Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.[CH3:38][O:39][C:40]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[C:46]2[C:41]=1[C:42](=[O:64])[NH:43][C:44]([C:52]1[CH:57]=[CH:56][C:55]([N:58]3[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]3)=[CH:54][CH:53]=1)=[N:45]2>C1COCC1>[CH3:38][O:39][C:40]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[C:46]2[C:41]=1[C:42](=[O:64])[NH:43][C:44]([C:52]1[CH:57]=[CH:56][C:55]([N:58]3[CH2:59][CH2:60][N:61]([C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[O:8])[CH2:62][CH2:63]3)=[CH:54][CH:53]=1)=[N:45]2
Reactant: O=C(O)c1cccs1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5cccs5)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.9 %

Procedure:
To a solution of 2-thiophenecarboxylic acid (0.087 g, 0.68 mmol) in THF (20 mL) was added HOBt (0.099 g, 0.74 mmol), EDCl (0.141 g, 0.74 mmol), Et3N (0.10 mL, 0.74 mmol) and 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.250 g, 0.68 mmol). The resulting solution was stirred at room temperature for 4 hours. The solution was concentrated in vacuo. The material was purified by flash chromatography, eluting with 0% to 50% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the title compound (0.100 g, 30%). 1H NMR (300 MHz, DMSO-d6): δ 11.78 (s, 1H), 8.12 (d, J=9.0 Hz, 2H), 7.75-7.84 (m, 1H), 7.46-7.53 (m, 1H), 7.12-7.20 (m, 1H), 7.03 (d, J=9.1 Hz, 2H), 6.69 (d, J=2.3 Hz, 1H), 6.47 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.74-3.92 (m, 4H), 3.37-3.49 (m, 4H). APCI MS m/z 477 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.Cl[CH2:25][C:26]1[N:27]=[C:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[S:29][CH:30]=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:25][C:26]2[N:27]=[C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)[N:3]=1
Reactant: ClCc1csc(N2CCOCC2)n1
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SCc3csc(N4CCOCC4)n3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2 g (6.13 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanylpyridine-3,5-dicarbonitrile and 2.68 g (12.26 mmol) of 4-(4-(chloromethyl)-1,3-thiazol-2-yl]morpholine are dissolved in dry DMF (50 ml), and 1.83 ml (12.26 mmol) of DBU are added. After 3 hours of stirring at RT, the solvent is removed using a rotary evaporator and the residue is purified by preparative HPLC (column: Kromasil 100 C18 250×20 mm, 10 μm; acetonitrile/water gradient: 3 minutes of 10% acetonitrile which is then, over a period of 30 minutes, increased to 80% acetonitrile; flow rate: 25 ml/min). This gives 1.70 g (55% of theory) of product.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:15]([I:16])=[CH:14][NH:13][C:12](=[O:17])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[C:1]([NH:9][C:10]1[C:15]([I:16])=[CH:14][N:13]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12](=[O:17])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(Nc1nc(=O)[nH]cc1I)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(I)c(NC(=O)c2ccccc2)nc1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 8.3 g of N-benzoyl-5-iodocytosine dissolved in 60 ml DMF, was added at 0° C. 1.06 g of 55% NaH in mineral oil, and the solution was stirred at RT for 2 h. After 2.7 ml ethyl bromoacetate was added to the reaction mixture, the reaction solution was stirred for another 24 h at RT, which was followed by removal of the solvent under reduced pressure. The resulting residue was dissolved and the insoluble material was filtered off. The filtrate was washed two times with saturated aq ammonium chloride, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by column chromatography (1:1 hexane/EA) to yield 6.5 g of compd 2 (compd b in Scheme 1) as a yellow solid. mp 154-5° C. 1H NMR (400 MHz; CDCl3) δ 13.31 (br s, 1H), 8.37 (d, J=7.2 Hz, 2H), 7.69 (s, 1H), 7.55 (t, J=7.4 Hz, 1H), 7.46 (t, J=7.6 Hz, 2H), 4.49 (s, 2H), 4.27 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:2]=[CH2:3].C(Br)(Br)(Br)Br.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:45]([O:47][C:48](=[O:60])[C@@H:49]([O:58][CH3:59])[CH2:50][C:51]1[CH:56]=[CH:55][C:54](O)=[CH:53][CH:52]=1)[CH3:46]>ClCCl>[CH2:45]([O:47][C:48](=[O:60])[CH:49]([O:58][CH3:59])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:5][C:4]=2[CH2:1][CH:2]=[CH2:3])=[CH:53][CH:52]=1)[CH3:46]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OC
Reactant: C=CCc1cc(-c2ccccc2)ccc1OCCCO
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=CCc1cc(-c2ccccc2)ccc1OCCCOc1ccc(CC(OC)C(=O)OCC)cc1

Procedure:
A solution of compound from Step B in dichloromethane was treated with CBr4 (1.12 eq) and PPh3 (1.4 eq) and allow to react for 1.5 hours. The product isolated after chromatography of this reaction was treated under Standard Procedure I with (2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[N:11]=1.C(O)C>O>[CH3:21][O:20][C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2ccc(N)nc2n1
Reactant: O=C(O)c1ccco1
Solvent: O
Solvent: CCO
Product: COc1ccc2ccc(NC(=O)c3ccco3)nc2n1
Temperature: 4 °C
Yield: 83.7 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 2-furancarboxylic acid (8.95 g), N,N'-carbonyldiimidazole (12.8 g) and 2-amino-7-methoxy-1,8-naphthyridine (10.5 g). The product produced by precipitation in water (15.5 g; m.p. 199° C.) is dissolved in boiling ethanol (500 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×10 cc) and dried at 45° C. under reduced pressure (0.067 kPa). N-(7-Methoxy-1,8-naphthyridin-2-yl)-2-furancarboxamide (13.5 g) is produced, m.p. 201° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[F:24][C:25]([F:29])([F:28])[CH2:26][NH2:27]>>[F:24][C:25]([F:29])([F:28])[CH2:26][NH:27][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23]
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Reactant: NCC(F)(F)F
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NCC(F)(F)F)nc1
Yield: 88 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using 2,2,2-trifluoroethylamine instead of isopropylamine, to the title compound (111 mg, 88%), which was obtained as a white solid. MS: m/e=393.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:18])([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:4][S:5]([CH2:8][C:9]#[N:10])(=[O:7])=[O:6].[F:19][C:20]([S:23][CH2:24][CH2:25]OS(C(F)(F)F)(=O)=O)([F:22])[F:21]>>[F:18][C:2]([F:1])([C:11]([F:16])([F:17])[C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:4][S:5]([CH:8]([CH2:25][CH2:24][S:23][C:20]([F:22])([F:21])[F:19])[C:9]#[N:10])(=[O:6])=[O:7]
Reactant: O=S(=O)(OCCSC(F)(F)F)C(F)(F)F
Reactant: N#CCS(=O)(=O)CCC(F)(F)C(F)(F)C(F)(F)F
Product: N#CC(CCSC(F)(F)F)S(=O)(=O)CCC(F)(F)C(F)(F)C(F)(F)F

Procedure:
Compound II-24 was prepared from (3,3,4,4,5,5,5-heptafluoro-pentane-1-sulfonyl)-acetonitrile and trifluoro-methanesulfonic acid 2-trifluoromethylsulfanyl-ethyl ester as described for compound II-1.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OCC3C=CC=CC=3)=O)=[N:9][C:10]=2Br)[CH:5]=[CH:6][N:7]=1.[CH2:27]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([NH:36][C:37](=[O:53])[C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH:31]=1)[CH2:28][CH3:29]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9][C:10]=2[C:41]2[CH:42]=[CH:43][C:38]([C:37]([NH:36][C:32]3[CH:31]=[C:30]([CH2:27][CH2:28][CH3:29])[CH:35]=[CH:34][N:33]=3)=[O:53])=[CH:39][CH:40]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(Br)c12
Reactant: CCCc1ccnc(NC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Product: CCCc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCN4)n4ccnc(N)c34)cc2)c1
Yield: 93 %

Procedure:
This intermediate was prepared, in an analogous manner as described for intermediate 2, from (S)-benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Intermediate 1e) and N-(4-Propylpyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (intermediate 8) to afford the title compound (147.8 mg, 93%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[NH2:9][C@H:10]([C:13]([OH:15])=[O:14])[CH2:11][SH:12].C>C(O)C>[N:1]1[CH:2]=[CH:3][C:4]([CH:7]2[NH:9][CH:10]([C:13]([OH:15])=[O:14])[CH2:11][S:12]2)=[CH:5][CH:6]=1
Reactant: O=Cc1ccncc1
Reactant: N[C@@H](CS)C(=O)O
Solvent: CCO
Product: O=C(O)C1CSC(c2ccncc2)N1
Yield: 57.1 %

Procedure:
Pyridine-4-carbaldehyde (1.07 g) and 1.21 g of L-cysteine were heated in 60% ethanol at a refluxing temperature for 4 hours. Activated charcoal (100 mg) was added to the reaction mixture while it was warm. The mixture was filtered. After cooling, the resultant crystalline precipitate was collected by filtration and washed with ethanol to give 1.2 g of 2-(4-pyridyl)-thiazolidine-4-carboxylic acid. Melting point 171°-173° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:17][CH2:16][CH:10]([C:11]([O:13]CC)=[O:12])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Li+].[OH-].O>C1COCC1>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:17][CH2:16][CH:10]([C:11]([OH:13])=[O:12])[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCN(c2ccncc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCN(c2ccncc2)CC1
Temperature: 0 °C

Procedure:
A solution of ester 21-1 (10 g, 42.7 mmol) in THF (50 mL) was treated with 1N LiOH (47 mL, 47.0 mmol) and H2O (50 mL). The resulting solution was concentrated and the aqueous residue cooled to 0° C., then adjusted to pH≈6 with 1N HCl and the resulting solid 21-2, collected by filtration.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[O:23][N:22]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:20]=2)=[O:18])=[C:10]([CH3:31])[N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([CH3:31])[C:11]([CH2:15][NH:16][C:17]([C:19]2[O:23][N:22]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:20]=2)=[O:18])=[C:12]([CH3:14])[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1nc(Cc2ccccc2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)nc(C)c1CNC(=O)c1nc(Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (5-{[(3-Benzyl-[1,2,4]oxadiazole-5-carbonyl)-amino]-methyl}-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (65 mg, 0.09 mmol), 2 mL TFA and 4 mL DCM was stirred of room temperature for 1 h. The mixture was evaporated in vacuo and the residue was purified by prep HPLC (Macherey-Nagel Nucleosil 250×40 mm, 5 to 100% ACN and 0.1% TFA, flow 40ml/min). Aq. NaHCO3-solution was added to the product containing fractions and after evaporation the aq. layer was extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated to give the title compound. 1H-NMR (DMSO-d6, 400 MHz) 9.43 (t, 1H), 7.25-7.36 (m, 5H), 6.10 (s, 1H), 5.70 (s, 2H), 4.35 (d, 2H), 4.18 (s, 2H), 2.29 (s, 3H), 2.16 (s, 3H); LCMS (method A) RtA=1.024 min; [M+H]+=338.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([OH:17])=O)[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:12]=1[O:13][CH3:14].C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([Cl:21])=[O:17])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:12]=1[O:13][CH3:14]
Reactant: COc1cc(C(=O)O)c2c(c1OC)CCCC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)c2c(c1OC)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,4-dimethoxy-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.20 g, 0.85 mmol) in DCM (5 mL) was added oxalyl chloride (0.09 mL, 1.06 mmol) and 1 drop of DMF. The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the 3,4-dimethoxy-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride was used without purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl.[CH3:17][S:18]([NH:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:20])=[O:19].C(N(CC)CC)C>C(O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[N:27]1[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22][NH:21][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:29][CH2:28]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CS(=O)(=O)NCCC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2ncnc(N3CCC(CCNS(C)(=O)=O)CC3)c2cc1OC
Temperature: 25 °C
Yield: 88 %

Procedure:
4-Chloro-6,7-dimethoxy quinazoline (1.1 g.), 4- (2-methanesulphonamidoethyl)piperidine hydrochloride (1.5 g.) and triethylamine (1.5 ml.) in ethanol (30 ml.) were heated together under reflux for 1.5 hours. The solution was then cooled to room temperature, concentrated in vacuo, suspended in water (70 ml.) and basified to pH 10 with 10% aqueous sodium carbonate solution. The mixture was extracted with chloroform (2×70 ml.), the extracts combined, dried (MgSO4), and taken to dryness in vacuo. The resultant pale yellow oil was triturated with ether (70 ml.) to give a white solid which was collected by filtration. Crystallization of this solid from ethanol yielded 6,7-dimethoxy-4-[4-(2-methanesulphonamidoethyl)-piperidino]quinazoline (1.7 g.), m.p. 162°-164° C.
Reaction SMILES: [F:1][C:2]([F:21])([C:17]([F:20])([F:19])[F:18])[C:3]([F:16])([F:15])[C:4]1[NH:9][C:8](=[O:10])[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.[Cl:22]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:22][C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[C:8](=[O:10])[NH:9][C:4]=1[C:3]([F:15])([F:16])[C:2]([F:1])([F:21])[C:17]([F:19])([F:18])[F:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(C(F)(F)C(F)(F)C(F)(F)F)[nH]c1=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Cl)c(C(F)(F)C(F)(F)C(F)(F)F)[nH]c1=O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
16.7 g (52 mmol) of methyl 6-(heptafluoropropyl)-2-oxo-1,2-dihydropyridine-3-carboxylate were dissolved in 160 ml of N,N-dimethylformamide, and 7.08 g (52 mmol) of N-chlorosuccinimide were added at room temperature. After 3 hours of stirring at 50° C., the reaction mixture was added to water and extracted repeatedly with ethyl acetate. The organic phase was then separated off, washed with water and dried. The resulting crude product was then purified by preparative RP-HPLC. This gave 10.1 g (54% of theory) of the product as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].FC(F)(F)S(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:23])([F:21])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:39][C:40]([F:43])([F:42])[F:41])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NC1CCN(CC(F)(F)F)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol) in THF (5.0 mL) was added TEA (0.06 mL, 0.64 mmol) and stirred for 10 min. Then 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.03, 0.16 mmol) was added and stirred for 16 h at ambient temperature. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3 solution and brine solution. The combined EtOAc layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a brown solid (0.05 g, 44%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1COCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11](=[S:25])[NH2:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1ccc(N2CCOCC2)cc1
Solvent: C1CCOC1
Product: NC(=S)c1ccc(N2CCOCC2)cc1
Temperature: 70 °C
Yield: 83.4 %

Procedure:
To a solution of 4-morpholinobenzamide (4.91 g, 23.80 mmol) in THF (70 mL) was added Lawesson's Reagent (10.60 g, 26.20 mmol) with stirring. The mixture was heated at 70° C. for 4 h, then cooled to rt and concentrated in vacuo. CH2Cl2 (30 mL) and water (100 mL) was added to the residue. The mixture was then filtered and the filter cake was washed with water and dried to give the title compound as a yellow solid (4.41 g, 83.3%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([NH:12][C:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16](=[O:23])[O:15][N:14]=1)([CH:9]([CH3:11])[CH3:10])[C:5]([O:7]C)=O.[O:24]1CCCC1.S(=O)(=O)(O)O>O.C(Cl)Cl>[OH:15][N:14]1[C:5](=[O:7])[C:4]([CH:9]([CH3:11])[CH3:10])([CH3:3])[N:12]=[C:13]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([OH:23])=[O:24]
Reactant: COC(=O)C(C)(Nc1noc(=O)c2ccccc12)C(C)C
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)C1(C)N=C(c2ccccc2C(=O)O)N(O)C1=O
Temperature: 45 °C
Reaction time: 36 h
Yield: 76 %

Procedure:
Sodium hydroxide (0.58 g, 0.0145 mol) in water is added to a solution of methyl 2,3-dimethyl-2-[(1-oxo-2,3-benzoxazin-4-yl)amino]butyrate (2.0 g, 0.00689 mol) and tetrahydrofuran under a nitrogen atmosphere. The reaction mixture is stirred at 45° C. for 36 hours then at room temperature for 6 days. The reaction mixture is concentrated in vacuo to give an oil. The oil is dissolved into water. The aqueous solution is cooled with an ice-bath and concentrated sulfuric acid is added until a pH of about 1 is obtained then the solution is extracted with ethyl acetate. The combined ethyl acetate extracts are dried with anhydrous magnesium sulfate and concentrated in vacuo to give a pale yellow solid. The solid is added to boiling methylene chloride and after 2/3 of the methylene chloride has evaporated, the mixture is filtered to give the title compound as a white solid (1.44 g, 76%), mp 186°-188° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12]([OH:14])=[O:13].[N+](=[CH2:23])=[N-]>C1COCC1>[CH3:23][O:13][C:12](=[O:14])[CH:11]([S:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C(Sc1nc2ccccc2s1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(Sc1nc2ccccc2s1)c1ccccc1

Procedure:
1 g of 2-(benzothiazol-2-ylthio)-2-phenylacetic acid is dissolved in 20 ml of THF, an ethereal solution of diazomethane is added dropwise until a yellow coloration is produced and the mixture is evaporated to give 2-(benzothiazol-2-ylthio)-2-phenylacetic acid methyl ester, in the form of an oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][CH:19]([C:24]2([CH3:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][C:21]([OH:23])=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14](F)[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1.[Cl:31]C1C=C2C(B3OC(C)(C)C(C)(C)O3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.FC1C=C2C(B3OC(C)(C)C(C)(C)O3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.C(O)=O>C(#N)C>[Cl:31][C:14]1[CH:15]=[C:16]2[C:8]([C:5]3[N:4]=[C:3]([NH:18][CH:19]([C:24]4([CH3:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:20][C:21]([OH:23])=[O:22])[C:2]([F:1])=[CH:7][N:6]=3)=[CH:9][NH:10][C:11]2=[N:12][CH:13]=1
Reactant: CC1(C(CC(=O)O)Nc2nc(-c3c[nH]c4ncc(F)cc34)ncc2F)CCCCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Solvent: CC#N
Solvent: O=CO
Product: CC1(C(CC(=O)O)Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)CCCCC1

Procedure:
Compound 83 was synthesized in a manner similar to 3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3-(1-methylcyclohexyl)propanoic acid, 78, using 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine instead of boronate ester, 7a: 1H NMR (400 MHz, MeOD) δ 9.05 (d, J=2.1 Hz, 1H), 8.39-8.24 (m, 2H), 8.16 (d, J=4.9 Hz, 1H), 5.23 (d, J=10.4 Hz, 1H), 2.86 (d, J=15.6 Hz, 1H), 2.65 (m, 1H), 1.58 (m, 7H), 1.37 (m, 3H), 1.05 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.37 minutes (M+H) 442.36.
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7](=[O:28])[C:8]([NH:19][NH:20]C(OC(C)(C)C)=O)([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)(=[O:3])[CH3:2].Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>ClCCl>[C:1]([O:4][CH2:5][O:6][C:7](=[O:28])[C:8]([NH:19][NH2:20])([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:12]([O:17][C:5]([O:4][CH2:1][CH3:2])=[O:6])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCOC(=O)C(C)(Cc1ccc(O)c(O)c1)NNC(=O)OC(C)(C)C
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(CC(C)(NN)C(=O)OCOC(C)=O)cc1OC(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.5 %

Procedure:
To an ice cold reaction mixture containing compound 103 (0.358 g, 0.9 mmol) and TEA (0.224 mL, 1.8 mmol) in dichloromethane (5 mL) was added ethyl chloroformate (0.18 mL, 1.8 mmol). The mixture was stirred at 0° C. for 30 min and then at room temperature for 1 h. After removal of solvent, 10% citric acid was added and the organic phase was separated and dried over MgSO4. After removing the solvent under reduced pressure, the resulting residue was treated with 50% trifluoroacetic acid in dichloromethane at room temperature for 30 min. After removing the solvent under reduced pressure, the resulting residue was purified by reverse phase preparative HPLC to afford 208 mg of the title compound. 1H NMR (CD3OD, 400 MHz): 1.35 (t, 6H), 1.45 (s, 3H), 3.08 (dd, 2H), 3.80 (s, 3H), 4.28 (q, 4H), 5.83 (dd, 2H), 7.12–7.24 (m, 3H). MS (ESI) m/z 443.28 (M+H+).