Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])N.[F:5][C:6]1[CH:36]=[CH:35][C:9]([C:10]([NH:12][C@@H:13]2[C:19]3[CH:20]=[C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH:30]5[CH2:33][O:32][CH2:31]5)[CH2:26][CH2:25]4)[CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][C@H:14]2[OH:34])=[O:11])=[CH:8][CH:7]=1.[CH3:37][NH:38][C:39](=O)[O-:40]>ClCCl.CO>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][C@H:13]2[C:19]3[CH:20]=[C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH:30]5[CH2:33][O:32][CH2:31]5)[CH2:26][CH2:25]4)[CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][C@@H:14]2[O:34][C:39](=[O:40])[NH:38][CH3:37])=[O:11])=[CH:35][CH:36]=1
Reactant: O=C(N[C@@H]1c2cc(N3CCN(C4COC4)CC3)ccc2CCC[C@H]1O)c1ccc(F)cc1
Reactant: CNC(=O)[O-]
Agent: NC(=O)[O-]
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)O[C@H]1CCCc2ccc(N3CCN(C4COC4)CC3)cc2[C@@H]1NC(=O)c1ccc(F)cc1

Procedure:
Prepare the racemic carbamate using racemic-trans-4-fluoro-N-[8-hydroxy-2-[4-(oxetan-3-yl)piperazin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-9-yl]benzamide by essentially following the procedure for Example 1, above. LC-ES/MS m/z 497 [M+H]+. Dissolve racemic-trans-9-[(4-fluorobenzoyl)amino]-2-[4-(oxetan-3-yl)piperazin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-8-yl]N-methylcarbamate (1.03 g) in dichloromethane (8 mL) and methanol (3 mL). Separate the enantiomers in 300 μL portions by SFC on a CHIRALPAK® AD-H column (2.1×25 cm, 5 μm). Mobile phase: 30% isopropanol with 0.2% isopropylamine/carbon dioxide. Flow rate: 70 mL/min. Detection: 225 nm. Obtain the title compound as isomer 1 (333 mg, 99% ee) and the 8R, 9R enantiomer as isomer 2 (359 mg, 97.5% ee). Determine enantiomeric excess by SFC on a CHIRALPAK® AD-H (4.6×150 mm, 5 μm) column using 30% isopropanol with 0.2% isopropylamine/carbon dioxide. Flow rate: 5 mL/min. Detection: 225 nm. Isomer 1 (title compound) TR=1.76 min. Isomer 2 TR=2.30 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[NH:9][C:6]2=[CH:7][N:8]=1.S(=O)(=O)(O)O.[CH3:20]O>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH3:20])=[O:13])[NH:9][C:6]2=[CH:7][N:8]=1
Reactant: CO
Reactant: COc1cc2cc(C(=O)O)[nH]c2cn1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2cc(OC)ncc2[nH]1
Reaction time: 8 h

Procedure:
To 5-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (1 g, 5.20 mmol) in methanol (100 ml) was added sulfuric acid (0.014 ml, 0.260 mmol). The resulting solution was heated to reflux and stirred at this temperature overnight. Then extra sulfuric acid (0.277 ml, 5.20 mmol) was added and heated at reflux for five days. The heating was stopped and the reaction mixture was concentrated to a smaller volume. The resulting suspension was diluted with ethyl acetate and washed with an aqueous saturated sodium hydrogen carbonate solution. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to give methyl 5-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (910 mg).
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.Cl.[NH2:13]O.[H-].[Na+].[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C=O.O1CCCC1>[Si:17]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[C:2]#[N:13])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: COc1ccc(C=O)cc1O
Reactant: NO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
A solution of iso-vanillin (10.0 g) in dimethylformamide (100 mL) was treated with hydroxylamine hydrochloride (9.14 g) and heated under reflux for 1 hour. The dimethylformamide was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The aqueous fraction was exhaustively extracted with ethyl acetate and the combined organic fractions were dried over sodium sulfate and concentrated in vacuo to afford a brown solid, which was dissolved in tetrahydrofuran (200 mL). After treatment with sodium hydride (2.8 g), the reaction mixture was stirred at room temperature for 1 hour. A solution of tert-butyldimethylsilyl chloride (10.9 g) in tetrahydrofuran (50 mL) was added and the mixture stirred under nitrogen overnight. The mixture was partitioned between water and diethyl ether. The organic extract was dried over sodium sulfate, concentrated in vacuo and subjected to flash column chromatography on silica eluting with a mixture of pentane and dichloromethane (1:3, v/v) to give the title compound (14.7 g) as a colourless oil which was used immediately in the next reaction. 1H NMR [(CD3)2SO]: δ 7.30 (1H, d, J=8.0 Hz); 7.11 (1H, s); 7.01 (1H, s); 3.70 (3H, s); 0.81 (9H, s); 0.01 (6H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=C([CH:8]=[CH:9][C:10]=1[I:11])C(O)=O.CI.[C:14](=O)([O-])[O-].[K+].[K+].[C:20]([O:23][CH2:24]C)(=[O:22])[CH3:21]>CN(C=O)C>[I:11][C:10]1[CH:9]=[CH:8][C:21]([C:20]([O:23][CH3:24])=[O:22])=[CH:3][C:2]=1[O:1][CH3:14]
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Reactant: O=C(O)c1ccc(I)c(O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(I)c(OC)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
14.9 g (56.4 mmol) of 3-hydroxy-4-iodobenzoic acid was dissolved in 200 ml of DMF. 17.5 ml (282 mmol) of methyl iodide and 39 g (282 mmol) of potassium carbonate was added to the obtained solution, and they were stirred at 50° C. for 3 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[CH:31]=[CH:30][N:29](S(C4C=CC(C)=CC=4)(=O)=O)[C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:12]=2)[CH2:3]1.[OH-].[K+]>CO>[N:20]1([C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:11]3[N:12]=[C:7]([N:4]4[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]4)[C:8]4[CH:31]=[CH:30][NH:29][C:9]=4[N:10]=3)=[CH:15][CH:16]=2)[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]1.[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[CH:31]=[CH:30][NH:29][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:12]=2)[CH2:3]1
Reactant: CC(=O)N1CCN(c2ccc(Nc3nc(N4CC[C@H](O)C4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N4CC[C@H](O)C4)c4cc[nH]c4n3)cc2)CC1
Product: O[C@H]1CCN(c2nc(Nc3ccc(N4CCNCC4)cc3)nc3[nH]ccc23)C1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-1-(4-(4-(4-(3-hydroxypyrrolidin-1-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (80 mg, 0.14 mmol) in MeOH (3 mL), aq. 1N KOH (1 mL) was added. It was stirred at 60° C. for 4 h. After being concentrated in vacuo, the residue was acidified with HOAc (1 mL). The mixture was then purified by HPLC to give (S)-1-(2-(4-(piperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ol (5 mg) (MS 380.5 (M+H)) and (S)-1-(4-(4-(4-(3-hydroxypyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (20 mg) (MS 422.5 (M+H)).
Reaction SMILES: [C:1]([C:3]1[C:4]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])=[CH:5][S:6][CH:7]=1)#[N:2].C(OCC)(=O)C.[ClH:40]>C(OCC)(=O)C.CC(O)C>[ClH:40].[F:23][C:14]1[C:13]([CH2:24][NH:25][CH3:26])=[CH:12][N:11]([S:8]([C:4]2[C:3]([C:1]#[N:2])=[CH:7][S:6][CH:5]=2)(=[O:9])=[O:10])[C:15]=1[C:16]1[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cscc2C#N)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cscc2C#N)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of tert-butyl {[1-[(4-cyano-3-thienyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (181 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound as a white solid (yield 116 mg, 74%).
Reaction SMILES: Cl[C:2]1[CH:6]([N:7]2[C:11](=[O:12])[C:10]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]3[C:8]2=[O:17])[CH2:5][O:4][N:3]=1.[C:18]1(C)[C:23]([SH:24])=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:26](O)C>C(N(CC)CC)C>[C:20]1([CH3:26])[CH:19]=[CH:18][C:23]([S:24][C:2]2[CH:6]([N:7]3[C:11](=[O:12])[C:10]4=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]4[C:8]3=[O:17])[CH2:5][O:4][N:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccccc1S
Reactant: O=C1c2ccccc2C(=O)N1C1CON=C1Cl
Reactant: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(SC2=NOCC2N2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Chloro-4-phthalimido-4,5-dihydroisoxazole (2.0 g, 8 mmol) was dissolved in 50 ml of ethanol (3A grade) and cooled to 0°-5° C. on ice bath. A solution of thiocresol (1.0 g, 8 mmol) in 30 ml of triethylamine was added to the first solution. The reaction mixture was stirred at room temperature for 4 hours. The reaction product was purified by flash chromatography on silica gel (230-400 mesh), eluted with 2:1 petroleum ether/ethyl acetate and collected in 20 ml fractions. Unreacted thiocresol eluted in fractions 2-6, and the reaction product 3-(p-tolylthio)-4-phthalimido-4,5-dihydroisoxazole (1.65 g, 60.95%) was eluted in fractions 8-32.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH2:5][CH3:6])[CH2:3][CH3:4].C(O)C>[Rh].C(O)(=O)C>[CH3:1][C:2]([CH:7]1[CH2:8][CH2:9][CH:10]([OH:13])[CH2:11][CH2:12]1)([CH2:5][CH3:6])[CH2:3][CH3:4]
Reactant: CCC(C)(CC)c1ccc(O)cc1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CCO
Product: CCC(C)(CC)C1CCC(O)CC1
Yield: 93 %

Procedure:
A mixture of the 4-(3-methylpent-3-yl)phenol (365 g, 2.05 mol), ethanol (600 g), acetic acid (5.0 g) and 5% rhodium on carbon (8.0 g) was hydrogenated at 100 psi and 60° C. until the hydrogen absorption essentially ceased. The reaction mixture was filtered to remove the catalyst and the solvent was removed on a rotary evaporator. The resulting oil was washed with 10% sodium bicarbonate (200 ml) and then with water (200 ml portions) until a neutral pH (7) was indicated. Distillation of the crude oil under vacuum gave the desired 4-(3-methylpent-3-yl)cyclohexanol: 350 g, 93% yield; bp 110°-115° C. (2.0 mm); mol wt 184 (ms); nmr, 0.4-0.9 (9H, methyls), 1.0-1.5 (14H, m, CH2), 2.39 (1H, s, hydroxyl), 4.0 (1H, m, Hα to oxygen); ir, 3350, 2980, 2950, 2890, 1455, 1385, 1075, 1046, 960 cm-1.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(OP([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(OCC)=O)C>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH2:1][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:3]=1
Reactant: O=Cc1cccnc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Product: CCOC(=O)CCc1cccnc1

Procedure:
The procedure of Synthetic Example 4 was repeated using nicotinaldehyde and ethyl diethylphosphonoacetate to obtain ethyl 3-(pyridin-3-yl)propionate.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[C:8]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Cl>C1C=CC=CC=1>[C:10]([CH:9]([CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([F:17])[CH:19]=1)[C:8]([O:14][CH2:15][CH3:16])=[O:13])(=[O:11])[CH3:12]
Reactant: CCOC(=O)CC(C)=O
Reactant: Fc1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc(F)c1)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 500 mL of 10% dimethylformamide in benzene was added 58.6% NaH (41 g, 1.0 mol) cooled in an ice bath was added ethyl acetoacetate (130 g, 1.0 mol) was added. The reaction was stirred at room temperature for 30 minutes, and m-fluorobenzyl chloride (145 g, 1.0 mol) was added. The reaction was heated to reflux for 3 hours and gave an NaCl precipitate which was then removed by filtration. The filtrated was poured into H2O, acidified with concentrated HCl and was extracted with a mixture of ether and benzene. The organic layer was washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by distillation (112°-119° C./25 mmHg) to give compound A (133 g, 56%).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH2:19])=[S:18])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br.[C:21]([NH:24][C:25]1(NC2C=C(C=CC=2)C(O)=O)[NH:29][C:28]([CH3:35])(C2SC=NC=2)[CH2:27][S:26]1)(=[O:23])[CH3:22].[CH3:46][CH2:47]O>>[CH3:35][C:28]1[N:29]=[C:25]([NH:24][C:21](=[O:23])[CH3:22])[S:26][C:27]=1[C:46]1[N:19]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([S:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)(=[O:8])=[O:9])=[CH:15][CH:14]=2)[S:18][CH:47]=1
Reactant: NC(=S)Nc1ccc(S(=O)(=O)N2CCOCC2)cc1
Reactant: CCO
Reactant: CC(=O)NC1(Nc2cccc(C(=O)O)c2)NC(C)(c2cncs2)CS1
Agent: Br
Product: CC(=O)Nc1nc(C)c(-c2csc(Nc3ccc(S(=O)(=O)N4CCOCC4)cc3)n2)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
According to the general procedure 1, N-[4-(morpholin-4-ylsulfonyl)phenyl]thiourea (prepared from [4-(morpholin-4-ylsulfonyl)phenyl]amine (Maybridge), following procedure D) is added to a solution of N-[5-(bromoacetyl)-4-methyl-1,3-thiazol-2-yl]acetamide (Intermediate 1) in EtOH. The mixture is stirred 5 hours at RT. The solvents are evaporated and the desired product is purified by crystallization Compound (112) is isolated as a beige solid (24.82 mg; 19%). M+ (ESI): 480. HPLC, Rt: 8.55 min (purity: 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([N:17]1C=CN=C1)([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[S:11]>C(Cl)(Cl)Cl>[NH:1]=[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]1[NH:17][C:10]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[S:11]
Reactant: Cc1cc(C)nc(N)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)n(NC(=S)n2ccnc2)c(=N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
An adaptation of the method described in WO 96/01826 was used. To a solution of ethyl O-mesitylsulfonylacetohydroxamate 7 (1.7 g, 6.0 mmol) in 1,4-dioxane (10 mL) cooled in an ice bath (freezes at 8-9° C.) was added 70% perchloric acid (7.5 mL) dropwise over 15 minutes, maintaining internal temperature below 15° C. The mixture was then diluted with ice water (100 mL) to precipitate the product O-(mesitylsulfonyl)hydroxylamine 8 which was filtered off, washed thoroughly with water, and immediately dissolved in chloroform (10 mL) while still wet (CAUTION! 8 is explosive when dry!). The organic layer was separated and was passed through a plug of Na2SO4 in a fritted syringe to remove water. The so obtained solution of O-(mesitylsulfonyl)hydroxylamine 8 was added dropwise to a solution of 2-amino-4,6-dimethylpyridine 9 (0.611 g, 5.00 mmol) in chloroform (10 mL) cooled in an ice bath. The mixture was then warmed to room temperature and was stirred for 2 hours to effect conversion to intermediate 10. Into the reaction mixture was then added 1,1′-thiocarbonyldiimidazole 11 (1.16 g, 6.5 mmol) and the resulting mixture was stirred at 40° C. overnight. Volatiles were evaporated and the residue was chromatographed on silica gel (gradient elution with heptane:ethyl acetate 100:0→0:100) to yield imidazole-1-carbothioic acid (2-imino-4,6-dimethyl-2H-pyridin-1-yl)-amide 12 as an off-white solid (0.50 g, 40%) containing a minor amount of residual imidazole. 1H NMR (500 MHz, DMSO-d6): δ7.88 (s, 1H), 7.64 (s, 1H), 7.42 (br s, 2H), 6.93 (s, 1H), 6.69 (s, 1H), 6.67 (s, 1H), 2.28 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.[CH3:15][N:16]1[CH:20]2[CH2:21][C:22]([CH2:24][CH:17]1[CH2:18][CH2:19]2)=[O:23].[OH-].[Na+]>C1COCC1>[Cl:9][C:4]1[CH:3]=[C:2]([C:22]2([OH:23])[CH2:21][CH:20]3[N:16]([CH3:15])[CH:17]([CH2:18][CH2:19]3)[CH2:24]2)[CH:7]=[CH:6][C:5]=1[Cl:8]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: CN1C2CCC1CC(=O)C2
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1C2CCC1CC(O)(c1ccc(Cl)c(Cl)c1)C2
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 28 %

Procedure:
To 4.0 mL (7.04 g, 31.18 mmol) 4-bromo-1,2-dichloro-benzene in 100 mL THF at −78° C. is added 12.47 mL of a 2.5 M solution of n-BuLi in hexanes in drops over 5 min. After stirring at −78° C. for 45 min, 4.34 g (31.18 mmol) tropinone is added as a solid. The resulting mixture is warmed to 23° C. and stirred for 18 h. After pouring into 2.5 N NaOH, the reaction mixture is extracted with 2×100 mL EtOAc, the organics are combined and washed with 1×100 mL H2O, 1×100 mL brine, dried over MgSO4, filtered and evaporated to an off-white solid. Flash chromatography on SiO2 gel, eluting with CHCl3/MeOH (20/1 to 5/1), gives 2.58 g (9.02 mmol, a 28% yield) of the title compound as a white solid. mp: 153-154° C.; MS (ES) m/z 287 (MH)+.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([NH2:27])=O)[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:18][CH:19]1[CH2:20][CH2:21][CH:22]([C:25]#[N:27])[CH2:23][CH2:24]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OC1CCC(C(N)=O)CC1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OC1CCC(C#N)CC1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6.42 g of 4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxamide and 2.39 ml of dimethylsulfoxide in 90 ml of methylene chloride was added a solution of 2.06 ml of oxalyl chloride in 10 ml of methylene chloride at −78° C., followed by stirring the reaction mixture at −78° C. for 15 minutes. To the reaction mixture was added 7.05 ml of triethylamine at −78° C., followed by stirring the reaction mixture at −78° C. for 30 minutes and then stirring at room temperature for 1.5 hours. The reaction mixture was washed with water and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The obtained residue was purified by a silica gel column chromatography (eluent: hexane to hexane/ethyl acetate=4/1) to give the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[N:11]([CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([C:22]#[N:23])[C:16]=2[CH3:24])O)[CH2:10][CH2:9][N:8]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:7]1)(=[O:3])[CH3:2].S(Cl)([Cl:34])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([S:4][CH2:5][C@H:6]1[N:11]([CH2:12][CH:13]([Cl:34])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([C:22]#[N:23])[C:16]=2[CH3:24])[CH2:10][CH2:9][N:8]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(O)c1ccc(F)c(C#N)c1C
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(Cl)c1ccc(F)c(C#N)c1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of (3S)-tert-butyl 3-(acetylthiomethyl)-4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)piperazine-1-carboxylate (30.8 mg, 0.0680 mmol) in toluene (0.62 mL) was added thionyl chloride (14.9 μL, 0.205 mmol). The mixture was cooled with an ice bath and then pyridine (22.1 μL, 0.273 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 20 min, and then allowed to warm to room temperature over an hour and finally heated at 70° C. for 30 min. The reaction mixture was concentrated and the residue was diluted with ethyl acetate, washed with a minimum amount of saturated sodium bicarbonate aqueous solution, and then brine. The organic layer was separated, filtered through a pad of anhydrous sodium sulfate and concentrated. Used directly in the next step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2SC(NC3C=CC(O)=CC=3)=N[CH:7]=2)=[CH:2]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH2:30])=[S:29])=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1.NC(N)=S.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]2[S:29][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[CH:7][N:30]=2)=[C:23]([C:31]([F:34])([F:32])[F:33])[CH:22]=1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Reactant: COc1ccc(NC(N)=S)c(C(F)(F)F)c1
Agent: NC(N)=S
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1
Temperature: 50 °C

Procedure:
The title compound is prepared as described in Example 12 (Procedure B) for 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol but starting from (4-methoxy-2-trifluoromethyl-phenyl)-thiourea. After addition of the thiourea, the reaction mixture is heated to 50° C. for 30 min. The mixture is heated to 70° C. for 16 h, after addition of DIEA. The title compound: ES-MS: 357.0 [M+H]+; single peak at tR=4.36 min (System 2); Rf=0.56 (CH2Cl2/MeOH, 95/5).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([NH:7][CH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([N:42]([CH3:44])[CH3:43])[C:15]2[CH2:27][C@@H:26]3[C:21](=[C:22]([OH:41])[C@:23]4([OH:40])[C:31](=[O:32])[C:30]([C:33]([NH2:35])=[O:34])=[C:29]([OH:36])[C@@H:28]([N:37]([CH3:39])[CH3:38])[C@@H:24]4[CH2:25]3)[C:19](=[O:20])[C:16]=2[C:17]=1[OH:18])=[O:10])([CH3:6])[CH3:5].C(Cl)[Cl:46]>>[CH3:6][C:4]([NH:7][CH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([N:42]([CH3:44])[CH3:43])[C:15]2[CH2:27][C@@H:26]3[C:21](=[C:19]([OH:20])[C:16]=2[C:17]=1[OH:18])[C:22](=[O:41])[C@@:23]1([OH:40])[C@H:24]([C@H:28]([N:37]([CH3:38])[CH3:39])[C:29]([C:30]([C:33]([NH2:35])=[O:34])=[C:31]1[OH:32])=[O:36])[CH2:25]3)=[O:10])([CH3:3])[CH3:5].[ClH:46]
Reactant: CN(C)c1cc(NC(=O)CNC(C)(C)C)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)c1cc(NC(=O)CNC(C)(C)C)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]3(O)C(=O)C1=C2O
Product: Cl

Procedure:
The collected main pool was transferred into a 2 L Schmizo double coated reactor before, 488 mL methylene chloride were added. A pH of 8.0±0.1 was adjusted by the addition of 10 mL 20% aqueous sodium hydroxide while vigorously stirring. After stirring for 10 minutes the two phases were separated. The aqueous phase was washed two times with 488 mL methylene chloride, whereas the pH was held at 8.0±0.1 by the addition of either 0.1 M sodium hydroxide or 0.2 M hydrochloric acid. The obtained aqueous phase was thrown away. The collected methylene chloride phases were filtered over a fluted filter before the volume was reduced to 500 ml on the rotavapor (50-55° C., 500 mbar). Then 500 ml acetonitrile were added and the solution was again reduced to a volume of 230 ml. The solution is transferred into a 2 l Schmizo double coated reactor and 845 ml acetonitrile are added to obtain a total volume of 1075 ml. The solution was adjusted to a methylene chloride amount of 5% by the addition of approximately 20 ml methylene chloride. 0.2 g Tigecycline dihydrochloride (e.g. obtained from example 1) were added as seed crystals and Tigecycline crystallized at room temperature before 7.8 ml 5 M hydrochloric acid in 50 ml acetonitrile were added over a period of 15 to 20 minutes. The suspension was stirred for 16 hours at 20 to 25° C. whereas a change in color from yellow to orange was observed. To complete the crystallization the suspension was further stirred for 1 hour at 0 to 5° C. The solid was filtered off, washed with 80 ml of cold acetonitrile and dried under vacuum at room temperature for 16 hours to obtain 14 g of crystalline Tigecycline hydrochloride form C.