Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[N:6][CH:7]=1.CO.[BH4-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[N:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)c2ccccc2[N+](=O)[O-])nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccccc2N)nc1
Yield: 94.8 %

Procedure:
To a stirring solution of N-(5-methylpyridin-2-yl)-2-nitrobenzamide (1.5 g, 5.8 mmol) and Ni(OAC)2.4H2O (2.9 g, 11.7 mmol) in THF (20 mL) and methanol (40 mL) at 0° C. was added, in small portions, sodium borohydride (0.88 g, 23.2 mmol). After complete addition and an additional 5 min, the solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (200 mL) and 50% conc NH4OH (200 mL). The organic phase was separated and washed again with 50% conc NH4OH, followed by brine, then dried with MgSO4, filtered and concentrated in vacuo to give 1.25 g (95%) of a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[S:16][C:17]2[C:18]([N:28]=1)=[C:19]1[C:24](=[CH:25][CH:26]=2)[CH:23]([CH3:27])[NH:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][CH:26]=[C:17]5[S:16][C:15]([CH3:14])=[N:28][C:18]5=4)[CH:23]3[CH3:27])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1nc2c3c(ccc2s1)C(C)NCC3
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: Cc1nc2c3c(ccc2s1)C(C)N(C(=O)c1cc2ncc(Br)cn2n1)CC3

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,6-Dimethyl-6,7,8,9-tetrahydro-thiazolo[4,5-f]isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][C:9]=2[OH:18])[N:3]=1.[OH-].[Na+].O.Cl>CO>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=2[OH:18])[N:3]=1
Reactant: COC(=O)c1ccc(-n2nc(C)cc2C)c(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C)n(-c2ccc(C(=O)O)cc2O)n1
Reaction time: 3.5 h
Yield: 43.3 %

Procedure:
100 mg of methyl 4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzene carboxylate was dissolved in 1 ml of methanol, and 1.6 ml of 1N-sodium hydroxide was added at room temperature and stirred for 3.5 hours. To the reaction mixture, 20 ml of water was added, neutralized with 1N-hydrochloric acid, and extracted with 20 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield 40.8 mg of the title compound.
Reaction SMILES: [CH2:1]([P:3]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])(=O)[O:4]C)[CH3:2].S(Cl)([Cl:30])=O>>[CH2:1]([P:3]([Cl:30])([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])=[O:4])[CH3:2]
Reactant: CCP(=O)(OC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: CCP(=O)(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of methyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate (700 mg, 1.65 mmol) and thionyl chloride (5 ml) is heated under reflux for 2 hours. The reaction mixture is concentrated to dryness to give P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic chloride. To a solution of the phosphinic chloride in methylene chloride (8 ml) is added methyl 2-hydroxyimino-3-methylbutanoate (320 mg, 2.48 mmol) in one portion. The mixture is stirred at RT for 3 hours. The reaction is then worked up in methylene chloride, washed, dried, evaporated to dryness and purified by prep. TLC to yield methyl 2-[P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinyloxyimino]-3-methylbutanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14]1([NH2:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(Nc1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with Phenylamine to produce 4-Chloro-3-nitro-N-phenyl-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 22A and 22B to provide the title product.
Reaction SMILES: CC(C)=O.[N-:5]=[N+:6]=[N-:7].[Na+].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>O>[N:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N+:6]=[N-:7]
Reactant: CCOC(=O)CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CN=[N+]=[N-]
Temperature: 65 °C
Yield: 67 %

Procedure:
A mixture of 6:4 acetone:water (20 ml) to was added to sodium azide (1.30 grams, 20 mmol, 2 molequivalents) followed by addition of ethyl bromoacetate (1.67 grams, 10 mmol, 1 molequivalent). The resulting mixture was refluxed overnight at 65° C. The acetone was thereafter evaporated under reduced pressure and the mixture was extracted with dichloromethane. The aqueous phase was washed with dichloromethane and the combined organic phase was washed with water, dried over sodium sulfate and evaporated to give 865 mg (76% yield) of ethyl azidoacetate as colorless oil having purity higher than 98% (as determined by NMR).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([N+:12]([O-:14])=[O:13])=[CH:5][C:4]=1[O:15]C.Br>C(O)(=O)C>[OH:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([N+:12]([O-:14])=[O:13])=[CH:5][C:4]=1[OH:15]
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OC
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(O)c(O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 9869.8 %

Procedure:
8B, FIG. 8. In a dry 500 mL round bottom flask, 1,2-dimethoxy-4,5-dinitrobenzene (3.2 g, 0.12 mmol) 8A was stirred vigorously in 40 mL of glacial acetic acid at 30° C. Once a homogeneous solution 200 mL of 48% HBr was added to the flask and the reaction was slowly heated to reflux. The reaction was complete as indicated by TLC after 4 hours. The work up involved pouring the cooled solution into 800 mL of ice water and then extracting the aqueous phase with CHCl3 (3×150 mL) in order to remove any organic impurities. The dinitro catechol was extracted out of the aqueous layer with ethyl acetate (3×150 mL). The combined ethyl acetate extracts were washed with water and brine (3×100 mL), then dried over MgSO4 and concentrated to an orange residue. Approximately 100 mL of dichloromethane was added to the residue and then placed in the freezer for several hours. The light yellow needles that formed were filtered and washed with dichloromethane to yield 2.37 g of product (84%). 1H NMR (d6 -acetone): δ3.45 (OH), 7.42 (Ar-H); 13C NMR (d6 -acetone): δ112.44, 137.00, 149.97, EI MS M+ 200.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[S:9][C:10]3[CH:16]=[C:15]([C:17]4[CH2:18][CH2:19][N:20]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH2:21][CH:22]=4)[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:3][CH2:2]1.[C:29](Cl)(=[O:35])[O:30][CH2:31][CH2:32][O:33][CH3:34]>>[CH2:26]([S:23]([N:20]1[CH2:19][CH:18]=[C:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([O:7][CH:4]4[CH2:3][CH2:2][N:1]([C:29]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[O:35])[CH2:6][CH2:5]4)[S:9][C:10]=3[CH:16]=2)[CH2:22][CH2:21]1)(=[O:25])=[O:24])[CH2:27][CH3:28]
Reactant: COCCOC(=O)Cl
Reactant: CCCS(=O)(=O)N1CC=C(c2ccc3nc(OC4CCNCC4)sc3c2)CC1
Product: CCCS(=O)(=O)N1CC=C(c2ccc3nc(OC4CCN(C(=O)OCCOC)CC4)sc3c2)CC1

Procedure:
Example 25 was prepared from Compound 15A and 2-methoxyethyl carbonochloridate in a similar manner to the procedure described in Example 15. 1H NMR (599 MHz, DMSO-d6) δ ppm 8.22 (s, 1H), 7.88 (s, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 6.19 (br. s., 1H), 5.28-5.39 (m, 2H), 4.05-4.19 (m, 2H), 3.92 (br. s., 2H), 3.65-3.77 (m, 2H), 3.49-3.58 (m, 2H), 3.45 (t, J=5.6 Hz, 2H), 2.96-3.11 (m, 2H), 2.60 (br. s., 2H), 2.08 (d, J=8.8 Hz, 3H), 1.63-1.84 (m, 6H), 1.00 (t, J=7.3 Hz, 3H). LC/MS (m/z)=524 (M+H)+.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:29]=[N:30][N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:32]=3)=[CH:18][CH:17]=2)[CH:6]=[C:5]([CH3:52])[N:4]=1>O1CCOCC1>[ClH:1].[CH3:2][C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[CH:6]=[C:5]([CH3:52])[N:4]=1
Reactant: CCOC(=O)c1c(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)cc(C)nc1C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1c(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)cc(C)nc1C
Reaction time: 3 h

Procedure:
6M Hydrochloric acid (10 ml) was added to a solution of ethyl 2,6-dimethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine-3-carboxylate (A) (600 mg) in dioxane (15 ml) and the mixture was stirred for 3 hours. Volatile material was removed by evaporation and the residue stirred for 30 minutes in a mixture of ethanol and ether (1:3 v/v, 20 ml). The insoluble solid was collected by filtration and recrystallised from a mixture of ethanol and methanol (1:1 v/v) to give ethyl 2,6-dimethyl-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine-3-carboxylate hydrochloride (270 mg), as a white powder, m.p. 205° C; NMR (d6 -DMSO, d4 -acetic acid): 1.2(t,3H), 2.6(s,3H), 2.7(s,3H), 4.4(q,2H), 5.5(s,2H), 7.2(d,2H), 7.4(d,2H), 7.55-7.65(m,3H), 7.67-7.75(m,2H); mass spectrum [negative fast atom bombardment (-ve FAB), DMSO/glycerol (GLY)]: 428 (M-H)-, 234, 194; microanalysis, found: C,61.7; H,5.0; N,14.9%; C23H24N5O3.HCl requires: C,61.9; H,5.2; N,15.0%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[N:9]([CH3:27])[C:10](=[O:26])[C@H:11]([CH2:24][CH3:25])[C@@:12]([CH3:23])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[N:9]([CH3:27])[C:10](=[O:26])[C@H:11]([CH2:24][CH3:25])[C@:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)([CH3:23])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[C@H]1C(=O)N(C)C(NC(=O)OC(C)(C)C)=N[C@]1(C)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC[C@H]1C(=O)N(C)C(NC(=O)OC(C)(C)C)=N[C@]1(C)c1cccc(N)c1
Reaction time: 2 h
Yield: 107.1 %

Procedure:
A suspension of [(4S,5R)-5-ethyl-1,4-dimethyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (90 mg) in ethyl alcohol (2 ml), NEt3 (10 mg) and Pd/C (10%, 10 mg) was hydrogenated at normal pressure and 22° C. for 2 h. The mixture was filtered and the filtrate evaporated to give [(4S,5R)-4-(3-amino-phenyl)-5-ethyl-1,4-dimethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (89 mg) as a colorless foam. MS (ESI): m/z=361.4 [M+H]+.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[F:9][C:10]([F:20])([F:19])[C:11](=O)[CH2:12][C:13](OCC)=[O:14]>C(O)(=O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[N:8][C:3]=1[N:1]1[C:13]([OH:14])=[CH:12][C:11]([C:10]([F:20])([F:19])[F:9])=[N:2]1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: NNc1ncccn1
Solvent: CC(=O)O
Product: Oc1cc(C(F)(F)F)nn1-c1ncccn1
Yield: 33.8 %

Procedure:
A mixture of 2 g (9 mmol) of 2-hydrazinopyrimidine and ethyl trifluoroacetoacetate (2.6 ml; 9.1 mmol) in 10 ml of acetic acid was refluxed for 60 hours with stirring under nitrogen and then cooled. The mixture was concentrated in vacuo, the residue was diluted with 100 ml of water, and the mixture was extracted with ethyl acetate (3×). The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was dried in vacuo to afford 700 mg of 1-(2-pyrimidinyl)-3-trifluoromethyl-5-hydroxypyrazole as a red gum.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C(OCC)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc2c(c1)OCCO2
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 22.5 g (149 mmol) 2,3-dihydro-benzo[1,4]dioxin-6-ylamine and 25 ml (179 mmol) triethylamine in 1 l diethyl ether is added at 12° C. within 10 minutes 20 ml (164 mmol) pivaloyl chloride dissolved in 250 ml diethyl ether. The temperature is kept between 12-16° C. The reaction mixture is stirred at room temperature for 1 hour. Then it is washed with 2× with 300 ml water, 2× with 150 ml 1N HCl and 2× with brine, dried with Na2SO4 and partially evaporated to a volume of 80 ml. This leads to a suspension. Hexane is added and the solid is filtered to give N-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-2,2-dimethyl-propionamide.
Reaction SMILES: [C:1]([CH:4]([NH:13][CH:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].Br[CH2:27][C:28]#[N:29].[H-].[Na+]>CN(C)C=O>[C:1]([CH:4]([NH:13][CH:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([CH2:27][C:28]#[N:29])[C:15]1=[O:25])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: O=C(O)C(CCc1ccccc1)NC1CCc2ccccc2NC1=O
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCN1C(=O)C(NC(CCc2ccccc2)C(=O)O)CCc2ccccc21

Procedure:
3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one is alkylated with bromoacetonitrile in dimethylformamide solution in the presence of sodium hydride to yield after work-up, 3-(1-carboxy-3-phenylpropylamino)-1-cyanomethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one, used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=O)[CH2:11][NH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH:3]=1.B.[CH3:24]SC>C1COCC1.[Ni].CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][N:12]([CH3:24])[C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: Cc1cc(C)nc(NC(=O)CNc2ccc([N+](=O)[O-])cc2)c1
Reactant: CSC
Agent: [Ni]
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C)nc(NCCN(C)c2ccc(N)cc2)c1

Procedure:
From 1-fluoro-4-nitrobenzene by heating with glycine at reflux in a mixture of aqueous sodium bicarbonate and dioxane to give (4-nitro-phenylamino)-acetic acid, followed by treatment with formaldehyde and formic acid at reflux to give [methyl-(4-nitro-phenyl)-amino]-acetic acid. Treatment with thionyl chloride and catalytic DMF to give the acid chloride followed by amide formation with 2-amino-4,6-dimethylpyridine in triethylamine and chloroform gives N-(4,6-dimethyl-pyridin-2-yl)-2-(4-nitro-phenylamino)-acetamide. The amide is the reduced with borane-dimethylsulfide in THF at reflux then catalytic hydrogenation over Raney nickel in methanol gives the required aniline.
Reaction SMILES: [CH:1]([S:4][C:5]1[C:6](/[CH:11]=[N:12]/[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].CCN(CC)CC>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH:1]([S:4][C:5]1[C:6]([CH:11]2[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][NH:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCC/N=C/c1ncccc1SC(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCNC1c1ncccc1SC(C)C
Reaction time: 3 h

Procedure:
To 65C (10 mmol) in CH2Cl2 (100 mL) at −15° C. was added Et3N (1.4 mL, 10 mmol) followed by TiCl4 (1.0 M in CH2Cl2, 20 mL, 20 mmol). The mixture was stirred from −15° C. to rt over 3.0 h before it was quenched with sat. K2CO3 (100 mL) at 0° C. and stirred at rt for 1.0 h. Methylene chloride was removed under vacuum and the crude was diluted with EtOAc. The mixture was filtered through a pad of wet Celite®, extracted with EtOAc (3×40 mL). The organic layer was washed with water, dried over Na2SO4. A small portion of the dried organic layer was concentrated to give crude ethyl 2-(3-(isopropylthio)pyridin-2-yl)pyrrolidine-3-carboxylate: 1H NMR indicated a mixture of cis and trans isomer in ca. 1:3 ratio. LC-MS 295 (M+H). To the above ethyl 2-(3-(isopropylthio)pyridin-2-yl)pyrrolidine-3-carboxylate in THF (10 mL) was added Et3N (1.4 mL) and di-tert-butyl dicarbonate (1.0 M in THF, 10 mL, 10 mmol). The mixture was stirred at rt over night before it was quenched with 0.5 N HCl (50 mL). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The resulting residue was purified via silica gel chromatography (gradient ethyl acetate in hexanes) to provide a major product trans 65D (1.8 g, 45% yield) and a minor product cis 65E (900 mg still contaminated with 65D, 20% yield). 65D: 1H NMR (400 MHz, CDCl3) δ ppm two rotomers: 1.07-1.16 (m, 6H) 1.25 (t, J=6.81 Hz, 3H) 1.30 and 1.39 (s, 9 H) 2.12-2.20 (m, 1H) 2.22-2.32 (m, 1H) 2.93-3.04 (m, 1H) 3.32-3.44 (m, 1H) 3.60-3.70 (m, 1H) 3.73-3.83 (m, 1H) 4.17 (q, J=7.18 Hz, 2H) 5.61 and 5.75 (d, J=3.95 Hz, 1H) 7.11 (dd, J=7.47, 4.83 Hz, 1H) 7.62 (d, J=7.91 Hz, 1H) 8.38 (d, J=3.52 Hz, 1H); LC-MS 395 (M+H). 65E: 1H NMR (400 MHz, CDCl3) δ ppm two rotomers: 0.93 (t, J=6.81 Hz, 3H) 1.12-1.33 (m, 15H) 2.48-2.58 (m, 1H) 3.35-4.12 (m, 6H) 5.67 and 5.88 (d, J=7.91 Hz, 1H) 7.08 (dd, J=7.47, 4.39 Hz, 1H) 7.53-7.65 (m, 1H) 8.36 (d, J=3.08 Hz, 1H). LC-MS 395 (M+H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[SH:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>[Cu].O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[S:20][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Fc1ccc(F)c(S)c1
Reactant: COc1ccc(Br)c(C=O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Sc2cc(F)ccc2F)c(C=O)c1
Temperature: 150 °C
Yield: 51.8 %

Procedure:
A mixture of 19.7 g of 2-bromo-5-methoxybenzaldehyde (of Example 9, reference above), 14.1 g of 2,5-difluorothiophenol (of Example 11, reference above), 14.0 g of potassium carbonate, 75 ml dimethylformamide and 2.1 g of copper catalyst is stirred and heated to 150° C. for 6 hours. It is then diluted with 150 ml of water and extracted with benzene. The extract is washed with water, dried with magnesium sulfate and evaporated. The residue is processed by distillation. There are obtained 13.3 g (52%) of 2-(2,5-difluorophenylthio)-5-methoxy-benzaldehyde boiling at 163°-165° C./40 Pa. The product is crystallized from cyclohexane and melts in a pure state at 67°-68° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[CH3:13][CH:14]([CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[CH3:15]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:21][CH:17]([CH2:18][CH2:19][CH3:20])[CH2:16][CH:14]([CH3:15])[CH3:13])=[O:9])=[CH:5][C:4]=1[CH3:12]
Reactant: CCCC(N)CC(C)C
Reactant: COc1ccc(C(=O)O)cc1C
Product: CCCC(CC(C)C)NC(=O)c1ccc(OC)c(C)c1
Yield: 45 %

Procedure:
Prepared in a similar manner as described in example 4 using 4-methoxy-3-methylbenzoic acid and 2-methyl-4-heptanamine (example 2a). Yield: 45%. 1H NMR (500 MHz, CDCl3): δ 0.93 (m, 9H); 1.39 (m, 5H); 1.53 (m, 1H); 1.67 (m, 1H); 2.24 (s, 3H); 3.86 (s, 3H); 4.23 (m, 1H); 5.64 (d, 1H); 6.82 (d, 1H); 7.54 (s, 1H); 7.61 (d, 1H). MS (278, M+H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10]CC#N.[C:14]([OH:17])(=[O:16])[CH3:15]>>[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:15][C:14]([OH:17])=[O:16]
Reactant: CC(=O)O
Reactant: N#CCCCc1ccccc1Br
Agent: Cl
Product: O=C(O)CCCc1ccccc1Br
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (7.7 mL, 97 mmol) in 100 mL dry THF is added to a solution of 3-(2-bromo-phenyl)-propan-1-ol (17.4 g, 80.9 mmol) and triethyl amine (14.7 g, 146 mmol) in 200 mL dry THF at 0° C. under an argon atmosphere. Water is added and the mixture is extracted with ethyl acetate. The organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo to give 23 g (97%) methanesulfonic acid 3-(2-bromo-phenyl)-propyl ester as an oil. Methanesulfonic acid 3-(2-bromo-phenyl)-propyl ester (23 g, 78 mmol) in 300 mL dry DMF is added to a suspension of potassium cyanide (15.3 g, 235 mmol) in dry DMF. The reaction mixture is stirred at 60° C. for 16 hours. Water is added and the mixture is extracted with ethyl acetate (3 times). The organic phase is washed with brine (twice), dried with MgSO4 and concentrated in vacuo. The residue is placed on a plug of silica gel and eluted with ethyl acetate/heptane (1:4) and concentrated in vacuo to give 16.0 g 4-(2-bromo-phenyl)-butyronitrile (91%) as an oil. 300 mL concentrated HCl is added to 4-(2-bromo-phenyl)-butyronitrile (16.0 g, 71 mmol) in 150 mL acetic acid. The reaction mixture is stirred at 60° C. for 16 hours. The reaction mixture concentrated in vacuo partly and is poured into water. The mixture is extracted with ethyl acetate (3 times). The organic phase is washed with brine (twice), dried with MgSO4 and concentrated in vacuo to give the title compound as a crystalline material.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.C(Cl)Cl.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:19]([F:27])[CH:18]=1>>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:24])=[O:25])=[C:19]([F:27])[CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: Nc1nccs1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1nccs1)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of 2-aminothiazole (4.51 g, 0.0450 mol) and pyridine (24.26 mL, 0.3000 mol) in methylene chloride (40 mL, 0.6 mol) at 0° C. was added portionwise 4-bromo-2-fluorobenzenesulfonyl chloride (8.2 g, 0.030 mol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc, washed with 1N HCl solution, H2O and brine. The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to give the crude product that was purified via automated flash chromatography (silica gel, 25% EtOAc in hexanes to 100% EtOAc) to give the product as a light brown solid (3.6 g, 36%).