Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:32][C:33]1[CH:58]=[CH:57][C:36]2[N:37]3[C:41]([CH2:42][NH:43][CH2:44][C:35]=2[CH:34]=1)=[N:40][N:39]=[C:38]3[C@H:45]1[CH2:50][CH2:49][C@H:48]([C:51]2[CH:55]=[C:54]([CH3:56])[O:53][N:52]=2)[CH2:47][CH2:46]1.C(N(C(C)C)C(C)C)C>CN(C)C=O.O.CO>[Cl:32][C:33]1[CH:58]=[CH:57][C:36]2[N:37]3[C:41]([CH2:42][N:43]([C:4](=[O:5])[CH2:3][N:2]([CH3:7])[CH3:1])[CH2:44][C:35]=2[CH:34]=1)=[N:40][N:39]=[C:38]3[C@H:45]1[CH2:46][CH2:47][C@H:48]([C:51]2[CH:55]=[C:54]([CH3:56])[O:53][N:52]=2)[CH2:49][CH2:50]1
Reactant: Cc1cc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)no1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: Cc1cc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CN(C(=O)CN(C)C)C4)CC2)no1
Reaction time: 1 h

Procedure:
A solution of N,N-dimethylglycine (16.1 mg, 0.156 mmol) and HATU (59.4 mg, 0.156 mmol) in N,N-dimethylformamide (1.0 ml) was stirred for 5 minutes at room temperature. trans-8-Chloro-1-[4-(5-methyl-isoxazol-3-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.130 mmol) and N-ethyl diisopropylamine (0.055 ml, 0.31 mmol) were added consecutively. The reaction mixture was stirred for 1 h. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (51 mg, 76%) as off-white solid. MS m/e: 469 ([M+H]+).
Reaction SMILES: C([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=2)[C:7]([C:16](O)=[O:17])=[C:6]1[C:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([I:30])[CH:23]=1)([CH3:21])[CH3:20])(C)(C)C>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(#N)C>[CH2:28]([C:25]1[C:24]([I:30])=[CH:23][C:22]2[C:19]([CH3:21])([CH3:20])[C:6]3[NH:5][C:13]4[C:8]([C:7]=3[C:16](=[O:17])[C:27]=2[CH:26]=1)=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=4)[CH3:29]
Reactant: CCc1ccc(C(C)(C)c2c(C(=O)O)c3ccc(C#N)cc3n2C(C)(C)C)cc1I
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CC#N
Product: CCc1cc2c(cc1I)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
Tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylic acid (11 g) was dissolved in Eaton's reagent (200 g) and stirred at room temperature for 30 min. The reaction solution was diluted with acetonitrile (200 ml) and distilled water (400 ml). The precipitated solid was collected by filtration, washed with distilled water, and then dried. The crude product was dissolved in DMA (45 ml), diluted with acetonitrile (20 ml) and distilled water (18 ml), and re-precipitated to obtain the title compound (6.62 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7]23[O:18][C:8]2([C:14](OC)=[O:15])[C:9]([CH3:13])([CH3:12])[CH2:10][CH2:11]3)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7]23[O:18][C:8]2([CH2:14][OH:15])[C:9]([CH3:13])([CH3:12])[CH2:10][CH2:11]3)=[CH:4][CH:3]=1
Reactant: COC(=O)C12OC1(Cc1ccc(Cl)cc1)CCC2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC1(C)CCC2(Cc3ccc(Cl)cc3)OC12CO
Reaction time: 0.08 h
Yield: 99.1 %

Procedure:
10.7 g (36.3 mmols) 1-(4-chlorobenzyl)-1,2-epoxy-3,3-dimethyl-2-methoxycarbonylcyclopentane prepared as described in (g) were dissolved in diethyl ether and the resulting solution was then added to a slurry of 1.5 g (36.6 mmols) lithium aluminium hydride in 50 ml diethyl ether at a rate such that reflux of the reaction mixture was maintained. Heating was continued for 5 minutes after the last addition of 1-(4-chlorobenzyl)-1,2-epoxy-3,3-dimethyl-2 -methoxycarbonylcyclopentane solution. 1.25 ml water were then added, followed by 1.25 ml 15% aqueous sodium hydroxide solution and a further 4 ml water. The solid was filtered off and the filtrate was then dried over anhydrous magnesium sulphate and flashed to give a clear oil which crystallised on cooling to give 9.6 g 1-(4-chlorobenzyl)-1,2-epoxy-3,3-dimethyl-2-hydroxymethylcyclopentane as a solid. m.pt. 36°-38° C., which can be reduced to 1-(4-chlorobenzyl)-3,3-dimethyl-2-hydroxy-2-hydroxymethylcyclopentane in a conventional method.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:8]2[CH:23]=[C:24]([Cl:26])[CH:25]=[C:7]2[C:6]=1[OH:27])=[O:4].[NH2:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30].C[O-].[Na+]>>[Cl:26][C:24]1[CH:25]=[C:7]2[C:6]([OH:27])=[C:5]([C:3]([NH:28][C@@H:29]([CH3:30])[C:31]([OH:33])=[O:32])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][CH:14]=3)[N:8]2[CH:23]=1
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(C(F)(F)F)cc2)c1=O
Agent: C[O-]
Agent: [Na+]
Product: C[C@H](NC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(C(F)(F)F)cc2)c1=O)C(=O)O

Procedure:
Prepared according to the reaction condition used in Example 19 step a) from 6-chloro-4-hydroxy-2-oxo-1-(4-trifluoromethyl-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester, L-alanine and NaOMe. ESI (m/z): 458 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=CC(C)C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:14][CH:13]=[C:12]([CH3:17])[CH3:4])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)=CCNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.093 g, 0.22 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 2% methanol in choroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.51 (s, 3 H) 1.61 (s, 3 H) 3.64 (d, J=6.99 Hz, 2 H) 5.32 (t, J=8.09 Hz, 1 H) 6.65 (s, 1 H) 7.43 (d, J=5.52 Hz, 1 H) 7.55 (t, J=7.54 Hz, 1 H) 7.64 (d, J=8.46 Hz, 1 H) 7.78 (t, J=7.17 Hz, 1 H) 7.92 (d, J=7.72 Hz, 1 H) 8.32 (m, 1 H) 14.21 (s, 1 H) 14.82 (s, 1 H). MS (ESI−) m/z 429 (M−H)−.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([CH2:17][C:18]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([O:28]C)[C:21]([C:30]2[CH:34]=[CH:33][O:32][CH:31]=2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].BrC1C(O)=C(C(CS(C2C=CC(F)=CC=2/C=C\CN(CC)CC)(=O)=O)=CC=1)C(OC)=O.O1C=CC(B(O)O)=C1>>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([CH2:17][C:18]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([OH:28])[C:21]([C:30]2[CH:34]=[CH:33][O:32][CH:31]=2)=[CH:20][CH:19]=1)(=[O:15])=[O:16])[CH3:36]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC
Agent: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(Br)c(O)c1C(=O)OC
Agent: OB(O)c1ccoc1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(O)c1C(=O)OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 160, starting from (Z)-methyl 3-bromo-6-((2-(3-(diethylamino)prop-1-enyl)-4-fluorobenzenesulfonyl)methyl)-2-hydroxybenzoate (Intermediate 197) and furan-3-boronic acid.
Reaction SMILES: Br[C:2]([CH3:15])([CH3:14])[C:3]([NH:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]>C(OCC)C>[CH3:15][C:2](=[CH2:14])[C:3]([NH:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(Br)C(=O)NOCc1ccccc1
Solvent: CCOCC
Product: C=C(C)C(=O)NOCc1ccccc1

Procedure:
Elimination product from the reaction attempted cycloaddition of 4g with LiClO4/Et3N in diethyl ether. 1H NMR (400 MHz, CDCl3) δ 8.19 (br s, 1H), 7.49-7.29 (m, 5H), 5.55 (pent, J=1 Hz, 1H), 5.32 (dq, J=1.6, 1.0 Hz, 1H), 4.96 (s, 2H), and 1.92 (dd, J=1.6, 1.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.2, 138.0, 135.4, 129.5, 129.0, 128.8, 120.4, 78.3, and 18.6; IR (film) 3199 (br), 3064, 3032, 2954, 2878, 1658, 1620, 1496, 1453, 1372, 1322, 1209, 1039 cm-1; HR-ESIMS calculated for C11H13NNaO2 (M+Na)+ 215.0871, found 215.0869.
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[C:7]([Cl:13])=[C:6]([NH2:14])[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1C[O:25][CH2:24][CH2:23]1>O=[Mn]=O>[Cl:13][C:7]1[C:8]([O:10][CH2:11][CH3:12])=[CH:9][C:4]([CH:3]=[O:15])=[CH:5][C:6]=1[NH:14][C:24](=[O:25])[CH3:23]
Reactant: CCOc1cc(C(=O)OC)cc(N)c1Cl
Reactant: C1CCOC1
Agent: O=[Mn]=O
Agent: [Al+3]
Agent: [H-]
Product: CCOc1cc(C=O)cc(NC(C)=O)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
To a solution of 3-amino-4-chloro-5-ethoxy-benzoic acid methyl ester (1.8 g, 6.63 mmol, 1.0 equiv) in anhydrous THF (50 mL) was added lithium aluminium hydride (0.50 g, 13.25 mmol, 2.0 equiv) and the reaction mixture stirred at rt for 4 h. The crude reaction mixture was filtered, the filtrate extracted with diethyl ether (3×50 mL) and the combined organic phases dried over MgSO4 providing 1.58 g (100%) of the benzyl alcohol. The crude reaction product (0.13 g, 0.53 mmol, 1.0 equiv) was dissolved in THF (20 mL) and activated MnO2 (0.46 g, 5.34 mmol, 10.0 equiv) was added. After stirring at rt for 1 h, the reaction mixture was filtered and the solvent removed by evaporation under reduced pressure. A conc. solution of sodium chloride (100 mL) was added, the mixture extracted with ethyl acetate (3×100 mL) and the combined organic phases dried over MgSO4. Purification of the crude material with column chromatography on silica eluting with heptane/ethyl acetate (2:1) provided 0.058 g (45%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.49 (t, J=7.0 Hz, 3H), 2.29 (s, 3H), 4.19 (q, J=7.0 Hz, 2H), 7.22 (d, J=1.6 Hz, 1H), 7.78 (br s, 1H), 8.56 (br s, 1H), 9.94 (br s, 1H). MS (ISP): 242.1 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:40])[CH:17]([C:24]3[N:25]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[N:26]=[C:27]4[C:32]=3[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:11]([F:41])[CH:10]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Li+]>C1COCC1.CO>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([N:25]2[C:24]([CH:17]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:16]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]4([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]4)=[CH:10][C:11]=3[F:41])=[O:40])=[C:32]3[C:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)=[N:26]2)=[CH:38][CH:37]=1
Reactant: COC(=O)C1(Oc2ccc(NC(=O)C(c3c4c(nn3-c3ccc(Cl)cc3)CCCC4)C3CCCCC3)c(F)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(OC2(C(=O)O)CC2)cc1F)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-1-(4-{2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-acetylamino}-3-fluoro-phenoxy)-cyclopropanecarboxylic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as colorless foam. MS: m/e=566.4 [M+H+].
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[C:13]2[C:8]=1[CH2:9][CH2:10][CH2:11][O:12]2>>[Br:6][C:7]1[C:16]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[C:13]2[C:8]=1[CH2:9][CH2:10][CH2:11][O:12]2
Reactant: O=C(O)c1ccc(Br)c2c1OCCC2
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1cc(S(=O)(=O)Cl)c(Br)c2c1OCCC2

Procedure:
817 ml of chlorosulphonic acid were introduced into a 2-liter round-bottomed flask and 210 g of 5-bromochroman-8-carboxylic acid were then added in small amounts. The temperature rose to 40° C.
Reaction SMILES: [C:1]([C:3]#[C:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:7])[CH3:6])#[N:2].C(C1(C2C=CC(OC)=C(C=2)[CH:26]=[O:27])CC1)#N>>[C:1]([C:3]#[C:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH:9]=1)[CH:26]=[O:27])([CH3:7])[CH3:6])#[N:2]
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Reactant: COc1ccc(C(C)(C)C#CC#N)cc1
Product: COc1ccc(C(C)(C)C#CC#N)cc1C=O

Procedure:
This compound was prepared from Compound 63 in the same manner of Compound 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[NH:17][C:18]([C:21](OCC)=[O:22])=[N:19][N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:30][CH2:29]1.C[Al](C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:26])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[NH:17][C:18]([C:21]([N:38]3[CH2:37][CH2:36][N:35]([CH2:34][CH:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH2:40][CH2:39]3)=[O:22])=[N:19][N:20]=2)(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: CCOC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)[nH]1
Reactant: CN1CCC(CN2CCNCC2)CC1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)[nH]2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using ethyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-4H-1,2,4-triazole-3-carboxylate (30 mg, 0.08 mmol), 1-[(1-methylpiperidin-4-yl)methyl]piperazine (31 mg, 0.16 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (5 mL). A portion of the crude product was purified using prep method B.
Reaction SMILES: [C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]([CH2:20]Cl)[CH:5]=1)(=[O:3])[CH3:2].[CH3:22][SH:23].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]([CH2:20][S:23][CH3:22])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CS
Reactant: CC(=O)c1cc(CCl)c(OCCCCCCC#N)cc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCc1cc(C(C)=O)c(O)cc1OCCCCCCC#N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 600 mg of the compound from Example 127 was dissolved in 50 ml of methylene chloride and cooled to 0° C. Fifteen grams of methanethiol were added followed by the addition of 2 ml of triethylamine. The reaction was allowed to warm to room temperature and was stirred overnight. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and an acidic sodium chloride solution. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography over silica gel eluting with 40% ethyl acetate in hexane providing 200 mg of the desired title product, m.p. =78° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[OH:11].C([Li])CCC.[Cl:17][Si:18](Cl)([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[O:11][Si:18]([Cl:17])([CH3:20])[CH3:19]
Reactant: C[Si](C)(Cl)Cl
Reactant: Oc1c(F)c(F)cc(F)c1F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: C[Si](C)(Cl)Oc1c(F)c(F)cc(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.32 g (20 mmol) of 2,3,5,6-tetrafluorophenol are dissolved in 50 ml of toluene, and 8 ml of n-butyllithium (2.5 M in hexane) are added at 0° C. After warming to room temperature, the solution is stirred for 2 hours. Then 2.6 g of dichlorodimethylsilane (20 mmol) are added dropwise. The resulting suspension is filtered and the solvent is stripped off in vacuo. The colorless liquid which remains is subjected to fractional distillation.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[F:13])[CH2:2][CH2:3][CH3:4].[Li]CCCC.[CH2:19]([CH:22]1[CH2:27][CH2:26][CH:25]([CH:28]2[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]2)[CH2:24][CH2:23]1)[CH2:20][CH3:21].Cl>C1COCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:31]2([OH:34])[CH2:30][CH2:29][CH:28]([CH:25]3[CH2:26][CH2:27][CH:22]([CH2:19][CH2:20][CH3:21])[CH2:23][CH2:24]3)[CH2:33][CH2:32]2)=[C:8]([F:12])[C:7]=1[F:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC1CCC(C2CCC(=O)CC2)CC1
Reactant: CCCCOc1cccc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCOc1ccc(C2(O)CCC(C3CCC(CCC)CC3)CC2)c(F)c1F
Reaction time: 2 h

Procedure:
31.0 g (0.17 mol) of 1-butoxy-2,3-difluorobenzene are initially introduced in 200 ml of THF, and 100 ml (0.16 mol) of n-BuLi (15% soln. in hexane) are added at −70° C. After 2 h at this temperature, a solution of 35.6 g (0.16 mol) of 4′-propylbicyclohexyl-4-one in 200 ml of THF is metered in, and the batch is stirred for 2.5 h. The reaction mixture is hydrolysed with ice-cooling and acidified using 2 N HCl. The solution is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product (66.3 g of yellow solid) is used directly for the following reaction.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](OS(C)(=O)=O)([CH3:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>C(O)C>[CH:1]([N:14]1[CH2:17][C:16]([NH:27][CH:24]2[CH2:26][CH2:25]2)([CH3:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: NC1CC1
Solvent: CCO
Product: CC1(NC2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 20 °C
Reaction time: 96 h

Procedure:
A suspension of 16.6 g of 1-benzhydryl-3-methane-sulphonyloxy-3-methylazetidine and 28.84 g of of cyclopropylamine in 250 cm3 of ethanol is stirred for 96 hours at approximately 20° C. The reaction mixture is concentrated under reduced pressure (20 kPa) at approximately 30° C. The dry extract is taken up with 50 cm3 of water and 8.8 g of methanesulphonic acid. The aqueous phase is washed with 3 times 25 cm3 of dichloromethane, treated with 12 cm3 of 35% aqueous sodium hydroxide and extracted with 3 times 50 cm3 of ethyl acetate. The combined organic phases are washed with twice 50 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 kPa) at approximately 25° C. 14.6 g of 1-benzhydryl-3-cyclopropylamino-3-methylazetidine are obtained in the form of a yellow oil, which is used without further purification for the subsequent steps.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=1)=[O:3].[C:22]([O:26][C:27]([N:29]([C:37]1[C:38](Cl)=[N:39][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:41][CH:42]=1)C(OC(C)(C)C)=O)=[O:28])([CH3:25])([CH3:24])[CH3:23].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(O)=O.[Na+].CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:11][C:10](=[O:19])[NH:9][CH2:8][C:7]2[CH:20]=[CH:21][C:4]([C:2]([NH:1][C:38]3[C:37]([NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])=[CH:42][CH:41]=[C:40]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:39]=3)=[O:3])=[CH:5][CH:6]=2)[CH:14]=1
Reactant: NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(-c2ccccc2)nc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
Pyridin-3-ylmethyl [4-(aminocarbonyl)benzyl]carbamate (0.35 g, 1.24 mmol), di-tert-butyl(2-chloro-6-phenylpyridin-3-yl)imidodicarbonate (0.5 g, 1.24 mmol), Xanthphos (0.07 g, 0.12 mmol), potassium phosphate, tribasic (0.79 g, 3.70 mmol), and Pd2(dba)3 (0.57 g, 0.06 mmol) were combined in a 20 mL microwave vial and dioxane was added. The mixture was degassed for 20 mins, then sealed and heated to 100° C. overnight. Reaction was not complete and was continued another 24 h, for a total of 48 h at 100° C. The reaction was cooled to RT, diluted with saturated NaHCO3 solution and EtOAc, and the layers were separated. The water layer was extracted with EtOAc (2×100 mL). The combined organic fractions were washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified on a Biotage 65i column to yield pyridin-3-ylmethyl{4-[({3-[(tert-butoxycarbonyl)amino]-6-phenylpyridin-2-yl}amino)carbonyl]benzyl}carbamate. MS: cal'd 554 (MH+), exp 554 (MH+).
Reaction SMILES: BrBr.[CH:3]1[C:18]2[C:19]3[C:6]([C:7](=[O:21])[O:8][C:9](=[O:20])[C:10]=3[CH:11]=[C:12]3[C:17]=2[CH2:16][O:15][CH2:14][O:13]3)=[CH:5][CH:4]=1.[CH3:22][OH:23]>C(Cl)(Cl)Cl>[CH3:22][O:23][CH:16]1[O:15][CH2:14][O:13][C:12]2[C:17]1=[C:18]1[CH:3]=[CH:4][CH:5]=[C:6]3[C:7](=[O:21])[O:8][C:9](=[O:20])[C:10]([CH:11]=2)=[C:19]13
Reactant: CO
Reactant: O=C1OC(=O)c2cc3c(c4cccc1c24)COCO3
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: COC1OCOc2cc3c4c(cccc4c21)C(=O)OC3=O

Procedure:
Bromine (0.3 mL, 5.8 mmol) was added to a suspension of 11H-5,8,10-trioxabenzo[de]anthracene-4,6-dione (0.3 g, 1.2 mmol, from Example K1) in chloroform (20 mL). The mixture was refluxed for 3 hours under nitrogen atmosphere. Methanol (10 mL) was added and the reaction mixture refluxed for additional 3 hours and concentrated in vacuo. The solids obtained were washed with methanol and dried to give 0.16 g of the title compound.
Reaction SMILES: C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[C:38]([OH:48])(=[O:47])[C@@H:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[OH:40].[Cl:49][C:50]1[CH:55]=[CH:54][C:53]([N:56]=[C:57]=[O:58])=[CH:52][CH:51]=1.O>ClCCl>[Cl:49][C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:57]([O:40][C@H:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([OH:48])=[O:47])=[O:58])=[CH:52][CH:51]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)O[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.1 400 mg (0.63 mmol) of dibutyltin dilaurate are added to a solution of 10.0 g (65.7 mmol) of (R)-mandelic acid and 10.0 g (65.1 mmol) of 4-chlorophenyl isocyanate in 100 ml of dichloromethane, and the mixture is stirred at room temperature for 24 hours. The reaction mixture is introduced into water and extracted with ethyl acetate. The organic phase is evaporated, giving (R)-(4-chlorophenylcarbamoyloxy)phenylacetic acid as a colourless solid; ESI 306.