Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([O:13][C:14]([C:16]1[CH:20]=[CH:19][NH:18][CH:17]=1)=[O:15])[CH3:12].[Sn](Cl)(Cl)(Cl)Cl.Cl>C1C=CC=CC=1>[CH2:11]([O:13][C:14]([C:16]1[CH:20]=[C:19]([C:4]([C:3]2[C:2]([Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=2)=[O:5])[NH:18][CH:17]=1)=[O:15])[CH3:12]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CCOC(=O)c1cc[nH]c1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)c1c[nH]c(C(=O)c2cccnc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A solution of 2-chloronicotinoyl chloride (493 mg, 2.8 mmol) in benzene (1 mL) was added to a mixture of 1H-pyrrole-3-carboxylic acid ethyl ester (390 mg, 2.8 mmol) in benzene (3 mL), followed by a dropwise addition of tin (IV) chloride (0.5 mL). The mixture was stirred at room temperature under nitrogen for overnight. The reaction was treated with 2N HCl and extracted with ethyl acetate. The combined ethyl acetate was washed, dried and concentrated to give 390 mg (50%) of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: Cl.C(O[C@H](C)C([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[CH:22]([CH3:24])[CH3:23])=O)C1C=CC=CC=1>C(O)C>[CH:22]([CH:14]1[CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13]1)([CH3:24])[CH3:23]
Reactant: CC(C)C1Cc2ccccc2N1C(=O)[C@@H](C)OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(C)C1Cc2ccccc2N1
Temperature: 120 °C
Yield: 66.9 %

Procedure:
5.6 ml of concentrated hydrochloric acid are added to a solution of 1.2 g of (R)-2-benzyloxy-1-(2-isopropyl-2,3-dihydroindol-1-yl)propan-1-one in 34 ml of absolute ethanol. The reaction mixture is microwave-heated at 120° C. for 1 hour, and is then cooled to ambient temperature and concentrated to dryness under reduced pressure. The residue is cooled in an ice bath and taken up in 200 ml of water, and then alkalinized with concentrated sodium hydroxide. The mixture is extracted with 2×150 ml of dichloromethane. The organic phases are combined, washed with 150 ml of water, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 70 g cartridge of 15-40 μm silica, elution being carried out with a 95/5 v/v cyclohexane/ethyl acetate mixture at a flow rate of 50 ml/min, and then on a 30 g cartridge of 15-40 μm silica, elution being carried out with pure cyclohexane and then with a 98/2 cyclohexane/ethyl acetate mixture, at a flow rate of 30 ml/min. 0.40 g of (−)-2-isopropylindoline is thus obtained in the form of a colorless oil, the characteristics of which are the following:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([N:15]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])=[CH:12][C:7]=2[N:6]=[C:5]1[NH:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1.[CH:37]1([CH:43]=O)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.[BH4-].C(OC1C=CC=CC=1C=O)C1C=CC=CC=1>CO.ClCCl>[CH:37]1([CH2:43][NH:1][CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[CH:10][C:11]([C:13]([N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:20][CH:21]([CH3:22])[CH3:23])=[O:14])=[CH:12][C:7]=3[N:6]=[C:5]2[NH:24][C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: COc1cc(Nc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCN)cc(OC)c1OC
Reactant: O=CC1CCCCC1
Agent: O=Cc1ccccc1OCc1ccccc1
Agent: [BH4-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Nc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCNCC2CCCCC2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
A solution of 1-(2-aminoethyl)-N,N-diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide (30 mg, 1 eq) and cyclohexanecarboxaldehyde (5 mg, 0.8 eq) in methanol (0.7 ml) is stirred at a temperature of approximately 20° C. for 4 hours. Borohydride resin (48 mg, 2.5 mmol/g, Amberlite®, IRA-400) is added and the mixture is stirred for 18 hours then dichloromethane (0.5 ml) and benzyloxybenzaldehyde Wang resin (37 mg, 3.22 mmol/g, Novabiochem) are added. After stirring overnight, the mixture is filtered and the filtrate is evaporated under reduced pressure in order to produce the expected compound in the form of a beige foam (18 mg, 65%).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].C(N(C(F)([F:26])C1C=CC=C(C)C=1)CC)C>CCCCCCC>[F:26][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: CCN(CC)C(F)(F)c1cccc(C)c1
Reactant: C=CCCCCCCCCCO
Solvent: CCCCCCC
Product: C=CCCCCCCCCCF
Yield: 91 %

Procedure:
In the same apparatus as that used in Example 14, 10-undecene-1-ol (10 mmole; 1.7 g) as the substrate and N,N-diethyl-α,α-difluoro(3-methyl)benzylamine (12 mmole; 2.56 g) as the fluorinating agent were added to heptane as the solvent. While the resultant mixture was stirred at the room temperature, the mixture was irradiated with microwave for 10 minutes. As the product, 1-fluoro-10-undecene was obtained at a yield of 91%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH3:15][O:16][CH2:17][CH2:18][CH2:19][NH2:20]>>[Cl:8][C:6]1[CH:7]=[C:2]([NH:20][CH2:19][CH2:18][CH2:17][O:16][CH3:15])[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=1
Reactant: COCCCN
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Product: COCCCNc1cc(Cl)nc(-c2ccccc2)n1

Procedure:
In the same manner, 4,6-dichloro-2-phenylpyrimidine is reacted with 3-methoxypropylamine to produce 4-chloro-6-(3-methoxypropylamino)-2-phenylpyrimidine, which is then reacted with p-chlorothiophenol to afford 4-(4-chlorophenylthio)-6-[(3-methoxypropyl)amino]-2-phenylpyrimidine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]2[C:15]([C:16]#[N:17])=[C:14]([CH3:18])[NH:13][C:12]([CH3:19])=[C:11]2[C:20]#[N:21])[CH:6]=[CH:7][C:8]=1F)#[N:2].O.[NH2:23][NH2:24]>C(O)CCC>[NH2:2][C:1]1[C:3]2[C:8](=[CH:7][CH:6]=[C:5]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH3:18])[NH:13][C:12]([CH3:19])=[C:11]3[C:20]#[N:21])[CH:4]=2)[NH:24][N:23]=1
Reactant: CC1=C(C#N)C(c2ccc(F)c(C#N)c2)C(C#N)=C(C)N1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: CC1=C(C#N)C(c2ccc3[nH]nc(N)c3c2)C(C#N)=C(C)N1
Yield: 56.5 %

Procedure:
A mixture of 4-(3-cyano-4-fluorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile (9.5 g, 34.14 mmol), from Synthetic Example 1, and hydrazine hydrate (10 g, 312 mmol) in n-butyl alcohol (75 mL) was kept at 80° C. for 5 hr. The mixture was cooled and concentrated. Sodium bicarbonate solution (sat.) was added to the residue, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to afford 4-(3-amino-1H-indazol-5-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile (5.6 g, 57.01%) as a pale yellow solid (Cpd. No. 82, Table 2). 1H-NMR (300 MHZ, DMSO-D6): δ=11.39 (br. s, 1H), 9.47 (br. s, 1H), 7.50 (m, 1H), 7.20 (d, 1H), 7.11 (dd, 1H), 5.34 (br. s, 2H), 4.34 (s, 1H), 2.01 (s, 6H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:12])[C@H:9](O)[CH3:10])[CH:5]=[CH:6][CH:7]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:44][C:45]([CH3:49])([CH3:48])[CH2:46][OH:47]>C(#N)C>[C:2]1([CH3:1])[CH:7]=[CH:6][CH:5]=[C:4]([C@:8]2([OH:12])[O:47][CH2:46][C:45]([CH3:49])([CH3:48])[NH:44][C@H:9]2[CH3:10])[CH:3]=1
Reactant: CC(C)(N)CO
Reactant: Cc1cccc(C(=O)[C@@H](C)O)c1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: Cc1cccc([C@]2(O)OCC(C)(C)N[C@H]2C)c1
Yield: 65.4 %

Procedure:
Compound 4e was synthesized by a procedure similar to that described for (2S,3S)-4a using (R)-1-(3-methylphenyl)-2-hydroxypropan-1-one (10e, 4.2 g, 0.026 mol), Proton sponge (6.5 g, 0.030 mol), triflic anhydride (4.60 mL, 282 mmol), and 2-amino-2-methyl-1-propanol (5.0 g, 0.056 mol) in acetonitrile (55 mL). After purification, 4.0 g (66%) of the free base 4e was isolated and converted to 3.6 g of the hemi-D-tartrate salt, which had 94% ee: mp 104-105° C.; [α]20D +11.9° (c 0.85, CH3OH); 1H NMR (methanol-d4) δ 7.43-7.38 (m, 2H), 7.28 (t, 1H, J=7.8 Hz), 7.21-7.18 (m, 1H), 4.33 (s, 1H), 4.20 (d, 1H, J=12.0 Hz), 3.52-3.45 (m, 2H), 2.38 (s, 3H), 1.61 (s, 3H), 1.36 (s, 3H), 1.06 (d, 3H, J=6.6 Hz); 13C NMR (methanol-d4) δ 179.0, 142.3, 139.4, 130.9, 129.5, 128.4, 125.0, 97.2, 75.3, 67.4, 55.2, 24.2, 21.9, 21.4, 14.4; LCMS (ESI) m/z 236.2 [(M-tartrate)+, M=C16H24NO5]; Anal. (C16H24NO5.0.75H2O) calcd: C, 59.33; H, 7.94; N, 4.32. found: C, 59.20; H, 7.88; N, 4.34.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH3:6])[OH:5])[CH3:2].C(N(CC)CC)C.C[Si](Cl)(C)C.[F:19][C:20]([F:26])([F:25])/[CH:21]=[CH:22]/[C:23]#[N:24]>O1CCCC1>[C:23]([CH2:22][CH:21]([P:4]([CH3:6])(=[O:5])[O:3][CH2:1][CH3:2])[C:20]([F:26])([F:25])[F:19])#[N:24]
Reactant: CCOP(C)O
Reactant: N#C/C=C/C(F)(F)F
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)C(CC#N)C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 2.16 g (20 mmol) of O-ethyl-P-methyl-phosphonous acid and 4.05 g (40 mmol) of triethylamine in 100 ml of dry tetrahydrofuran is stirred under an atmosphere of argon at 25°. To this solution are added at 25° 4.35 g (40 mmol) of trimethylsilyl chloride over a period of 10 minutes. A white precipitate is formed. The reaction mixture is stirred at 25° for additional 16 hours. Then, 2.42 g (20 mmol) of 4,4,4-trifluorocrotononitrile, dissolved in 20 ml of dry tetrahydrofuran, are added at 25° over a period of 10 minutes. The reaction mixture is refluxed for 40 hours, cooled to 25°, poured into ice-water and extracted with dichloromethane. The extracts are combined, washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure to dryness. The crude product is chromatographed on 200 g of silica gel with trichloromethane as eluent. The product-containing fractions are combined and evaporated to give ethyl P-(3-cyano-1,1,1-trifluoro-prop-2-yl)-P-methyl-phosphinate as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH3:30][S:31]SC>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([S:31][CH3:30])=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)cc12
Reactant: CSSC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1c(F)ccc2onc(OCCNC(=O)OC(C)(C)C)c12
Temperature: -70 °C
Yield: 92.3 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-5-fluoro-1,2-benzisoxazole (0.30 g) in tetrahydrofuran (20 ml) was added lithium diisopropylamide (1.50 ml, 1.5 M hexane solution) dropwise with stirring at -70° C. under nitrogen atmosphere, then after being stirred at the same temperature for 15 minutes dimethyldisulphide (0.21 g) was added. The reaction mixture was stirred for 15 minutes at -70° C. and then the temperature was raised to 0° C. The reaction mixture was poured into ice water (40 ml), extracted with ethyl acetate (twice each with 40 ml) and the combined extracts were dried over anhydrous magnesium sulphate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (9/1) as an eluent, to give the title compound (0.32 g, 94% yield) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[C:4]([N:6]1[CH2:12][C:11]2[S:13][CH:14]=[CH:15][C:10]=2[CH2:9][C:8]2[N:16]=[CH:17][CH:18]=[CH:19][C:7]1=2)=[O:5].[Cl-]>C(O)C>[Cl:1][C:2]1[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:3]=1[C:4]([N:6]1[CH2:12][C:11]2[S:13][CH:14]=[CH:15][C:10]=2[CH2:9][C:8]2[N:16]=[CH:17][CH:18]=[CH:19][C:7]1=2)=[O:5]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1Cc2sccc2Cc2ncccc21
Agent: [Cl-]
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3sccc3Cc3ncccc32)c(Cl)c1

Procedure:
As described for Reference Example 204 5-(2-chloro-4-nitrobenzoyl)-6,10-dihydro-5H-pyrido[3,2-b]thieno[3,2-e]azepine is reduced with stannus chloride (SnCl2) in ethanol to give the product as a solid.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.N=C=N.C1C=CC2N(O)N=NC=2C=1.[Cl:25][C:26]1[CH:27]=[C:28]([N:33]([CH2:45][CH2:46][CH2:47][N:48]2[CH2:55][CH:54]3[CH:50]([CH2:51][NH:52][CH2:53]3)[CH2:49]2)[C:34]([CH:36]2[CH2:41][CH2:40][N:39]([C:42](=[O:44])[CH3:43])[CH2:38][CH2:37]2)=[O:35])[CH:29]=[CH:30][C:31]=1[CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:52]1[CH2:53][CH:54]2[CH2:55][N:48]([CH2:47][CH2:46][CH2:45][N:33]([C:28]3[CH:29]=[CH:30][C:31]([CH3:32])=[C:26]([Cl:25])[CH:27]=3)[C:34]([CH:36]3[CH2:37][CH2:38][N:39]([C:42](=[O:44])[CH3:43])[CH2:40][CH2:41]3)=[O:35])[CH2:49][CH:50]2[CH2:51]1)=[O:6]
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CC3CNCC3C2)c2ccc(C)c(Cl)c2)CC1
Reactant: Cc1cccc(C(=O)O)c1Br
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(C(=O)N(CCCN2CC3CN(C(=O)c4cccc(C)c4Br)CC3C2)c2ccc(C)c(Cl)c2)CC1
Reaction time: 24 h

Procedure:
A mixture of 2-bromo-3-methyl-benzoic acid (62, 0.016 g, 0.075 mmol), resin-bound carbodiimide (0.078 g, 0.15 mmol) and HOBT (0.012 g, 0.085 mmol) in DCM:DMF (1 mL, 10:1) was shaken for 18 h. A solution of 42b (0.022 g, 0.05 mmol) and DIPEA (0.03 mL, 0.17 mmol) and DCM (1 mL) was added. Shaking was continued for 24 h, the resin filtered and washed with DMF (1 mL) and twice with DCM (1 mL). The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC to afford II-244: ms (ES+) m/z 644 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=1[NH2:19]>O1CCOCC1>[Cl:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Solvent: C1COCCO1
Product: COC(=O)c1cnc(Nc2ccc(Cl)cc2Cl)nc1C(F)(F)F

Procedure:
To a solution of methyl 2-chloro-4-trifluoromethylpyrimidine-5-carboxylate (70 g, ex Maybridge 22 g, ex Fluorochem 48 g) in 1,4-dioxan (100 n−1) was added 2,4-dichloroaniline (142 g) and the solution stirred under reflux for 10.5 h. 1,4-Dioxan was partially removed (approx 50 ml) under reduced pressure and 2N HCl (800 ml) added. The mixture was stirred with overhead stirring for 3 h and the resulting solid filtered onto a sinter. The solid was washed with 2N HCl (2×300 ml) and water (4×400 ml) then dried over sodium hydroxide in vacuo at 50° C. to afford methyl 2-(2,4-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylate. The solid contained approximately 5% 2,4-dichloroaniline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17](N)=[C:16](Cl)[N:15]=[C:14](C(C)C)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:23]([NH2:25])[CH3:24]>C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:25][CH2:23][CH3:24])[N:15]=[C:14]([NH:1][CH:2]([CH3:7])[CH3:3])[N:13]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCN
Reactant: CC(C)c1nc(Cl)c(N)c(NS(=O)(=O)c2ccc(N)cc2)n1
Solvent: CCO
Product: CCNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(NC(C)C)n1
Temperature: 130 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
0.1 g (0.000293 mol) of 4-amino-N-(6-chloro-2-isopropyl-amino-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 20 ml of ethanol, treated with 1.93 ml (0.0293 mol) of ethylamine and stirred in an autoclave at 130° C. for 4 hours. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 min. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.044 g (43%) of 4-amino-N-(6-ethylamino-2-isopropylamino-pyrimidin-4-yl)-benzenesulfonamide as white crystals; m.p.: 266-267° C.
Reaction SMILES: Br[C:2]1[C:3]([CH2:19][CH:20]([CH3:22])[CH3:21])=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]([CH:12]([F:14])[F:13])=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[S-2:23].[Li+].[Li+]>CN(C=O)C.Cl>[F:13][CH:12]([F:14])[C:5]1[C:4]([C:15]([O:17][CH3:18])=[O:16])=[C:3]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:2]([SH:23])=[C:7]([C:8]([F:11])([F:10])[F:9])[N:6]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(Br)c1CC(C)C
Reactant: [S-2]
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(S)c1CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a stirred solution of 10.11 g (0.026 mol) of methyl 5-bromo-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (example 122 of U.S. Pat. No. 5,019,153) in 75 mL dry DMF was added 1.42 g (0.031 mol) of lithium sulfide in one portion and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 150 mL of 10% HCl solution and extracted with ether (3×100 mL). The combined extracts were washed with water, dried (MgSO4) and evaporated. The residue was purified by kugelrohr distillation (oven temperature 100-110° C., 1.5 torr) to give 7.35 g (83%) of product as a yellow-green oil:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:7]=1[CH2:23]Br)=[O:5])[CH3:2].[CH2:25]([O:27][C:28](=[O:38])[CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH3:26]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[N:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C:7]=1[CH2:23][N:30]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:38])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Br)c(C(C)(C)C)n(-c2ccc(F)cc2)c1CBr
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Br)c(C(C)(C)C)n1-c1ccc(F)cc1)C(=O)OC(C)(C)C

Procedure:
Prepared in analogy to that of Example 1(c) from 4-bromo-2-bromomethyl-5-tert-butyl-1-(4-fluoro-phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester and tert-butoxycarbonylamino-acetic acid ethyl ester. The title compound, ESI MS (m/z): 605 (M+Na+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15](=[N:17][OH:18])[CH3:16])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:19][C:20](OC(C)=O)=[O:21]>>[C:20]([O:18]/[N:17]=[C:15](/[C:10]1[CH:9]=[C:8]([C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:6]2)[CH:13]=[CH:12][C:11]=1[OH:14])\[CH3:16])(=[O:21])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1(c2ccc(O)c(C(C)=NO)c2)CC1
Product: COC(=O)C1(c2ccc(O)c(/C(C)=N/OC(C)=O)c2)CC1
Yield: 99 %

Procedure:
The solution of 1-[4-hydroxy-3-(1-hydroxyimino-ethyl)-phenyl]-cyclopropanecarboxylic methyl ester (10.0 g, 40.1 mmol) in Ac2O (250 mL) was heated at 45° C. for 4 h. The Ac2O was removed by evaporation under vacuum before water (100 mL) and EtOAc (100 mL) were added. The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give (E)-methyl 1-(3-(1-(acetoxyimino)ethyl)-4-hydroxyphenyl)cyclopropanecarboxylate (10.5 g, 99%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][CH:4]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]>CO.[OH-].[OH-].[Pd+2]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH:4]([CH2:3][CH:2]([CH3:1])[CH3:25])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:11][C:12]=1[O:19][CH2:20][C:21]([F:22])([F:23])[F:24]
Reactant: CCOC(=O)C(CC(C)C)c1ccc([N+](=O)[O-])c(OCC(F)(F)F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C(CC(C)C)c1ccc(N)c(OCC(F)(F)F)c1
Reaction time: 6 h
Yield: 87.2 %

Procedure:
To a stirred solution of ethyl 4-methyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)pentanoate (1.5 g), in dry MeOH (100 mL), Pd(OH)2 (500 mg) was added and the mixture reduced under an atmosphere of H2 for 6 h at room temperature. The mixture was filtered through a pad of Celite™ washing with MeOH. The combined filtrates were concentrated under reduced pressure to give ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (1.2 g) as a thick liquid.
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].C([NH:12][C:13]1[CH:29]=[CH:28][C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[C:22]([CH:24]=2)N)=[CH:15][CH:14]=1)(=O)C>CCO.O>[N+:25]([C:21]1[CH:22]=[CH:24][C:18]([O:17][C:16]2[CH:28]=[CH:29][C:13]([NH2:12])=[CH:14][CH:15]=2)=[CH:19][CH:20]=1)([O-:27])=[O:26]
Reactant: CC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])c(N)c2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
Na2S2O4 (28.2 g, 160 mmol) was added to a solution of 5-(4-Acetamidophenoxy)-2-nitroaniline (Intermediate 1) (13.7 g, 48 mmol) in EtOH (600 ml) and H2O (150 ml). The yellow mixture was refluxed with vigorous stirring until the color disappeared. After cooling, the mixture was washed with brine and the product was extracted with AcOEt. The AcOEt layer was dried over MgSO4, filtered and evaporated to give intermediate 2 as a brown film (10.2 g, 83%): MS m/e 258 (M+1).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]2[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][N:24]2[C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)=[O:37])[CH:16]=1>CO>[ClH:46].[ClH:1].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]2[CH2:28][NH:27][CH2:26][CH2:25][N:24]2[C:36]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=2)=[O:37])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccc(Cl)cc2)C(COc2cccnc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CO
Product: O=C(OCc1ccc(Cl)cc1)N1CCNCC1COc1cccnc1
Reaction time: 12 h
Yield: 98 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of 1-(4-chlorobenzyl) 4-tert-butyl 2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate TFA salt (129 mg, 0.224 mmol) in MeOH (1 mL). After 12 h, the reaction mixture was concentrated under reduced pressure, yielding 95.7 mg (98%) of the desired product as a white solid. LC-MS: RT=4.74 min, [M+H]+=362.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[CH3:9][O-:10].[Na+].CO>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:10][CH3:9])[CH:7]=1
Reactant: C[O-]
Reactant: Brc1cncc(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cncc(Br)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A solution of 3,5-dibromopyridine (134a, 20 g, 84.4 mmol) in DMF (200 mL) was stirred at RT under nitrogen atmosphere and then 21.3 mL of sodium methoxide (25% by wt. in methanol (92.8 mmol) was added slowly. The reaction mixture was stirred overnight at 70° C. under N2. The reaction was cooled to RT and quenched with water (200 mL) and extracted with Et2O (2×200 mL). The combined organic extracts was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude 3-bromo-5-methoxypyridine (134b 14.8 g, 93% theory) afforded a colorless oil after purification by flash chromatography on silica gel (EtOAc:hexane 1:10).