Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1>COC>[NH2:1][C:2]1[N:7]=[C:6]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)[C:5]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])=[CH:4][N:3]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(N)nc1Cl
Reactant: Cc1cccc(N)c1
Agent: COC
Product: Cc1cccc(Nc2nc(N)ncc2S(=O)(=O)NC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a suspension of 2-amino-4-chloro-N-(1,1-dimethylethyl)-5-pyrimidinesulfonamide (2.64 g, 10 mmol) in 7 mL dimethylether was added meta-toluidine (2.46 g, 23 mmol) and the reaction stirred at room temperature for 1 hour and then at 60° C. for 1/2 hour. The solvent was removed and the residue taken up in ethyl acetate. The ethyl acetate was washed with water, saline, dried, and the solvent removed in vacuo. The residue was triturated with ether and the crystals collected by suction filtration and dried to give 2.10 g of the identical product obtained in Step 1.
Reaction SMILES: C([O:5][C:6](=[O:46])[C@@H:7]([NH:38]C(OC(C)(C)C)=O)[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])(C)(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:38][C@@H:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[C:6]([OH:46])=[O:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN(CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCCCN(CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 23 h
Yield: 66.9 %

Procedure:
Under argon, 8 (271 mg, 0.422 mmol) was added to a mixture of trifluoroacetic acid (770 mg, 6.7 mmol), CH2Cl2 (3.0 mL), and triethylsilane (330 mg, 2.8 mmol); this was stirred at room temperature for 23 hours. The reaction mixture was concentrated; the resultant oil was dissolved in water (5.0 mL) and adjusted to pH 7 with saturated NaHCO3 solution. This solution was then concentrated; the residue was purified by chromatography on a C-18 column (30% acetone/water, followed by 55% acetone/water) to give 9 (137 mg, 67%) as a colorless oil: 1H NMR (19.7° C.) δ1.30-1.66 (m, 8 H), 1.78 (m, 2 H), 3.09 (m, 2 H), 3.20-3.33 (m, 4 H), 3.45 (m, 1 H), 5.05(s, 2H), 5.09 (s, 2 H), 7.26-7.37 (m, 10 H); HRMS m/z calcd for C26H36N3O6 486.2604, found 486.2614.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH:9]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][NH2:22])[CH2:17][CH2:16]1)=[O:14])([CH3:11])[CH3:10].[Cl:23][C:24]1[C:29]([C:30](=O)[CH3:31])=[C:28](Cl)[N:27]=[CH:26][N:25]=1>C1(C)C=CC=CC=1>[CH:9]([O:12][C:13]([N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[C:28]3=[N:27][CH:26]=[N:25][C:24]([Cl:23])=[C:29]3[C:30]([CH3:31])=[N:22]2)[CH2:19][CH2:20]1)=[O:14])([CH3:11])[CH3:10]
Reactant: CC(=O)c1c(Cl)ncnc1Cl
Reactant: CC(C)OC(=O)N1CCC(NN)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1nn(C2CCN(C(=O)OC(C)C)CC2)c2ncnc(Cl)c12
Yield: 33.3 %

Procedure:
Triethylamine (0.33 mL, 2.4 mmol) was added to a stirred mixture of 4-hydrazino-piperidine-1-carboxylic acid isopropyl ester hydrochloride (Intermediate 10; 188 mg, 0.8 mmol) and 1-(4,6-dichloro-pyrimidin-5-yl)-ethanone (Intermediate 17; 150 mg, 0.8 mmol) in toluene (5 mL) at room temperature under nitrogen and the resulting mixture was heated to reflux for 8 hours. The solvent was removed in vacuo and the crude reaction mixture was purified on a flash silica column (30 mm×4″) eluting with 10-33% ethyl acetate/hexanes to give 4-(4-chloro-3-methyl-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid isopropyl ester (90 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ 1.19 (d, 6H, J=6.3 Hz), 1.86-1.99 (m, 4H), 2.63 (s, 3H), 2.94-3.10 (m, 2H), 4.04-4.15 (m, 1H), 4.74-4.82 (m, 1H), 4.91-4.98 (m, 1H), 8.77 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([C:16]2[N:21]=[C:20]3[N:22]([CH2:25][C:26]4[CH:27]=[C:28]5[C:33](=[CH:34][CH:35]=4)[N:32]=[CH:31][CH:30]=[CH:29]5)[N:23]=[N:24][C:19]3=[CH:18][CH:17]=2)[CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][C:8]([O:10]C)=[O:9])=[O:5].[OH-].[Li+].Cl>CO.O>[F:1][C:2]1[CH:15]=[C:14]([C:16]2[N:21]=[C:20]3[N:22]([CH2:25][C:26]4[CH:27]=[C:28]5[C:33](=[CH:34][CH:35]=4)[N:32]=[CH:31][CH:30]=[CH:29]5)[N:23]=[N:24][C:19]3=[CH:18][CH:17]=2)[CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5]
Reactant: COC(=O)CNC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CNC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.9 %

Procedure:
To a solution of Example 50 (0.055 g, 0.113 mmol) in methanol (0.5 ml), lithium hydroxide (0.045 g, 1.05 mmol) in water (0.5 ml) was added and stirred at RT. After 12 h, pH was adjusted to ca. 7 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as a pale green solid (0.050 g, 96%). M.P.: 252-254° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.70 (s, 1H), 9.01 (d, J=3.9 Hz, 1H), 8.73 (d, J=8.7 Hz, 1H), 8.64 (m, 2H), 8.25 (d, J=8.8 Hz, 1H), 8.20 (m, 4H), 7.97 (d, J=8.9 Hz, 1H), 7.86 (t, J=8.1 Hz, 1H), 7.71 (dd, J=7.8, 4.2 Hz, 1H), 6.27 (s, 2H), 3.96 (d, J=5.8 Hz, 2H). MS (m/z): 456.85 (M+).
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:2].Cl[C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15](S(C)(=O)=O)[N:14]=1.C(N(C(C)C)CC)(C)C.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>CS(C)=O>[C:1]([CH2:3][CH2:4][N:5]([C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[N:14]=1)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:2]
Reactant: Cc1cc(Cl)nc(S(C)(=O)=O)n1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)CNCCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)CN(CCC#N)c1cc(C)nc(-n2ccnc2)n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 34.6 %

Procedure:
To N-cyanoethylglycine, ethyl ester (15.9 g, 102 mmol) (a compound of formula (Y2)) dissolved in DMSO (70 mL) was added 4-chloro-6-methyl-2-methylsulfonylpyrimidine (18.8 g, 91 mmol) (a compound of formula (Y1)) and diisopropylethylamine (18 mL, 100 mmol). After stirring for 16 hours, the reaction temperature was raised to 70° C. and imidazole (26.5 g, 0.39 mol) was added. After stirring for 1 day, the reaction was cooled to ambient temperature and added to ice water. The solid that formed was suction filtered and collected on paper to give 9.9 g of 2-[(2-cyanoethyl)[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]acetic acid, ethyl ester (a compound of formula (Yc1)).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[C:13]([F:16])([F:15])[F:14])[CH3:2].[Br:18][C:19]1[CH:20]=[CH:21][C:22](F)=[C:23]([CH:26]=1)[CH:24]=[O:25]>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:22]2[CH:21]=[CH:20][C:19]([Br:18])=[CH:26][C:23]=2[CH:24]=[O:25])[CH:9]=[CH:8][C:7]=1[C:13]([F:15])([F:16])[F:14])[CH3:2]
Reactant: CCOC(=O)Cc1cc(O)ccc1C(F)(F)F
Reactant: O=Cc1cc(Br)ccc1F
Product: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2C=O)ccc1C(F)(F)F

Procedure:
Prepared according to the procedure described in Example 24, Step 4, using the following starting materials: (5-hydroxy-2-trifluoromethyl-phenyl)-acetic acid ethyl ester and 5-bromo-2-fluorobenzaldehyde.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:9][CH3:10])=[N:6][S:7][CH:8]=1)(=[O:3])N.S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+]>O>[C:1]([C:4]1[C:5]([O:9][CH3:10])=[N:6][S:7][CH:8]=1)([OH:12])=[O:3]
Reactant: COc1nscc1C(N)=O
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1nscc1C(=O)O
Temperature: 60 °C

Procedure:
To a solution of 7.9 g. (0.05 mole) of 4-carbamoyl-3-methoxyisothiazole prepared as in Example 19 in 90 ml. of 80% sulfuric acid at 10°-15° C. was added slowly beneath the surface of the liquid a solution of 9.5 g. (0.137 mole) of sodium nitrite in 13 ml. of H2O. When addition was complete the solution was allowed to come to 25° C., and then was heated to 60° C., for several minutes. After cooling to 25° C. the reaction solution was poured onto ice to precipitate 3.64 g. (46%) of 4-carboxy-3-methoxyisothiazole as a white solid, m.p. 182°-185° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:7]#[N:8])=[CH:5][N:6]=1.C[O-].[Na+].[Cl-].[NH4+:13]>CO>[ClH:1].[Cl:1][C:2]1[S:3][C:4]([C:7]([NH2:13])=[NH:8])=[CH:5][N:6]=1
Reactant: N#Cc1cnc(Cl)s1
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: N=C(N)c1cnc(Cl)s1
Reaction time: 0.25 h
Yield: 159.6 %

Procedure:
0.43 g 2-chloro-5-cyanothiazole was dissolved in 8 ml anhydrous methanol, and 0.16 g sodium methoxide was added, to carry out the reaction with stirring for 15 min; and then, 0.48 g ammonium chloride was added, to further carry out reaction in closed state for 24 hr; finally, the reaction product was filtered to remove insoluble matters, and the resultant filtrate was concentrated, and recrystallized from isopropanol to obtain 0.47 g a yellow crystalline solid (yield 79%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH:6]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH:6]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(-c2cc(CCCO)ccn2)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2cc(CCCOS(C)(=O)=O)ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(3-Hydroxypropyl)-2-(3,4,5-Trimethoxyphenyl)-pyridine (486 mg) was dissolved in chloroform (10 mL), and to the solution methanesulfonyl chloride (186 μL) and triethylamine (400 μL) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with chloroform, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.Cl.[C:20]([C:22]1[CH:30]=[CH:29][C:25]([CH2:26][NH:27][NH2:28])=[CH:24][CH:23]=1)#[N:21].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:27]([CH2:26][C:25]2[CH:29]=[CH:30][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)[N:28]=1
Reactant: N#Cc1ccc(CNN)cc1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1ccc(Cn2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1

Procedure:
5.0 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one, 3.9 g of 4-cyanobenzylhydrazine hydrochloride and 6 ml of triethylamine are boiled under reflux for 3 h in 50 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from ethanol/water. After drying, 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-ylmethyl]benzonitrile remains as colorless crystals of m.p. 147-149° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:12])[C:8]([Cl:11])([Cl:10])[Cl:9])[NH:5][CH:6]=1.Cl[C:14](Cl)(Cl)C(C1N(C)C=CC=1)=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:12])[C:8]([Cl:9])([Cl:10])[Cl:11])[N:5]([CH3:14])[CH:6]=1
Reactant: Cn1cccc1C(=O)C(Cl)(Cl)Cl
Reactant: O=C(c1cc(Br)c[nH]1)C(Cl)(Cl)Cl
Product: Cn1cc(Br)cc1C(=O)C(Cl)(Cl)Cl
Yield: 81 %

Procedure:
Using the same general procedure as used for the synthesis of 1-(4-bromo-1H-pyrrol-2-yl)-2,2,2-trichloro-ethanone 7, 5.00 g of 2-trichloroacetyl-1-methylpyrrole afforded 5.46 g (81%) of the title compound 13 as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.66 (d, 1H, J=1.2 Hz), 7.42 (d, 1H, J=1.8 Hz), 3.91 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 171.48, 134.40, 123.62, 121.19, 95.36, 95.12; HRMS (FAB) calcd for C7H6BrCl3NO (MH+) 303.8698, found 303.8678.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]=[C:4]2[NH:14][CH:15]=[CH:16][C:3]=12.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:17][C:16]1[C:3]2[C:4](=[N:5][CH:6]=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]=2[Cl:1])[NH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1c(-c2ccccc2)cnc2[nH]ccc12
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Clc1c(-c2ccccc2)cnc2[nH]cc(Br)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
4-Chloro-5-phenyl-1H-pyrrolo[2,3-b]pyridine (0.912 g, 3.99 mmol) was placed in CHCl3 (5 mL) at room temperature. N-Bromosuccinimide (0.710 g, 3.99 mmol) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was diluted with DCM and washed with saturated NaHCO3. The organic fraction was dried, filtered, and concentrated to give the crude product 3-bromo-4-chloro-5-phenyl-1H-pyrrolo[2,3-b]pyridine (1.1 g, 89.7% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:25]([O:27][CH3:28])=[O:26])=[N:11][C:12]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([O:33][C:34]([NH:36][CH2:37][C:38]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:39]=1[O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45](O)=[O:46])=[O:35])([CH3:32])([CH3:31])[CH3:30].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:25]([O:27][CH3:28])=[O:26])=[N:11][C:12]([N:19]2[CH2:24][CH2:23][N:22]([C:45](=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41][O:40][C:39]3[CH:48]=[C:49]([F:52])[CH:50]=[CH:51][C:38]=3[CH2:37][NH:36][C:34]([O:33][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:35])[CH2:21][CH2:20]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(N2CCNCC2)c2cccnc2c1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1OCCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc(N2CCN(C(=O)CCCCOc3cc(F)ccc3CNC(=O)OC(C)(C)C)CC2)c2cccnc2c1OCc1ccccc1
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a solution of methyl 8-(benzyloxy)-5-(piperazin-1-yl)-1,6-naphthyridine-7-carboxylate (Example 13; 1.3 mmol), 5-(2-((tert-butoxycarbonylamino)methyl)-5-fluorophenoxy)pentanoic acid (Example 17; 1.6 mmol) and diisopropyl ethylamine (3.9 mmol) in dichloromethane (10 ml) was added HBTU (2.0 mmol). The mixture was stirred overnight. The mixture was washed with saturated NaHCO3, 10% citric acid and brine and dried over Na2SO4. The solvent was removed under vacuum. The residue was purified by flash column chromatography over SiO2 (eluent: methanol/CH2Cl2, 1:100) to afford the title compound (800 mg).
Reaction SMILES: [F:1][C:2]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:29][CH3:30])[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:21][C@H:18]1[CH2:19][CH2:20][N:16]([S:13]([NH:12][C:10]2[CH:9]=[C:8]([O:29][CH3:30])[N:7]=[C:6]([S:5][CH2:4][C:3]3[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:2]=3[F:1])[N:11]=2)(=[O:14])=[O:15])[CH2:17]1
Reactant: COc1cc(NS(=O)(=O)N2CC[C@H](NC(=O)OC(C)(C)C)C2)nc(SCc2cccc(F)c2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)N2CC[C@H](N)C2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 188 h

Procedure:
To a solution of tert-butyl {(3S)-1-[({2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}amino)sulfonyl]pyrrolidin-3-yl}carbamate (the product from step ii), 0.75 g) in DCM (10 ml) was added TFA slowly. The reaction then stirred at room temperature for 188 h. The reaction was reduced in vacuo and the residue purified by prep HPLC to give the title compound as a white solid. Yield: 70 mg
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([OH:20])=[O:19].[CH3:21][C:22]([S:25]([N:27]=[C:28]1[CH2:31][O:30][CH2:29]1)=[O:26])([CH3:24])[CH3:23]>O1CCCC1>[CH3:23][C:22]([CH3:24])([S:25]([NH:27][C:28]1([C:17]2[S:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=2)[CH2:31][O:30][CH2:29]1)=[O:26])[CH3:21]
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: O=C(O)c1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)S(=O)NC1(c2ccc(C(=O)O)s2)COC1
Temperature: 25 °C

Procedure:
Butyllithium (6.16 ml, 15.41 mmol) was added dropwise to a stirred solution of diisopropylamine (1.919 ml, 13.69 mmol) in tetrahydrofuran (10 ml) at −78° C. The solution was allowed to warm to room temperature and then added dropwise by syringe to a stirred −78° C. solution of thiophene-2-carboxylic acid (0.877 g, 6.85 mmol) in tetrahydrofuran (30 ml). The resulting suspension was stirred for 40 minutes at −78° C. when a solution of 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (1 g, 5.71 mmol) in tetrahydrofuran (10 ml) was added dropwise. After the addition was complete, the reaction mixture was allowed to warm to room temperature, quenched with saturated ammonium chloride and diluted with a water to dissolve the remaining solids. The aqueous solution was extracted with ethyl acetate, adjusted to pH 2 by addition of 1N aqueous hydrochloric acid and re-extracted with ethyl acetate and methylene chloride. The organic extracts were dried with magnesium sulfate, filtered, concentrated and purified by normal phase chromatography to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].[C:11]([Si](C)(C)C)#[CH:12].[OH-].[Na+]>CCN(CC)CC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[CH:12])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(N)cccc1Br
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#Cc1cccc(N)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 2-amino-6-bromobenzonitrile (1.25 g, 6.34 mmol) and ethynyltrimethylsilane (2.42 g, 12.7 mmol) in dry Et3N (15 mL) was added under N2 Cu(I) (60 mg), Pd(PPh3)4 (360 mg) and the mixture was stirred at 80° C. for 20 hours. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate and washed with brine. The organic layer was evaporated and the residue was dissolved in methanol (20 mL), treated with 1M aqueous NaOH solution (1.05 equiv.) and stirred at room temperature for 1 hour. Methanol was evaporated off and the aqueous residue was extracted with CH2Cl2, dried over MgSO4, and purified over silica gel (ethyl acetate/hexanes 75/25) to furnish the desired product in 93% yield as light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 4.54 (s, 1H), 6.24 (br s, 2H), 6.76 (dd, J=0.8, 7.6 Hz, 1H), 6.82 (dd, J=0.8, 8.4 Hz, 1H), 7.28 (dd, J=7.6, 8.4 Hz, 1H). MS 143 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].I[CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C.O>[CH2:13]([O:11][C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:2]([F:1])[C:3]=1[CH:4]=[O:5])[CH3:14]
Reactant: CCI
Reactant: O=Cc1c(O)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(F)cc(F)c1C=O
Temperature: 80 °C

Procedure:
A mixture of 2,4-difluoro-6-hydroxybenzaldehyde (4.340 g; 27.50 mmol), iodoethane (8.562 g; 54.90 mmol), and K2CO3 (4.553 g; 32.90 mmol) in anh. DMF (75 ml) was heated to 80° C., under nitrogen, for 45 min. Et2O and water were added, and the organic layer was further washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-ethoxy-4,6-difluorobenzaldehyde as an orange solid. LC-MS (conditions A): tR=0.70 min.; [M+H]+: 187.39 g/mol.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][N:44]=[N+]=[N-])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][NH2:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCN=[N+]=[N-])C[C@@H]3c3ccc(OC)cc3)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCN)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 70.0 mg of (2S,4R,5R)-2-(2-azido-ethyl)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester in 4.0 ml of tetrahydrofuran and 0.4 ml of water are added 30 mg of triphenyl-phosphine. The reaction mixture is stirred for 2 days at room temperature; concentrated under reduced pressure and the residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a colourless oil. Rf=0.05 (dichlormethane-methanol 10:1); Rt=4.27.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:9]2[C:10]([F:26])=[CH:11][C:12]([O:14][CH2:15][C:16]3[N:20]([CH3:21])[N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[CH:13][C:8]=2[S:7][CH:6]=1.[OH-].[Na+].C1COCC1.Cl>O.CO>[F:26][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:27])=[O:2])=[CH:6][S:7][C:8]=2[CH:13]=[C:12]([O:14][CH2:15][C:16]2[N:20]([CH3:21])[N:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2cc(OCc3cc(C(F)(F)F)nn3C)cc(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc(C(F)(F)F)cc1COc1cc(F)c2c(CC(=O)O)csc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.8 %

Procedure:
A mixture of methyl(4-fluoro-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-1-benzothiophen-3-yl)acetate (220 mg), 1N NaOH (2 mL), THF (2 mL) and MeOH (2 mL) was stirred at room temperature for 1.5 h. To the mixture were added 1N HCl (2 mL) and water. The mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residual solid was washed with hexane to give the title compound (180 mg). The crystals were crystallized from acetone-hexane.