([C:15]#[N:14])=[CH:17][CH:18]=1)=[O:11]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1ccccc1Cl
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccccc1Cl

Procedure:
(RS)-(2-Chloro-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-2-(2-chloro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide. Light yellow oil. MS 315.1 ([M+H]+)
Reaction SMILES: COC1C=C(C=C(OC)C=1OC)C=O.C(NCC(O)=O)(=O)C.C[O:24][C:25](=[O:44])[C@H:26]([CH2:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=1)[NH:27]C(=O)C>>[NH2:27][C@@H:26]([CH2:31][C:32]1[CH:33]=[C:34]([O:42][CH3:43])[C:35]([O:40][CH3:41])=[C:36]([O:38][CH3:39])[CH:37]=1)[C:25]([OH:44])=[O:24]
Reactant: COC(=O)[C@H](Cc1cc(OC)c(OC)c(OC)c1)NC(C)=O
Agent: CC(=O)NCC(=O)O
Agent: COc1cc(C=O)cc(OC)c1OC
Product: COc1cc(C[C@H](N)C(=O)O)cc(OC)c1OC

Procedure:
The title compound is prepared from commercially available 3,4,5-trimethoxybenzaldehyde and N-acetylglycine according to a literature procedure (E.M. Oltz, R. C. Bruening, M. J. Smith, K. Kustin and K. Nakanishi in J. Am. Chem. 1998, 110 (18), 6162-6172). The resolution of the racemic N-acetyl-3,4,5-trimethoxy-phenylalanine methyl ester is performed by enzyme-catalyzed hydrolysis of the L-ester using Alcalase® (Novo Nordisk) as described in the literature (J. J. Nestor, Jr., T. L. Ho, R. A. Simpson, B. L. Horner, G. H. Jones, G. I. McRae and B. H. Vickery in J. Med. Chem. 1982, 25 (7), 795-801; or O. D. Tyagi & P. M. Boll in Indian J. Chem. 1992, pp. 851-854).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:27]1([CH2:33][S:34][CH:35]([C:39](O)=[O:40])[C:36](O)=[O:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:11][C:36](=[O:37])[C:35]([S:34][CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:39]([OH:40])[CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)c1cc(C)cc(C)c1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using 3',5'-dimethylacetophenone (0.785 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 170° C.; 1H NMR (400 MHz, DMSO-d6) δ2.33 (s, 6 H), 3.99 (s, 2 H), 6.67 (s, 1 H), 7.21 (m, 6 H), 7.39 (s, 2 H).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:16]=[C:17]([CH2:21][NH:22][C:23]([CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([O:33][C:34](=[O:48])[NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH2:29][CH2:28]3)=[O:24])[CH:18]=[CH:19][CH:20]=2)=[O:14])=[CH:8][CH:7]=1.Cl.C(=O)(O)[O-].[Na+]>C(#N)C>[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:16]=[C:17]([CH2:21][NH:22][C:23]([CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][CH:30]([O:33][C:34](=[O:48])[NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH2:31][CH2:32]3)=[O:24])[CH:18]=[CH:19][CH:20]=2)=[O:14])=[CH:8][CH:7]=1)=[O:1]
Reactant: O=C(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)NCc1cccc(C(=O)Nc2ccc(C3OCCO3)cc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1ccc(NC(=O)c2cccc(CNC(=O)CCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of biphenyl-2-ylcarbamic acid 1-(2-{[3-(4-(1,3-dioxolan-2-yl)phenylcarbamoyl)phenyl]methylcarbamoyl}ethyl)piperidin-4-yl ester (345 mg containing some solvent residue, ca. 0.500 mmol) in acetonitrile (2.00 mL) at room temperature was added aqueous hydrochloric acid (1 N, 2.00 mL). The reaction mixture was stirred at room temperature for 3 h. LC-MS (Method 10-90) showed product was present (Rt 3.45 min; m/z 605.0 [M+H]+. Saturated aqueous sodium bicarbonate solution was added and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used in the next reaction without further purification.
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[F:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14]Cl>>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:14][C:13]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=2[F:11])[NH:6][C:7](=[O:9])[CH:8]=1
Reactant: Nc1cc(O)nc(S)n1
Reactant: COc1ccc(CCl)c(F)c1
Solvent: O
Product: COc1ccc(CSc2nc(N)cc(=O)[nH]2)c(F)c1

Procedure:
The subtitle compound was prepared according to the procedure of Example 1 step i) treating 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate (1.86 g) with 2-fluoro-4-methoxybenzyl chloride (2.00 g) to afford the subtitle compound as a white solid. Yield: 2.64 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=Cc1ccnc(Cl)c1

Procedure:
A suspension of 2-chloro-4-pyridinemethanol (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol), and K2CO3 (11.75 g, 97.1 mmol) in EtOAc was refluxed for 3 h. A Second portion of NBS (14.9 g, 83.9 mmol) and Na2CO3 (12.0 g, 114 mmol) were added and the reaction was heated to reflux for an additional 3.5 h, cooled and filtered through a pad of celite. The filtrate, after concentrattion to a small volume, was subjected to flash chromatography eluting with 0.5-4% CH3OH/CH2Cl2. The fractions containing product were combined, washed successively with sat aq NaHCO3 10% Na2S2O3, and brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a light yellow solid; yield 5.3 g (67%). 1H NMR (CDCl3) δ 10.06 (s, 1H), 8.66 (d, 1H, J=5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H, J=5.0 Hz).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([NH:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15](O)=[O:16])[O:12][C:13]=2[CH3:14])=[CH:3][CH:2]=1.[C:24]1([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.O1CCCC1.C(#N)C>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:2]=[CH:3][C:4]([NH:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]([NH:33][S:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:32])=[O:31])=[O:16])[O:12][C:13]=2[CH3:14])=[CH:5][CH:6]=1
Reactant: Cc1oc(C(=O)O)cc1CNc1ccc(-c2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1oc(C(=O)NS(=O)(=O)c2ccccc2)cc1CNc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 49.8 %

Procedure:
A stirred solution of 4-(biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid (160) (15 mg, 0.036 mmoles), benzenesulphonamide (17 mg, 0.107 mmoles) and 4-(N,N-dimethylamino)-pyridine (1 mg) in a mixture of tetrahydrofuran (3 ml) and acetonitrile (0.5 ml) was treated with triethylamine (5.5 μl, 0.039 mmoles) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.5 mg, 0.053 mmoles). The mixture was stirred at room temperature for 19 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford compound 161(8 mg) as a white solid. LC/MS System D; Rt=8.84 mins, m/z (ES+)=447 (M+H for C25H22N2O4S).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C(O)(=[O:14])C.OO>O1CCCC1>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:14]
Reactant: Cc1cccc(B(O)O)c1F
Reactant: CC(=O)O
Agent: OO
Solvent: C1CCOC1
Product: Cc1cccc(O)c1F
Reaction time: 24 h
Yield: 98 %

Procedure:
To a solution of 2-fluoro-3-methyl-phenylboronic acid (25.0 g, 0.162 mol) in tetrahydrofuran (220 mL) was added glacial acetic acid (150 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 30 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 24 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated which afforded 2-fluoro-3-methyl-phenol (20.0 g, 98%) as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH:16]1([CH2:19][NH:20][CH2:21][CH2:22][CH3:23])[CH2:18][CH2:17]1>ClCCl.CO>[CH:16]1([CH2:19][N:20]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=2[O:14][CH3:15])[CH2:21][CH2:22][CH3:23])[CH2:18][CH2:17]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Reactant: CCCNCC1CC1
Solvent: ClCCl
Solvent: CO
Product: CCCN(CCOc1ccc([N+](=O)[O-])cc1OC)CC1CC1

Procedure:
Prepared analogously to Example 1.1.c. from 1 g (3.62 mmol) of 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and 1.51 mL (10.57 mmol) of cyclopropylmethylpropylamine. Yield: 0.95 g (85% of theory); C16H24N2O4 (M=308.37); calc.: molecular ion peak (M+H)+: 309; found: molecular ion peak (M+H)+: 309; Rf value: 0.4 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]([C:14]([F:17])([F:16])[F:15])=[CH:5][C@@H:6]1[C@H:8]([C:9]([OH:11])=[O:10])[C:7]1([CH3:13])[CH3:12].CCCCCCC.Cl[CH2:26][C:27]1[C:28]([CH3:39])=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:31][CH:32]=1>O.C(Cl)Cl.CCCCCC.C(OCC)C.C(#N)C>[Cl:3][C:4]([C:14]([F:15])([F:16])[F:17])=[CH:5][C@@H:6]1[C@H:8]([C:9]([O:11][CH2:26][C:27]2[C:28]([CH3:39])=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:30]=[CH:31][CH:32]=2)=[O:10])[C:7]1([CH3:13])[CH3:12]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O
Reactant: Cc1c(CCl)cccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: Cc1c(COC(=O)[C@H]2[C@@H](C=C(Cl)C(F)(F)F)C2(C)C)cccc1-c1ccccc1
Yield: 54.8 %

Procedure:
To a solution of 0.62 g (0.011 mole) of potassium hydroxide in 3.65 ml distilled water was added, with stirring, 1.8 g (0.0074 mole) of cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylic acid and 14.6 ml of heptane. The reaction mixture was heated at reflux temperature, and the water was collected in a Dean-Stark trap. The anhydrous reaction mixture was then cooled, and 1.5 g (0.0069 mole) of 3-chloromethyl-2-methyl-[1,1'-biphenyl] and 14.6 ml of acetonitrile were added. The reaction mixture was stirred and heated at reflux temperature for 16 hours, then cooled and diluted with water. Diethyl ether was added and the two phases were separated. The aqueous phase was washed with heptane, then with diethyl ether. The organic phase and washings were combined, dried with anhydrous sodium sulfate and filtered. The solvents were removed from the filtrate under reduced pressure to give a yellow oil which was dissolved in methylene chloride and subjected to preparative liquid chromatography. A mixture of hexane and methylene chloride (2:1) was used as eluant. Appropriate fractions, as determined by thin layer and gas liquid phase chromatography, were combined to give 1.6 g of [2-methyl(1,1'-biphenyl)-3-yl]methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate as a clear, colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[N:24][NH:25][CH:26]=4)[N:19](S(C4C=CC=CC=4)(=O)=O)[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.N12CCCN=C1CCCCC2.[CH:47]1(/[CH:52]=[CH:53]/[C:54]#[N:55])[CH2:51][CH2:50][CH2:49][CH2:48]1>C(#N)C>[CH:47]1([CH:52]([N:25]2[CH:26]=[C:22]([C:20]3[NH:19][C:16]4=[N:17][CH:18]=[C:13]([CH2:12][CH2:11][C:5]5[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=5)[N:14]=[C:15]4[CH:21]=3)[CH:23]=[N:24]2)[CH2:53][C:54]#[N:55])[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: N#C/C=C/C1CCCC1
Reactant: COc1cc(CCc2cnc3c(cc(-c4cn[nH]c4)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(CCc2cnc3[nH]c(-c4cnn(C(CC#N)C5CCCC5)c4)cc3n2)cc(OC)c1
Reaction time: 16 h
Yield: 17.5 %

Procedure:
To a stirred solution of 2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-6-(1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine (25.0 mg, 51.1 μmol) in acetonitrile (1.0 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (9.2 μL, 61.5 μmol) and (2E)-3-cyclopentylacrylonitrile (from Adesis, cat#9-245, 6.8 μL, 61.7 μmol) were added sequentially at room temperature. After 16 hours, the volatiles were removed and the crude mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (4.2 mg) as its TFA salt. LCMS calculated for C27H31N6O2 (M+H)+: m/z=471.2. Found: 471.2.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:10])=[C:4]([F:22])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>C1(C)C=CC=CC=1.O.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:8][C:6]1[CH:7]=[C:2]([C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)[CH:3]=[C:4]([F:22])[C:5]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10]
Reactant: O=C(c1c(F)cc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: OB(O)c1cccnc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: O=C(c1c(F)cc(-c2cccnc2)cc1F)N1CCC[C@H]1CN1CCCC1
Yield: 2.2 %

Procedure:
Procedure WW: To a stirred solution of (4-Bromo-2,6-difluoro-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (100 mg, 0.268 mmol), sodium carbonate (85 mg, 0.802 mmol) and 3-pyridine boronic acid (164 mg, 1.34 mmol) in toluene (5 ml), water (1 ml) and ethanol (1.5 ml) under nitrogen is added Tetrakis (triphenylphosphine) palladium (0) (31.0 mg, 0.027 mmol). The reaction is heated at reflux for 48 h. The reaction is allowed to cool and bound to a SCX-2 cartridge (10 g). The cartridge is washed with one cartridge volume of dimethylformamide and two volumes of methanol. The product is eluted using 2M ammonia in methanol. The ammonia/methanol solution is evaporated on a Genevac HT4. The sample is further purified by prep-LCMS. The resulting acetonitrile/water fractions are combined and evaporated using a Genevac to give 2.2 mg of a colourless oil (2%). MS (ES+) 372.2 m/z
Reaction SMILES: [C:1]([S-:4])(=[S:3])[CH3:2].[Na+].Cl[CH:7]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[CH:17][CH:16]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C>[C:1]([S:4][CH:7]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[CH:17][CH:16]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[S:3])[CH3:2]
Reactant: CC(=S)[S-]
Reactant: CCOC(=O)C(Cl)CCc1ccc(-c2ccccc2Cl)cc1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccc(-c2ccccc2Cl)cc1)SC(C)=S

Procedure:
A mixture of 0.2 moles of sodium dithioacetate and 0.12 moles of ethyl α-chloro-γ-(2'-chloro-4-biphenylyl)butyrate in 300 ml. of absolute ethanol is stirred at room temperature for 15 hours. The reaction mixture is filtered, washed with absolute ethanol and evaporated to dryness in vacuo. The residue is treated with ether, filtered and evaporated to obtain ethyl α-thioacetylthio-γ-(2'-chloro-4-biphenylyl)butyrate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][N:19]3[CH2:23][CH2:22][CH:21]([CH:24]4[CH2:29][CH2:28][CH:27]([O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:26][CH2:25]4)[C:20]3=[O:48])=[C:13]([Cl:49])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-]>C1COCC1.CO.C(OCC)(=O)C>[C:44]([Si:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[O:30][CH:27]1[CH2:28][CH2:29][CH:24]([CH:21]2[CH2:22][CH2:23][N:19]([CH2:18][C:14]3[C:15]([Cl:17])=[CH:16][C:11]([C:8]4[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=4)=[CH:12][C:13]=3[Cl:49])[C:20]2=[O:48])[CH2:25][CH2:26]1)([CH3:47])([CH3:45])[CH3:46]
Reactant: COC(=O)c1ccc(-c2cc(Cl)c(CN3CCC(C4CCC(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC4)C3=O)c(Cl)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC1CCC(C2CCN(Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
Treat a solution of 4′-{3-[4-(tert-butyl-diphenyl-silanyloxy)-cyclohexyl]-2-oxo-pyrrolidin-1-ylmethyl}-3′,5′-dichloro-biphenyl-4-carboxylic acid methyl ester (0.56 g) in THF (5 mL ) and methanol (1 mL) with 2N LiOH (5 mL) and stir at 50° C. for 2 hours. Cool the reaction, dilute with ethyl acetate (25 mL), and wash with 1 N HCl (10 mL). Dry the organic layer (Na2SO4) and remove the solvent in vacuo to afford 0.55 g (99%) of the title compound. MS (m/z): 700 (M+).