Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[CH:7]=[C:8]([OH:13])[C:9]2=[O:12])=[CH:4][CH:3]=1.Cl.[CH3:16]O>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[CH:7]=[C:8]([O:13][CH3:16])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1C=C(O)C(=O)c2cc(Cl)ccc21
Reactant: CO
Agent: Cl
Product: COC1=CC(=O)c2ccc(Cl)cc2C1=O
Temperature: 25 °C

Procedure:
7-Chloro-2-hydroxy-1,4-naphthoquinone (0.73 g) was added to 4% (w/w) hydrogen chloride in methanol (14 mL). The solution was heated to reflux for 0.5 hour. Upon cooling to room temperature, a precipitate formed which was filtered, washed (methanol) and dried under vacuum (25° C., 15 Pa) to give an orange solid (0.72 g); 250 MHz NMR: 8.10 (d,1, J=2.2), 8.04 (d,1, J=8.3), 7.71 (dd,1, J=8.3, 2.2), 6.19 (s,1), 3.92 (s,3).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[O:17](S(C(F)(F)F)(=O)=O)[S:18]([C:21]([F:24])([F:23])[F:22])(=O)=[O:19]>C(Cl)Cl>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:2]=1[NH:1][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:19])=[O:17])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a solution of 2-amino-5-chlorobenzophenone (500 mg, 2.16 mmol) in anhydrous CH2Cl2 (30 mL) at 0° C. was added dropwise (CF3SO2)2O (545 μL, 3.24 mmol) in anhydrous CH2Cl2 (10 mL) over 10 min and the reaction allowed to warm to RT over 15 hours. The reaction mixture was washed with water, dried over MgSO4 and concentrated under vacuum. The residue was filtered through a pad of silica (eluting with CH2Cl2/PE, 7:3) to afford N-(2-benzoyl-4-chlorophenyl)trifluoromethanesulfonamide 25 (710 mg, 90%), as a pale yellow solid. 1H n.m.r. (200 MHz, CDCl3) δ 7.80-7.69, m, 3H, 7.66-7.51, m, 5H. HRMS (M+) 362.9928.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C@@H:15]1[CH2:19][C@@H:18]([C:20]([O:22][CH3:23])=[O:21])[NH:17][CH2:16]1)=[O:13])[CH2:7]2.[C:24]([O:28][C:29]([C@@H:31]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:32](O)=[O:33])=[O:30])([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC#N>[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C@@H:15]1[CH2:19][C@@H:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]([C:32](=[O:33])[C@@H:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:16]1)=[O:13])[CH2:7]2
Reactant: COC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Cl)c3C2)CN1
Reactant: CC(C)(C)OC(=O)[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Cl)c3C2)CN1C(=O)[C@@H](C(=O)OC(C)(C)C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 200 mL round-bottomed flask was charged with (3R,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl 4-chloroisoindoline-2-carboxylate hydrochloride (1.20 g, 3.32 mmol), (S)-2-(tert-butoxycarbonyl)-3,3-dimethylbutanoic acid (807 mg, 3.49 mmol) and HATU (1.90 g, 4.98 mmol) in dry MeCN (30 mL). The solution was then cooled on an ethanol-ice bath and treated with DIEA (1.74 mL, 9.97 mmol) by dropwise addition. The mixture was stirred at 0° C. for 1 h, then allowed to warm up and stirred at room temperature for 16 h. The mixture was then concentrated and the residue dissolved in EtOAc (100 mL) and washed with iced 5% citric acid (aq.) (3×30 mL), 1M NaOH (3×30 mL), water (3×30 mL) and brine (3×30 mL). The organic layer was dried over MgSO4, filtered and concentrated to an oil. The oil was purified by chromatography (Biotage) eluting with 35% EtOAc-hexanes to give the product as a white foam, 1.27 g, 71%. MS m/e 438 (M+H)+−Boc. 1H NMR (400 MHz, d6-DMSO) δ 7.3-7.4 (m, 3H), 6.7-6.76 (m, 1H), 5.24 (bs, 1H), 4.4-4.76 (m, 4H), 4.12-4.2 (m, 1H), 3.96-4.3 (m, 1H), 3.7-3.78 (m, 1H), 3.64 (d, 3H), 2.38-2.48 (m, 1H), 2.07-2.16 (m, 1H), 1.14 (d, 9H), 0.98 (s, 9H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:6]=[CH:7][C:8]([C:16]([OH:18])=O)=[N:9][C:10]=2[O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH2:3][CH2:2]1.[NH2:19][C@@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22]>>[C:21]([C@@H:20]([NH:19][C:16]([C:8]1[CH:7]=[CH:6][C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[C:10]([O:11][CH2:12][CH:13]2[CH2:14][CH2:15]2)[N:9]=1)=[O:18])[CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:22])[NH2:23]
Reactant: O=C(O)c1ccc(NC2CC2)c(OCC2CC2)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1ccc(NC2CC2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 133 b) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=361.3 [M+H]+.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][NH:21][CH2:22]4)=[CH:17][CH:16]=3)[N:12]=[C:11]([NH2:25])[N:10]=2)[CH2:5][CH2:4]1.F[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1.CN1CCOCC1>CN1CCCC1=O>[NH2:25][C:11]1[N:12]=[C:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][N:21]([C:27]4[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=4)[CH2:22]3)=[CH:17][CH:16]=2)[CH:14]=[C:9]([N:6]2[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]2)[N:10]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(c3ccc(C#N)cc3)CC4)nc(N)n2)CC1
Temperature: 180 °C

Procedure:
A mixture of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (17 mg, 0.039 mmol), 4-fluorobenzonitrile (7.1 mg, 0.058 mmol) and 4-methylmorpholine (13 μL, 0.12 mmol) in N-methylpyrrolidinone (0.4 mL) was heated at 180° C. overnight. After cooling, the mixture was filtered, diluted with methanol, and purified by RP-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=426.4.
Reaction SMILES: Br[CH2:2][C:3]([C@H:5]1[N:8]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C:7](=[O:16])[C@@H:6]1[CH3:17])=O.[C:18]([C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1)([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[C:18]([C:22]1[CH:23]=[CH:24][C:25]2[N:26]([CH:2]=[C:3]([C@H:5]3[N:8]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C:7](=[O:16])[C@@H:6]3[CH3:17])[N:28]=2)[CH:27]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: C[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)CBr
Reactant: CC(C)(C)c1ccc(N)nc1
Solvent: CC#N
Product: C[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1c1cn2cc(C(C)(C)C)ccc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(3R,4S)-4-(2-bromoacetyl)-1-(tert-butyldimethylsilyl)-3-methylazetidin-2-one (Preparation 72, 1144 mg, 3.57 mmol) and 5-(tert-butyl)pyridin-2-amine (537 mg, 3.57 mmol) were mixed in acetonitrile (10 mL) and the reaction mixture stirred for 18 hours at room temperature, then an additional 18 hours at 65° C. to complete the dehydration. The reaction solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in hexanes to afford the title compound which was immediately taken to the next step.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)(=O)=O.[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:22].[O-]CC.[Na+].S([O-])(=O)(=O)C.C(O)(=O)C>CCO>[C:21]([CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C#N)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 37.5 °C

Procedure:
Combine tert-butyl 4-(2-methylsulfonyloxyethyl)piperidine-1-carboxylate (5.26 kg, 17.1 mol), ethyl cyanoacetate (7 kg, 62 mol), 21% sodium ethoxide in EtOH (8.25 L, 24.75 mol) and EtOH (35 L) in a 50 L reactor under a nitrogen atmosphere. Heat the mixture at 35-40° C. for 18 h at which time NMR analysis shows 20% of the mesylate remaining Continue heating the mixture at 35-40° C. for 24 h at which time NMR analysis shows only a small amount of mesylate. Slowly cool the reaction to RT and add glacial acetic acid (1422 mL, 22.68 mol) over 30 min. Concentrate the mixture using vacuum distillation and then partition between water (25 L) and EtOAc (35 L). Separate the layers and extract the aqueous phase with EtOAc (10 L). Combine the organic portions, wash with brine (15 L), and concentrate to a red oil. Purify the oil using silica gel chromatography (75 kg silica gel, 65-250 mesh), eluting with hexane (40 L) and then 20% EtOAc/hexane to provide a fraction (7.8 kg) that is 30% ethyl cyanoacetate/70% desired product. Concentrate the material by wipe film distillation at 100° C. and 210 mtorr vacuum, collecting the non-volatile fraction to provide the title compound (4.54 kg, 82%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:17]([N:24]1[CH2:29][CH2:28][N:27]([C:14]([C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:16])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N1CCN(Cc2ccccc2)CC1
Yield: 74.3 %

Procedure:
A solution of (S)-(−)-1-Boc-2-piperidine carboxylic acid 1 g (4.27 mmol), 1-benzylpiperazine 0.77 g (4.27 mmol), EDC 1.64 g (8.54 mmol) and catalytic amount of 4-(dimethylamino)pyridine in methylene chloride (50 ml) was stirred at room temperature overnight. The reaction mixture was concentrated and applied to flash column chromatography using methylene chloride and methanol (100:5) as eluents to give 1.23 g of desired product in 74.5% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:25]3[CH:30]=[CH:29][C:28]([O:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH:17]C(OC(C)(C)C)=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[NH2:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:25]2[CH:30]=[CH:29][C:28]([O:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=2)([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[N:9]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(c2ccc(OS(C)(=O)=O)cc2)(c2cccc(Br)c2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Oc1ccc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)cc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To methanesulfonic acid 4-[1-(3-bromo-phenyl)-3-tert-butoxycarbonylamino-1H-isoindol-1-yl]-phenyl ester (Scheme #6, T) (730 mg, 1.31 mmol) was added 10% trifluoroacetic acid in dichloromethane (10 mL) and the reaction stirred 30 minutes. The solvents were removed under reduced pressure and the resulting oil put under high vacuum. Ether, 20 mL, was added to the gum and the solvent removed under reduced pressure giving the title compound (671 mg, 90%). 1H NMR (500 MHz, DMSO-d6) δ 8.32 (d, J=7.9 Hz, 1 H), 7.90-7.86 (m, 2 H), 7.76 (ddd, J=7.9, 6.1, 2.0 Hz, 1 H), 7.63 (d, J=8.0 Hz, 1 H), 7.46 (t, J=1.8 Hz, 1 H), 7.41-7.35 (m, 5 H), 7.31 (d, J=8.5 Hz, 1 H), 3.40 (d, J=4.0 Hz, 3 H); MS (ES+) m/z 457 [M+1]+; tR=1.84 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][C:15]1[N:16]=[N:17][NH:18][N:19]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:53]([O:55][C:56]([N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1)=[O:57])[CH3:54]>CN(C=O)C>[CH2:53]([O:55][C:56]([N:58]1[CH2:59][CH2:60][N:61]([C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][C:15]2[N:16]=[N:17][NH:18][N:19]=2)[CH2:62][CH2:63]1)=[O:57])[CH3:54]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1nn[nH]n1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCc2nn[nH]n2)NC(=O)OC(C)(C)C)CC1

Procedure:
To a solution of 82 mg (S)-2-tert-butoxycarbonylamino-4-(2H-tetrazol-5-yl)-butyric acid in 2 ml DMF were added 115 mg HATU, 100 μl DIPEA and 44 μl 1-ethoxycarbonyl-piperazine. After 1 h the solution was concentrated and the residue directly used in the next reaction step. Yield: 120 mg.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][CH:16]=[O:17])[CH2:6][C@@H:5]1[CH3:18])(=[O:3])[CH3:2].[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:24]3[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][CH:16]=[O:17])[CH2:6][C@@H:5]1[CH3:18])(=[O:3])[CH3:2]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC=O)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)N1c2ccc(-c3ccc(C=O)cc3)cc2[C@H](NC=O)C[C@@H]1C
Reaction time: 2 h

Procedure:
To a solution of [(cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]formamide (for a preparation see Intermediate 43) (82 g, 0.263 mol) in DME (2 L) are added (4-formylphenyl)boronic acid (51.4 g, 0.34 mol) at room temperature. A 2N solution of Na2CO3 (527 mL, 1.05 mol) and tetrakis(triphenylphosphine)palladium(0) (8.2 g, 10% w/w) are added and the mixture is heated to reflux under a nitrogen atmosphere. After 2 hours, the reaction is complete and the mixture is concentrated under reduced pressure. The residue is taken up in water (1 L) and the darkened mixture is diluted with EtOAC (1 L) and transferred to a separatory funnel. A dark precipitate has formed and is isolated by filtration after separation of the organic phase. The organic layer is dried over Na2SO4 and delivers the title compound (37.5 g) as a yellow solid after concentration under reduced pressure and precipitation of the organic residue in a DCM/hexane mixture. The dark solid is taken up in a DCM/MeOH mixture and purified by flash chromatography on silica gel eluting with a 80/2 ratio of DCM/MeOH to afford the title compound (45 g) as a yellow brown solid. Mp: 85.6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)#[N:18]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:17]#[N:18])[CH:20]=2)(=[O:27])=[O:26])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Product: N#Cc1cccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)c1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 100 mg of 3-cyano-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.36 (d, 1H, J=2.4 Hz), 7.57-7.62 (m, 4H), 7.68 (d, 1H, J=8.8 Hz), 7.80 (m, 1H), 8.04 (m, 2H), 8.90 (dd, 2H, J=4.8 Hz, 1.6 Hz), 10.3 (b, 1H). MS: m/z 398.8 (M++1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=1[O:25][CH3:26]>N1C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=1[O:25][CH3:26])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc(C#N)ccc1O
Solvent: c1ccncc1
Product: COc1cc(C#N)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
24 ml (141 mmol) of trifluoromethanesulfonic anhydride are slowly added dropwise to a solution of 20 g (134 mmol) of 4-hydroxy-3-methoxybenzonitrile in pyridine (80 ml), keeping the reaction temperature below 25° C. with the aid of an ice bath. The suspension is then stirred at RT for 1 h. Ice-water (400 ml) is added, and the suspension is stirred further until room temperature is reached. It is then filtered, the solid is dissolved in ethyl acetate, and this solution is washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. 37.13 g (92% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[C:5]1(=[O:12])[O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>[Zn].O>[OH:12][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:1][CH2:2][CH2:3][SH:4])=[O:11]
Reactant: NCCS
Reactant: O=C1CCCCCO1
Agent: [Zn]
Solvent: O
Product: O=C(CCCCCO)NCCS
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture, under an inert atmosphere, of 5 g of cysteamine and 7.2 cm3 of ε-caprolactone is stirred for 6 hours at ambient temperature. It is then left to stand overnight, after which the mixture is heated for 4 hours at a temperature of about 60° C. At the end of this time all the ε-caprolactone is transformed. The mixture is then poured into 100 cm3 of water to which 10 g of acid resin, "Dowex 50" are added and then 3 g of powdered zinc. The whole is stirred for 4 hours at ambient temperature. The water is then removed under reduced pressure and there are obtained 10 g of 6-hydroxy N-(2-mercaptoethyl) caproamide in the form of a viscous liquid at ambient temperature whose NMR1H spectrum and thiol dosages and residual amine correspond to the expected structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[C:16]([F:20])[C:17](F)=[CH:18][C:11]=3[O:10][CH2:9]2)=[CH:5][CH:4]=1.[CH3:23][NH2:24].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[C:16]([F:20])[C:17]([NH:24][CH3:23])=[CH:18][C:11]=3[O:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: CN
Reactant: COc1ccc(CN2COc3cc(F)c(F)cc3C2=O)cc1
Solvent: O
Solvent: CS(C)=O
Product: CNc1cc2c(cc1F)C(=O)N(Cc1ccc(OC)cc1)CO2
Temperature: 120 °C
Yield: 85.4 %

Procedure:
To 3-(4-methoxybenzyl)6,7-difluor-2,3-dihydrobenzo[e][1,3]oxazin-4-one (1.15 g, 3.7 mmol) in dimethyl sulfoxide (10 mL) was added methyl amine (2.5 mL, 5 mmol, 2M solution in tetrahydrofuran) and the reaction heated to 120° C. for 1 hr. Water was added and product extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give 1 g (85%) of 3-(4-methoxybenzyl)6-fluoro-7-(methylamino)2,3-dihydrobenzo[e][1,3]oxazin-4-one. RP-HPLC: 2.82 min; ES-MS (M+H)+=318.0; 1H-NMR (DMSO-d6) δ (ppm): 7.6 (d, 1), 6.8 (d, 2), 6.4 (d, 1H), 5.0 (s, 2), 4.6 (s, 2), 3.7 (s, 3), 2.8 (s, 3).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]([C@@H:11]1[CH2:14][C@H:13]([CH:15]([C:26]([O:28][CH3:29])=[O:27])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12]1)=[O:10].Br[CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]([C:15]([C@H:13]1[CH2:14][C@@H:11]([C:9]([O:8][CH3:7])=[O:10])[CH2:12]1)([CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:27]
Reactant: COC(=O)C(C(=O)OCc1ccccc1)[C@H]1C[C@@H](C(=O)OC)C1
Reactant: BrCc1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1cccc2ccccc12)(C(=O)OCc1ccccc1)[C@H]1C[C@@H](C(=O)OC)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of potassium t-butoxide (0.44 g, 3.93 mmol) in dry tetrahydrofuran (20 ml) cooled to 0° C. under a nitrogen atmosphere was added dropwise a solution of benzyl methyl cis-3-methoxycarbonylcyclobutylmalonate (1.25 g, 3.9 mmol) in dry tetrahydrofuran (20 ml) followed by dropwise addition of 1-(bromomethyl)naphthalene (2.58 g, 11.7 mmol) in dry toluene (15 ml). Stirring was continued at 0° C. for 4 hours, aqueous hydrochloric acid (2M, 15 ml) was then added and the mixture extracted with diethyl ether. The organic phase was dried, filtered and evaporated to an oil (2.5 g). The oil was dissolved in dichloromethane and filtered through a pad of flash silica, the solvent was removed and the resulting oil (2.0 g) purified by chromatography on silica using a Biotage Flash 40 eluting with dichloromethane to give the title compound as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([N+:13]([O-])=O)[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[H][H]>CO.[Pt]>[NH2:13][C:4]1[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[CH3:16]
Reactant: [H][H]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Product: COc1c(C(C)=O)cc(Cl)c(C)c1N

Procedure:
1-(5-Chloro-2-methoxy-4-methyl-3-nitrophenyl)ethanone (5.0 g, 20 mmol) was hydrogenated in 100 mL of methanol in the presence of 0.5 g of 10% Pt/C, under a balloon pressure of hydrogen overnight. The catalyst was filtered off and the filtrate was concentrated. The residue was dissolved in dichloromethane and dried over sodium sulfate and then evaporated to dryness. The crude product was used directly in next step (4.4 g, 100%). LCMS calculated for C10H13ClNO2 (M+H)+: m/z=214.1. found: 214.1.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[NH:21]1[CH:25]=[CH:24][CH:23]=[N:22]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N:21]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-n3cccn3)nc2c1
Temperature: 50 °C
Yield: 78.3 %

Procedure:
A mixture of 0.24 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.14 g of pyrazole, 0.69 g of potassium carbonate and 4 ml of DMF was stirred while heating at 50° C. for two hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.22 g of 2-[3-(pyrazole-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 58”).