Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][Mg]Cl.[Mg].CN(C)CCCCl.[F:17][C:18]1([F:36])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22](=[O:29])[C:21]2[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=2[C:19]1([F:35])[F:34]>O1CCCC1>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:22]1([OH:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:18]([F:36])([F:17])[C:19]([F:35])([F:34])[C:20]2[CH:33]=[CH:32][CH:31]=[CH:30][C:21]1=2
Reactant: O=C1c2ccccc2C(F)(F)C(F)(F)c2ccccc21
Reactant: CN(C)CCC[Mg]Cl
Agent: CN(C)CCCCl
Agent: [Mg]
Solvent: C1CCOC1
Product: CN(C)CCCC1(O)c2ccccc2C(F)(F)C(F)(F)c2ccccc21
Reaction time: 1 h

Procedure:
A solution of 3-dimethylaminopropylmagnesium chloride in 3 ml. of dry peroxide-free tetrahydrofuran is prepared under nitrogen from 0.136 g. (0.0056 g. atom) of magnesium turnings and 0.68 g. (0.0056 mole) of 3-dimethylaminopropyl chloride. To the solution of the Grignard reagent cooled in ice is added dropwise a solution of 0.829 g. (0.00296 mole) of 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-one in 3 ml. of tetrahydrofuran. The mixture is stirred 1 hour in the cold and allowed to stand overnight in the refrigerator. After decanting the solution from any unused magnesium, the bulk of the tetrahydrofuran is evaporated under reduced pressure. The residue is dissolved in benzene, again evaporated under reduced pressure, and the residue redissolved in benzene. The solution is cooled in ice and hydrolyzed by the dropwise addition of 1 ml. of water. The benzene solution is decanted and the residual gelatinous precipitate is re-extracted with benzene. Evaporation of the combined benzene extracts and recrystallization of the residual solid from cyclohexane yields the product, m.p. 155°-157°C. A sample for analysis is recrystallized twice from hexane; m.p. 158°-159°C.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([NH:10]C=O)[CH:8]=2)[NH:3][CH:2]=1.[ClH:13]>CO>[ClH:13].[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([NH2:10])[CH:8]=2)[NH:3][CH:2]=1
Reactant: O=CNc1cnc2[nH]cnc2c1
Agent: Cl
Solvent: CO
Product: Nc1cnc2[nH]cnc2c1

Procedure:
4.17 g of N-(3H-Imidazo[4,5-b]pyridin-6-yl)-formamide in 100 ml methanol and 100 ml concentrated hydrochloric acid were stirred 1 hr at 60° C. The solvents were evaporated and the residue dried to yield 4.3 g of the title product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH3:30][O:31][CH2:32]Cl>C(Cl)Cl>[CH3:30][O:31][CH2:32][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(c3ccc(O)cc3)CC2)cc1
Reactant: COCCl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COCOc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Reaction time: 16 h
Yield: 83 %

Procedure:
To a mixture of 10 (263.4 mg, 0.88 mmol) and diisopropylamine (DIPEA) (170.6 mg, 1.32 mmol) in CH2Cl2 (12 mL) was added slowly chloromethyl methyl ether (77.9 mg, 0.97 mmol) at room temperature. The reaction was stirred for 16 h, and then quenched by the addition of saturated aqueous ammonium chloride (10 mL). The resulting solution was extracted with more CH2O2, dried (Na2SO4), filtered, and concentrated to yield the crude product, which was purified by column chromatography (neat CH2Cl2→100:1 CH2Cl2-Acetone) to afford 11 (250.8 mg, 83%) as a yellow amorphous solid; 1H NMR (400 MHz, CDCl3, δH) 8.20-8.08 (m, 2H), 7.07-6.97 (m, 2H), 6.97-6.82 (m, 4H), 5.13 (s, 2H), 3.62-3.51 (m, 4H), 3.48 (s, 3H), 3.30-3.18 (m, 4H); 13C NMR (100 MHz, CDCl3, δC) 154.99, 151.98, 146.31, 138.84, 126.18, 118.59, 117.58, 113.04, 95.28, 56.13, 50.42, 47.43. MALDI-MS: 344.2 (M+H+), 366.2 (M+Na+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C=C(C#N)C=CC=3OCC2=O)CC1.[F:52][C:53]1[CH:58]=[CH:57][C:56]([F:59])=[CH:55][C:54]=1/[CH:60]=[CH:61]/[CH:62]=O.C([BH3-])#N.[Na+]>ClCCl.CO>[F:52][C:53]1[CH:58]=[CH:57][C:56]([F:59])=[CH:55][C:54]=1/[CH:60]=[CH:61]/[CH2:62][NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1
Reactant: N#Cc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Reactant: O=C/C=C/c1cc(F)ccc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N#Cc1ccc2c(c1)N(CCN1CCC(NC/C=C/c3cc(F)ccc3F)CC1)C(=O)CO2
Yield: 30.9 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 58) (1.5 mmol), (2E)-3-(2,5-difluorophenyl)acrylaldehyde (202 mg, 1.2 mmol) (FR 2872164) (200 mg, 1.1 mmol) and sodium cyanoborohydride were reacted as described under Example 21. Chromatography on silica gel with dichloromethane/methanol gave 168 mg (25%) product
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:8]([CH2:17][CH2:18][NH2:19])[C:7]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[C:27](Cl)(=[O:29])[CH3:28]>O.ClCCl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:8]([CH2:17][CH2:18][NH:19][C:27](=[O:29])[CH3:28])[C:7]=2[CH:20]=1
Reactant: NCCc1c(-c2ccccc2)sc2ccc(Cl)cc12
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)NCCc1c(-c2ccccc2)sc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound obtained in Step E is dissolved in a mixture of water/dichloromethane (2/3); 2 eq. of potassium carbonate are then added and 2 eq. acetyl chloride are added dropwise. After stirring for 2 hours at ambient temperature, the 2 phases are separated; the organic phase is washed with 1M HCl and then with water, until the washing waters are neutral, and is then dried as over MgSO4 and evaporated. The residue obtained is purified by chromatography on silica gel.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:16][CH:15]3[C:10]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)([N:11]=[C:12]([NH2:17])[S:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.C(O)C>C(=O)=O>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)([N:11]=[C:12]([NH2:17])[S:13][CH2:14]3)[CH2:9]2)=[N:4][CH:3]=1
Reactant: NC1=NC2(c3ccncc3)CN(c3ncc(F)cn3)CC2CS1
Agent: O=C=O
Solvent: CCO
Product: NC1=N[C@@]2(c3ccncc3)CN(c3ncc(F)cn3)C[C@H]2CS1
Yield: 21.6 %

Procedure:
Racemic 6-(5-fluoropyrimidin-2-yl)-7a-(4-pyridyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine (185 mg, 0.56 mmol) is separated into its constituent enantiomers by chiral SFC (Column: Chiralcel OJ-H (5μ), 21.2×250 mm; eluent: 25% ethanol (0.2% diethylmethylamine) in CO2; flow: 70 mL/min at UV 260 nm). The second eluting isomer is the title compound (40 mg). ES/MS (m/e): 331 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[C:20]([NH:25][NH2:26])(=O)[CH:21]([CH3:23])[CH3:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:20]([CH:21]([CH3:23])[CH3:22])=[N:25][N:26]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: CC(C)C(=O)NN
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Solvent: CCO
Product: CC(C)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione is heated in ethanol with isobutyric acid hydrazide and the resulting product heated to 250° C. to give 8-chloro-1-isopropyl-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.B(F)(F)F.[CH2:23](O)CC>C(N(CC)CC)C>[CH2:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[CH:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])[CH2:1][CH3:23]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CCCO
Agent: FB(F)F
Solvent: CCN(CC)CC
Product: CCCOCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1

Procedure:
Using the procedure of Step A of Example 8, 27.2 g of 7-amino-cephalosporanic acid, 170 ml of the etherate of of boron trifluoride, 131 ml of propanol and 128 ml of triethylamine were reacted to obtain 17.4 g of raw product which was purified with hot hydrochloric acid and ammonium hydroxide to obtain 7.45 g of 3-propoxymethyl-7-amino-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][O:6][B:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]CC(O)=O)=[CH:10][CH:9]=2)[O:4][CH2:3]1.BrC1C=CC(CC[O:30][C:31](=[O:41])[NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=2)=CC=1>>[CH3:20][C:2]1([CH3:1])[CH2:3][O:4][B:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][O:41][C:31](=[O:30])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=3)=[CH:12][CH:13]=2)[O:6][CH2:7]1
Reactant: N#Cc1cccc(NC(=O)OCCc2ccc(Br)cc2)c1
Reactant: CC1(C)COB(c2ccc(CCCC(=O)O)cc2)OC1
Product: CC1(C)COB(c2ccc(CCOC(=O)Nc3cccc(C#N)c3)cc2)OC1
Yield: 76 %

Procedure:
Using a procedure analogous to that used to prepare 2A, 11A (516 mg, 1.50 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 11B (434 mg, 76%). This crude material was taken on to the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH:12]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:13]([OH:15])=[O:14].C(=O)(O)[O-].[Na+]>O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:10])[NH:11][CH:12]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: COC(=O)CC(N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)CC(NC(=O)Nc1cccc(C)c1)C(=O)O
Reaction time: 16 h
Yield: 85.7 %

Procedure:
(RS)-2-[3-(3-Methylphenyl)uriedo]-3-methoxycarbonylpropionic acid may be prepared in the following manner: 3-methylphenyl isocyanate (13.3 g) is added in the course of 30 minutes at 17° C. to a solution of (RS)-2-amino-3-methoxycarbonylpropionic acid (16.1 g) and sodium bicarbonate (8.4 g) in water (160 cc). The reaction medium is stirred for a further 16 hours and the insoluble matter is then filtered off. The liltrate is taken to pH 1 with 4N hydrochloric acid and extracted with ethyl acetate (3×15 cc). The extracts are combined, washed with water (2×15 cc), dried over magnesium sulphate and then taken to dryness under reduced pressure (2.7 kPa) at 70° C. After crystallisation in petroleum ether, (RS)-2-[3-(3-methylphenyl)ureido]-3-methoxycarbonylpropionic acid (24 g) is obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>>[CH:31]1([NH:34][C:3](=[O:2])[C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)=[N:17][O:18][C:19]=4[C:20]([F:21])([F:23])[F:22])[N:12]=[CH:11]3)=[CH:8][CH:9]=2)[CH2:33][CH2:32]1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Yield: 27 %

Procedure:
As described for Example 10, 4-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester (70 mg, 0.17 mmol) was converted, using cyclopropylamine instead of cyclopropanemethylamine, to the title compound (20 mg, 27%) which was obtained as a white solid. MS: m/e=439.2 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](O)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14]([NH2:16])=O.S(Cl)([Cl:19])=O>CN(C)C=O>[C:14]([C:2]1[CH:1]=[C:10]2[C:5](=[CH:4][CH:3]=1)[CH:6]=[C:7]([C:11]([Cl:19])=[O:12])[CH:8]=[CH:9]2)#[N:16]
Reactant: NC(=O)c1ccc2cc(C(=O)O)ccc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1ccc2cc(C(=O)Cl)ccc2c1

Procedure:
2.8 g of naphthalene-2,6-dicarboxylic acid monoamide, 10 ml of thionylchloride and 1 drop of dimethylformamide are refluxed for 5 hours. The clear yellow solution is evaporated down in vacuo and the solid evaporation residue is mixed with 20 ml of diethylether and 20 ml of petroleum ether, then stirred and suction filtered. The filter cake is washed with petroleum ether and diethylether and dried in vacuo.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[S:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH2:2][CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:35][C@@H:36]1[CH2:45][CH2:44][C:43]2[C:38](=[C:39]([N:46]3[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]3)[CH:40]=[CH:41][CH:42]=2)[CH2:37]1>CN(C)C=O>[CH3:52][N:49]1[CH2:50][CH2:51][N:46]([C:39]2[CH:40]=[CH:41][CH:42]=[C:43]3[C:38]=2[CH2:37][C@H:36]([NH:35][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([S:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:17][CH2:18][CH3:19])(=[O:6])=[O:7])=[CH:16][CH:15]=2)[CH2:45][CH2:44]3)[CH2:47][CH2:48]1
Reactant: CCCN(CCC)S(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CCCN(CCC)S(=O)(=O)c1ccc(C(=O)N[C@@H]2CCc3cccc(N4CCN(C)CC4)c3C2)cc1
Temperature: 75 °C
Reaction time: 24 h
Yield: 27.6 %

Procedure:
To a solution of 4-(N,N-dipropylaminosulphonyl)benzoic acid (120 mg, 0.43 mmol) in anhydrous N,N-dimethylformamide (25 mL) was added 1,1′-carbonyldiimidazole (73 mg, 0.45 mmol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 30 min), the reaction was cooled to room temperature and a solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added. The reaction was allowed to stir at ambient temperature for 24 h and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent gave 58 mg (27% yield) of the title compound as a viscous oil: [α]21D −370 (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 512 (11, M+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH3:20])=[CH:14][C:13]=1[CH2:21][OH:22].Cl>C(Cl)Cl>[Br:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH3:20])=[CH:14][C:13]=1[CH:21]=[O:22]
Reactant: COc1cc(CO)c(Br)cc1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cc(C=O)c(Br)cc1Cl
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 95.2 %

Procedure:
To a solution of oxalyl chloride (0.58 mL, 6.9 mmol) in DCM (20 mL) was added dropwise a solution of dimethylsulfoxide (1.11 mL, 15.6 mmol) in DCM (10 mL), at temperature lower than −65° C. The resulting mixture was stirred for about 20 min at about −70° C. Then a solution of (2-bromo-4-chloro-5-methoxy-phenyl)methanol (1.56 g, 6.2 mmol) in DCM (20 mL) was added dropwise at temperatures lower than −65° C., and the resulting mixture was stirred for about another 20 min. Subsequently, TEA (3.52 mL, 25.2 mmol) was added dropwise at temperatures lower than −70° C., and the mixture was stirred for about 10 min at about −70° C. The mixture was allowed to warm to rt and stirred for about 16 h, treated with 1 M aqueous HCl (100 mL) and DCM (50 mL). The layers were separated and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were washed with water (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, diethyl ether/hexanes 5:95) to give 2-bromo-4-chloro-5-methoxybenzaldehyde (1.48 g, 5.9 mmol, 95%) as a white solid: 1H-NMR (CDCl3, Bruker 400 MHz) δ 3.96 (3 H, s), 7.46 (1 H, s), 7.68 (1 H, s), 10.3 (1 H, s).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]3[C:17]([C:31]#[N:32])=[C:18]([NH:20][C:21](=[O:30])/[CH:22]=[CH:23]/[C:24]4[CH:29]=C[CH:27]=[CH:26][CH:25]=4)[S:19][C:13]=3[CH2:12]2)=[O:10])[CH2:4][O:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.C([N:47](CC)CC)C>C(C#N)(C)=O.O>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[C:17]([C:31]#[N:32])=[C:18]([NH:20][C:21](=[O:30])/[CH:22]=[CH:23]/[C:24]3[CH:29]=[N:47][CH:27]=[CH:26][CH:25]=3)[S:19][C:13]=2[CH2:12]1)=[O:10]
Reactant: CCN(CC)CC
Reactant: CC1(C)OCC(COC(=O)N2CCc3c(sc(NC(=O)/C=C/c4ccccc4)c3C#N)C2)O1
Agent: CC(=O)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: N#Cc1c(NC(=O)/C=C/c2cccnc2)sc2c1CCN(C(=O)OCC(O)CO)C2
Yield: 80 %

Procedure:
0.26 mmol of 3-Cyano-2-((E)-3-phenyl-allanoylamino)-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester are dissolved in 10 ml AcCN/H2O (2/1) and 0.1 eq PTSA is added. After stirring over night, some triethylamine is added and the solvent removed. Recrystallization from ethanol gives the desired product in 80% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:17]([C:20]4[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:15]=[CH:16][C:9]=23)[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[I:37]I.[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:17]([C:20]4[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[C:15]([I:37])=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1ccnc2c1cc(I)n2S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.33 h

Procedure:
To a solution of Example 258B (98 g, 247.2 mmol) in tetrahydrofuran (3528 mL) was added lithium diisopropylamide (1.8M in tetrahydrofuran/heptane/ethylbenzene, 233.4 mL, 420.2 mmol) at −78° C. The mixture was stirred for 20 minutes and a solution of iodine (116.07 g, 457.3 mmol) in tetrahydrofuran (392 mL) was added drop wise over 20 minutes, maintaining the temperature below −70° C. After 30 minutes, the mixture was poured into a saturated ammonium chloride (980 mL) and extracted with ethyl acetate (twice). The combined extracts were washed with saturated sodium thiosulfate (twice) and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-11% ethyl acetate in 10% dichloromethane/petroleum ether to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:15]=3)[CH2:10][CH2:9][CH:8]2[NH:27]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.Cl>ClCCl>[ClH:1].[NH2:27][CH:8]1[CH:7]([CH2:6][C:5]2[CH:35]=[CH:36][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:16]2[CH:15]=[C:14]([CH2:17][CH2:18][CH2:19][NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9]1
Reactant: CCCS(=O)(=O)NCCCc1ccc2c(c1)C(Cc1ccc(Cl)cc1)C(NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Product: CCCS(=O)(=O)NCCCc1ccc2c(c1)C(Cc1ccc(Cl)cc1)C(N)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl [1-(4-chlorobenzyl)-7-{3-[(propylsulfonyl)amino]propyl}-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (150 mg, 0.281 mmol) was dissolved in dichloromethane (3 mL) and a solution of hydrochloric acid (0.5 mL, 5 M in isopropanol) was added. After stirring at room temperature for 2 hours the solvent was removed in vacuo. Water was added (15 mL) and the pH was adjusted to 9 with aqueous saturated sodium bicarbonate and the mixture was extracted with dichloromethane (3×15 mL). The combined organic extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, dichloromethane, methanol). The product was dissolved in dichloromethane (2 mL) and a solution of hydrochloric acid in ethanol (1.25 M) was added. The solvent was removed in vacuo. Yield: 31.4 mg (0.187 mmol, 36%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][CH2:18][CH:19]3[O:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[O:21][CH2:20]3)=[CH:14][C:13]2=[O:29])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:51][C:52]1[CH:56]=[CH:55][N:54]([CH2:57][C:58]([CH3:61])([OH:60])[CH3:59])[N:53]=1>ClCCl>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][CH2:18][CH:19]3[O:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[O:21][CH2:20]3)=[CH:14][C:13]2=[O:29])[C:9]([NH:51][C:52]2[CH:56]=[CH:55][N:54]([CH2:57][C:58]([OH:60])([CH3:59])[CH3:61])[N:53]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(OCC2COc3ccccc3O2)=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(OCC3COc4ccccc4O3)=CC2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.3 %

Procedure:
A solution of (S)-3-cyclohexyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (151 mg, 0.55 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (63 mg, 0.39 mmol) and 1-hydroxybenzotriazole (52 mg, 0.38 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 67 mg, 0.43 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified on Gilson HPLC system (C18 column, 10-99% acetonitrile/water gradient) to afford (S)-3-cyclohexyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1-H-pyrazol-3-yl]-propionamide (47 mg, 24%) as a white solid: HR-ES-MS m/z calculated for C29H38N4O6 [M+H]+ 539.2864, observed 539.2865; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.81-0.99 (m, 2H) 1.05 (s, 3H) 1.07-1.30 (m, 4H) 1.50-1.83 (m, 7H) 3.89 (s, 2H) 3.98 (dd, J=18.1, 4.0 Hz, 1H) 4.09 (dd, J=11.3, 7.5 Hz, 1H) 4.18-4.34 (m, 2H) 4.34-4.45 (m, 1H) 4.53-4.63 (m, 1H) 4.67 (s, 1H) 4.86 (dd, J=11.3, 4.0 Hz, 1H) 5.25 (s, 1H) 6.42 (d, J=2.1 Hz, 1H) 6.79-6.99 (m, 4H) 7.52 (d, J=2.1 Hz, 1H) 10.70 (s, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:6]=1.C[Si]([C:20]#[CH:21])(C)C.CO.[OH-].[K+]>C(Cl)Cl.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:20]([C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:6]=1)#[CH:21]
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(Cn2cc(I)cn2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#Cc1cnn(Cc2ccc(OC)cc2)c1
Reaction time: 3 h
Yield: 81.5 %

Procedure:
A vigorously stirred solution of 4-iodo-1-(4-methoxy-benzyl)-1H-pyrazole (1.0 g, 3.18 mmol) and Pd(Ph3P)2Cl2 (60 mg, 3 mol %) in a mixture of DCM (10 mL) and triethylamine (3 mL) was evacuated and backfilled with nitrogen three times and then treated sequentially with trimethylsilylacetylene (0.53 mL, 3.83 mmol) and copper (I) iodide (70 mg, 12 mol %). The reaction rapidly became dark and after stirring for 3 h the solvents were removed in vacuo and the residue treated with methanol (10 mL) and potassium hydroxide (300 mg, 5.35 mmol). After stirring for 30 minutes the mixture was concentrated onto silica gel and purified by flash column chromatography (eluent-hexane:diethyl ether 2:1) to afford the title compound as a white solid (550 mg, 81% yield over two steps). 1H-NMR (CDCl3) δ 7.61 (s, 1H), 7.46 (s, 1H), 7.17 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.18 (s, 2H), 3.78 (s, 3H), 2.96 (s, 1H).