Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:13]=[C:14]([CH:38]=[CH:39][CH:40]=1)[CH2:15][C@H:16]1[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1>>[N:2]1([CH2:7][C:8]([N:19]2[CH2:20][C@H:16]([CH2:15][C:14]3[CH:38]=[CH:39][CH:40]=[C:12]([F:11])[CH:13]=3)[CH2:17][C@H:18]2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(F)c2)CN1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(F)c2)CN1C(=O)Cn1cncn1
Yield: 31 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(3-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 51, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(3-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (59 mg, 31%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.00 (s, 1H), 8.42 (s, 1H), 7.95 (s, 1H), 7.58-7.52 (m, 2H), 7.40-7.31 (m, 1H), 7.25-6.92 (m, 10H), 5.24 (q, 2H), 4.55-4.48 (m, 1H), 3.89-3.76 (m, 1H), 2.84-2.66 (m, 3H), 2.03-1.90 (m, 2H). MS (EI) for C28H25F2N5O3. found 517.9 (MH+).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C([O-])([O-])=O.[Na+].[Na+].[F:21][C:22]1[CH:23]=[C:24]([C@H:28]2[NH:33][C:32](=O)[CH2:31][O:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>C1COCC1>[F:21][C:22]1[CH:23]=[C:24]([C@H:28]2[NH:33][C:32](=[S:2])[CH2:31][O:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1
Reactant: O=C1COC[C@@H](c2cccc(F)c2)N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cccc([C@@H]2COCC(=S)N2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
To a stirred room temperature suspension of P4S10 (6.0 g, 13.4 mmol) and Na2CO3 (1.42 g, 13.4 mmol) in THF (40 mL) was slowly added a solution of (R)-5-(3-fluoro-phenyl)-morpholin-3-one (2.16 g, 11.1 mmol) in THF (30 mL). The mixture was stirred at room temperature for two hours, and then quenched by addition of 10% aqueous Na3PO4 (50 mL). The mixture was stirred another five minutes and then extracted with a 1:1: mixture of ethyl acetate and diethyl ether. The organic layer was separated, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel using a 15-30% ethyl acetate/hexanes solvent gradient to give 1.84 g (78%) of (R)-5-(3-fluoro-phenyl)-morpholine-3-thione as a white solid, MP=124-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:33])[NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16](=[C:22]3[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:23]3=[O:32])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=2)=[CH:4][CH:3]=1.[CH2:34](O)[CH3:35].O1CCOCC1.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:33])[NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16](=[C:22]3[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([O:31][CH2:34][CH3:35])=[O:30])[C:23]3=[O:32])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=S)Nc2ccc(Cl)cc2)n1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CN1C(=O)C(=C(C(=O)OCC)c2csc(NC(=S)Nc3ccc(Cl)cc3)n2)SC1=S
Reaction time: 108 h

Procedure:
A mixture comprising 4.8 g of 5-{1-[2-(3-p-chloro-phenylthioureido)thiazol-4-yl]-1-ethoxycarbonylmethylene}-rhodanine-3-acetic acid, 10 g of ethanol and 50 ml of a 4N dioxane solution of hydrogen chloride was left to stand at room temperature for 4.5 days. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, and was then dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was recrystallized from a circa 1:1 by volume mixture of hexane and ethyl acetate. The resulting product was an orange powder having the following physical properties.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([Cl:12])[N:6]=1.CS(C)=O.[CH2:17]([N:19]([CH2:24][CH3:25])[C:20](=[O:23])[CH2:21]Cl)[CH3:18]>CO>[CH2:17]([N:19]([CH2:24][CH3:25])[C:20](=[O:23])[CH2:21][O:11][C:10]1[C:5]([Cl:4])=[N:6][C:7]([Cl:12])=[CH:8][CH:9]=1)[CH3:18]
Reactant: CCN(CC)C(=O)CCl
Reactant: Oc1ccc(Cl)nc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: CCN(CC)C(=O)COc1ccc(Cl)nc1Cl
Temperature: 25 °C

Procedure:
A solution of 4.6 g of sodium methylate (0.2 mole) in 50 ml of absolute methanol is slowly added at room temperature to 33.4 g (0.2 mole) of 2,6-dichloropyridin-3-ol. There is then added, with gentle heating, 100 to 150 ml of dimethylsulphoxide until the cloudy solution becomes clear. The solution is then heated to 80°-90° and methanol is distilled off. The reaction solution is cooled and an addition is slowly made dropwise at 0°-10° C of a solution of 60 g (0.2 mole) of chloroacetic acid diethylamide (dissolved in 300 ml of dimethylsulphoxide). After the dropwise addition is completed, the reaction mixture is stirred at room temperature for a further hour. The solvent is distilled off under reduced pressure; the oil remaining is taken up in ether, washed with water, dried and freed from solvent to leave N,N-diethyl-(2,6-dichloro-3-pyridyl)-oxy-acetic acid amide, which boils at 137°/0.4 torr; yield: 35 g (62% of theory). Treatment with ethereal hydrochloric acid yields the hydrochloride, which is recrystallised from isopropanol.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[C:6]1[CH:10]=[CH:9][S:8][CH:7]=1.[C:21]([CH2:23][NH:24][C:25](=[O:32])[C@@H:26]([OH:31])[CH2:27][CH:28]([CH3:30])[CH3:29])#[N:22].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.O>ClCCl>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([CH:5]([C:6]2[CH:10]=[CH:9][S:8][CH:7]=2)[O:31][C@@H:26]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:25]([NH:24][CH2:23][C:21]#[N:22])=[O:32])=[CH:16][CH:15]=1
Reactant: N=C(OC(c1ccc(Br)cc1)c1ccsc1)C(Cl)(Cl)Cl
Reactant: CC(C)C[C@H](O)C(=O)NCC#N
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@H](OC(c1ccc(Br)cc1)c1ccsc1)C(=O)NCC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-bromophenyl)(thien-3-yl)methyl 2,2,2-trichloroethanimidoate from step 2 (970 mg, 2.36 mmol) in dichloromethane (12 mL) was added (2S)-N-(cyanomethyl)-2-hydroxy-4-methylpentanamide (402 mg, 2.36 mmol) and camphorsulfonic acid (137 mg, 0.59 mmol). The reaction was stirred overnight at room temperature and the resulting mixture was poured into water. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried and evaporated and the crude residue was chromatographed on silica gel using 50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[C:21](=[O:28])[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:19][C:20]1[C:21](=[O:28])[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)=[O:17]
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: Nc1ccc(O)ccc1=O
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccc(O)ccc2=O)=C(O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Yield: 44.3 %

Procedure:
A mixture of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (0.65 g) and 2-amino-5-hydroxy-2,4,6-cycloheptatrien-1-one (0.40 g) in xylene (12 ml) was refluxed for 48 hours. The reaction mixture was cooled to room temperature. The crystals were collected by filtration and washed successively with methanol, water and methanol to give 4-hydroxy-N-(5-hydroxy-1-oxo-2,4,6-cycloheptatrien-2-yl)-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (0.4 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH:26]1([CH:30]=O)[CH2:29][CH2:28][CH2:27]1.O>O1CCCC1>[CH:26]1([CH:30]=[C:11]2[CH2:10][CH2:9][C:8]3[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]=3[C:2]2=[O:1])[CH2:29][CH2:28][CH2:27]1
Reactant: O=CC1CCC1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(c1)CCC(=CC1CCC1)C2=O
Temperature: 25 °C
Yield: 38 %

Procedure:
A solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (600 mg, 2.9 mmol) in tetrahydrofuran (10 mL) was cooled to ice bath temperature and treated with 1.0 M lithium hexamethyldisilazide in tetrahydrofuran (5 mL). After stirring for twenty minutes, cyclobutanecarboxaldehyde (J. Med. Chem. 1989, 32, 1001-6) (24 mL of 0.5 M solution in tetrahydrofuran) was slowly added and the mixture allowed to warm to room temperature and stir for 3 days. The mixture was poured into water, extracted three times with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by normal phase flash column chromatography on a 50 g silica gel column (5-50% ethyl acetate/hexanes gradient). Pure fractions were pooled and concentrated in vacuo to yield methyl 6-(cyclobutylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (300 mg, 1.1 mmol, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81-2.03 (m, 4H), 2.14-2.27 (m, 2H), 2.71 (t, J=6.58 Hz, 2H), 2.93-3.00 (m, 2H), 3.34-3.44 (m, 1H), 3.88 (s, 3H), 6.91 (d, J=9.13 Hz, 1H), 7.84-7.95 (m, 2H), 8.01 (d, J=8.06 Hz, 1H). ES-MS m/z 271 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([CH3:31])[N:24]=1>>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([NH:1][C:2]2[S:3][C:4]([C:10]3[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=3[F:16])=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])=[N:24][C:25]=1[CH3:31])#[N:28]
Reactant: Cc1nc(Cl)ccc1C#N
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1C#N

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 6-chloro-2-methylnicotinonitrile (73 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [C:1]([N:8]([CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CO.[OH-].[Na+]>C1COCC1>[C:1]([N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COC(=O)c1ccc(CCN(Cc2ccccn2)C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccc(C(=O)O)cc1)Cc1ccccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.7 %

Procedure:
The compound obtained in Example 9-3 (446.1 mg) was dissolved in THF (4.5 ml) and methanol (4.5 ml) After the addition of 1 mol/l aqueous solution of sodium hydroxide (4.5 ml), the mixture was stirred for 5 hours at room temperature. After the reaction, the solvent was removed by distillation and the residue was dissolved in distilled water. Aqueous solution of hydrochloric acid (1 mol/l) was added to the solution to adjust the pH to 3-4. The settled-down oily product was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was dried under vacuum to obtain the title compound (432.2 mg) as a white solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.C(=O)(O)[O-].[NH4+].[N:34]1C=CC=CC=1>C(#N)C.O>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([C:11](=[O:13])[NH2:34])[CH3:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: c1ccncc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)C(N)=O
Reaction time: 12 h
Yield: 89.7 %

Procedure:
DL-N-Boc-alanine (5.0 g, 26.4 mmol), di-tert-butylpyrocarbonate (7.9 mL, 34 mmol), and ammonium bicarbonate (2.5 g, 32 mmol) were stirred together in acetonitrile (101 mL). Pyridine (1.3 mL, 16 mmol) was added. The mixture stirred for 12 hours. Water was added and then the acetonitrile was removed in vacuo. The resulting slurry was filtered. The solid was collected, dissolved in methylene chloride and methanol (90:10), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (2.7 g, 55%): 1H NMR (400 MHz, d6-DMSO): 7.20 (br s, 1H), 6.90 (br s, 1H), 6.77 (d, 1H), 3.86 (quintet, 1H), 1.37 (s, 9H), 1.15 (d, 3H).
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:9]2[N:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[C:11]([Cl:17])[N:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>C(#N)C>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:9]2[N:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[C:11]([Cl:17])[N:10]=2)[N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1c[nH]cn1
Reactant: Clc1nc(C(Cl)(c2ccccc2)c2ccccc2)nc(Cl)c1Cl
Solvent: CC#N
Product: Clc1nc(C(c2ccccc2)(c2ccccc2)n2ccnc2)nc(Cl)c1Cl

Procedure:
34.0 g (0.1 mol) of diphenyl-4,5,6-trichloropyrimid-2-yl-chloromethane in 250 ml of absolute acetonitrile are stirred with 13.6 g (0.2 mol) of imidazole for 3 hours at room temperature and thereafter heated to the boil for 15 minutes. The mixture is then concentrated and the dark brown residue is washed with water and taken up in methylene chloride. After drying with sodium sulphate, treating with active charcoal and filtering, the solution is concentrated. The residue is extracted by boiling with petroleum ether, and the mixture is filtered and again concentrated. Finally, the material is recrystallised from a little acetonitrile. 17.0 g (40% of theory) of the compound of formula ##SPC9##
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][CH:25]=1>>[CH3:22][C:7]1([CH3:21])[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=3)[C:16]=2[C:17](=[O:18])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:30][C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)=[CH:23][C:6]1=2
Reactant: OCc1ccncc1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(OCc3ccncc3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and pyridin-4-yl-methanol.
Reaction SMILES: [NH2:1][C:2]1[C:14]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:13][C:5]2[N:6]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:8][C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+].[C:31](Cl)(Cl)=[S:32].CO>C(Cl)(Cl)Cl>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]=[C:31]=[S:32])[C:14]([N:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:20]3)=[CH:13][C:5]=2[N:6]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CCOC(=O)N1CCN(c2cc3nc(C(C)(C)C)sc3cc2N)CC1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)N1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2 g of 6-amino-2-tert-butyl-5[4-carbethoxypiperazin-1-yl]benzothiazole and 2 g of sodium bicarbonate in 200 ml of chloroform is cooled in an ice bath and 4 ml of thiophosgene in 10 ml of chloroform is added and the mixture is stirred at ambient temperature for 2 hours. The solid is filtered off and the filtrate is evaporated to give an oil which is applied on a silica gel column with 1% methanol in chloroform to yield 2-tert-butyl-5-[4-carbethoxypiperazin-1-yl]-6-isothiocyanato-benzothiazole, melting at 131°-134°.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH2:17][C:18]([NH2:20])=[O:19])[CH:11]=[CH:12][C:13]=2[N+:14]([O-])=[O:15])=O)=[CH:4][CH:3]=1.[Sn].Cl>O1CCCC1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[O:15][N:14]=[C:13]3[CH:12]=[CH:11][C:10]([CH2:17][C:18]([NH2:20])=[O:19])=[CH:9][C:8]=23)=[CH:4][CH:3]=1
Reactant: NC(=O)Cc1ccc([N+](=O)[O-])c(C(=O)c2ccc(Cl)cc2)c1
Agent: Cl
Agent: [Sn]
Solvent: C1CCOC1
Product: NC(=O)Cc1ccc2noc(-c3ccc(Cl)cc3)c2c1
Reaction time: 1 h
Yield: 14 %

Procedure:
A solution of 400 mg (0.00125 mole) of 3-(4-chlorobenzoyl)-4-nitrobenzene acetamide in 20 ml of tetrahydrofuran was warmed to 50° C. and treated with 1 g of tin powder and 1 ml of concentrated hydrochloric acid. The mixture was stirred for 1 hr, then filtered. The filtrate was poured into water and the solid was collected and recrystallized from ethanol-isopropanol to give 50 mg (14%) of light-yellow crystals, m.p. 242.0°-43.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:21])([CH2:15][O:16]S(C)(=O)=O)[CH2:10]OC(=O)C.[OH-].[K+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:21][CH2:10]1)[CH2:15][OH:16]
Reactant: CC(=O)OC[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: OC[C@@]1(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.2 %

Procedure:
In 250 ml of toluene was dissolved 50 g of (S)-2-(2,4-difluorophenyl)-1-acetoxy-3-methanesulfonyloxy-2-propanol and thereto was added 250 ml of 20% aqueous solution of potassium hydroxide and then the resulting liquid was stirred at room temperature for 12 hours. A toluene-layer was separated and the aqueous layer was extracted three times with 100 mg of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by column chromatography on silica gel to give 21 g of (S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-propanol. The optical purity thereof was determined by HPLC analysis (column: CHIRALPAK AS made by Daicel Chemical Industries, Ltd., eluent: n-hexane/isopropanol=98/2, detection wavelength: 254 nm, flow rate: 1.2 ml/min).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[C:15]([O:19][C:20]([N:22]1[CH2:27][C@@H:26]2[CH2:28][C@H:23]1[CH2:24][NH:25]2)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[C:15]([O:19][C:20]([N:22]1[CH2:27][C@@H:26]2[CH2:28][C@H:23]1[CH2:24][N:25]2[S:2]([CH3:1])(=[O:4])=[O:3])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2S(C)(=O)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Methanesulfonyl chloride (120 μL, 1.55 mmol) and DIPEA (187 μL, 1.07 mmol) were added to a solution of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (200 mg, 1.01 mmol) in DCM (20 mL) and the reaction mixture stirred at ambient temperature for 17 h, then partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo to give (1S,4S)-5-methanesulfonyl-2,5-diazabicyclo[2.2.1]-heptane-2-carboxylic acid tert-butyl ester. TFA (3 mL) was added to a solution of (1S,4S)-5-methanesulfonyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g); the cartridge was washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a white solid (170 mg, 96%). 1H NMR (CDCl3, 400 MHz) δ 4.37 (d, J=2.0 Hz, 1H); 3.83 (d, J=2.0 Hz, 1H); 3.41 (dd, J=9.2, 2.19 Hz, 1H); 3.25 (d, J=9.2 Hz, 1H); 3.20 (d, J=10.3 Hz, 1H); 3.01 (dd, J=10.3, 2.14 Hz, 1H); 2.89 (s, 3H); and 1.79 (bs, 2H)
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=O)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.CCOCC>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:22][CH:23]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of sodium hydride (60% weight dispersion in mineral oil, 1.35 g, 33.8 mmol) in PhMe (35 mL) at 0° C. was added ethyl 2-(diethoxyphosphoryl)acetate (7.57 g, 33.8 mmol, 6.7 mL). The reaction mixture was stirred at 0° C. for 20 min and a solution of bis(4-fluorophenyl)methanone (5.65 g, 25.9 mmol) in PhMe (35 mL) was added. The reaction mixture was warmed to room temperature, stirred for 1 h, and heated to 50° C. for 3 d. The reaction mixture was diluted with Et2O, washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated to give ethyl 3,3-bis(4-fluorophenyl)acrylate which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:29]([CH3:36])([C:30]([NH:32][CH:33]3[CH2:35][CH2:34]3)=[O:31])[C:28](=[O:37])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[N:9]=2)[N:7]=1.[CH3:38][O-:39].[Na+].Cl>CO>[NH2:1][C:2]1[C:3]2[C:29]([CH3:36])([C:30]([NH:32][CH:33]3[CH2:35][CH2:34]3)=[O:31])[C:28](=[O:37])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13]([O:39][CH3:38])=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[N:9]=2)[N:7]=1
Reactant: C[O-]
Reactant: CC1(C(=O)NC2CC2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4nc(Cl)ccc34)nc(N)c21
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(-c3nc(N)c4c(n3)NC(=O)C4(C)C(=O)NC3CC3)nn(CCC(F)(F)C(F)(F)F)c2n1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
A methanol (1.5 mL, anhydrous) solution containing 4-amino-2-(6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N-cyclopropyl-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, as described in Example 176, (62 mg, 0.114 mmol) and sodium methoxide (0.21 ml, 0.91 mmol, 25% in methanol) was stirred for 10 hours at 60° C. The reaction mixture was cooled and adjusted to pH 7.0 with 2N HCl aq. at 0° C. The residue was purified by reverse phase HPLC to afford the indicated product. Chiral separation using SFC on a Chiralcel OJ column provided both enantiomers of the title compound. 1H NMR (500 MHz, CD3COCD3): δ 0.61 (m, 2H); 0.77 (M, 2H); 1.83 (s, 3H); 2.85 (m, 1H); 3.04 (m, 2H); 4.05 (s, 3H); 4.88 (m, 2H); 6.78 (d, J=8.7 Hz, 2H); 7.72 (br, 1H); 7.84 (d, J=8.6 Hz, 1H); 9.13 (d, J=8.6 Hz, 1H). m/z=541.21 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.[CH3:10][NH2:11].CCO>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([NH:11][CH3:10])=[N:6][CH:7]=1
Reactant: Fc1cc(Br)cnc1F
Reactant: CN
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1ncc(Br)cc1F
Temperature: 100 °C

Procedure:
A mixture of 5-bromo-2,3-difluoropyridine (Matrix, Columbia, USA, 2.53 mmol) and 8 M methylamine in EtOH (Aldrich, Buchs, Switzerland, 2 ml, 16 mmol) was sealed in a vial and heated with microwave irradiation at 100° C. for 30 min. The cooled RM was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title product as an off-white solid. (HPLC: tR 1.94 min (Method A); M+H=205, 207, M−H=203, 205 MS-ES)