Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@@:15]2([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt]=O.CO>[CH2:1]([N:8]1[CH2:16][C@@:15]2([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@H:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=CC[C@@]2(Cc3ccccc3)CN(Cc3ccccc3)C[C@H]2C1
Agent: O=[Pt]
Solvent: CO
Product: c1ccc(CN2C[C@H]3CCCC[C@@]3(Cc3ccccc3)C2)cc1
Reaction time: 1 h
Yield: 103.3 %

Procedure:
A mixture of 0.46 g (1.3 mmoles) of cis-2,3a-dibenzyl-3a,4,7,7a-tetrahydroisoindoline (Ex. 13), 0.46 g of platinum oxide and 100 mL of methanol were hydrogenated at 50 p.s.i. for 1 h. The catalyst was removed by 5 filtration through celite and the filtrate was evaporated to give 0.41 g of the title compound as a clear oil.
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:10])[NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[Br:11]Br>CC(O)=O.O>[Br:11][C:2]1[S:1][C:5]2[C:6](=[O:10])[NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=1
Reactant: BrBr
Reactant: O=C1NCCc2ccsc21
Solvent: O
Solvent: CC(=O)O
Product: O=C1NCCc2cc(Br)sc21
Reaction time: 1.5 h
Yield: 72.8 %

Procedure:
To a 0° C. solution of 5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (820 mg, 5.36 mmol) in HOAc (7 mL) and (5 mL) water was added bromine (303 μL, 5.9 mmol) and the reaction was stirred 1.5 h. The reaction was diluted in water (30 mL) and the aqueous mixture was extracted with EtOAc (2×50 mL). The combined organics were washed with 5% aq. Na2SO3 (40 mL), sat. aq. NaHCO3 (40 mL), and brine (40 mL). The organic was dried over Na2SO4, then filtered and concentrated. After purification by flash chromatography over silica gel (50-100% EtOAc/hexane eluent), 2-bromo-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (906 mg, 73% yield) was isolated as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.10 (s, 1H), 3.55 (t, J=7.0 Hz, 2H), 2.88 (t, J=7.0 Hz, 2H); MS (EI) m/z=233.1 [M+1]+.
Reaction SMILES: [C:1]([O:4][CH:5]1[NH:8][C:7](=[O:9])[CH:6]1[CH2:10][CH2:11][CH3:12])(=[O:3])[CH3:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([N:8]1[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]([CH2:10][CH2:11][CH3:12])[C:7]1=[O:9])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CCCC1C(=O)NC1OC(C)=O
Solvent: c1ccncc1
Product: CCCC1C(=O)N(C(C)=O)C1OC(C)=O
Reaction time: 24 h
Yield: 23 %

Procedure:
A mixture of 56 mg (0.33 mM) 4-acetoxy-3-propylazetidin-2-one, 1 ml acetic anhydride and 1 ml pyridine was stirred at 100° in a sealed tube for 24 hours. After concentrating in vacuo the residue was chromatographed on silica gel in hexane/ethyl acetate, to yield 16 mg (23%) 1-acetyl-4-acetoxy-3-n-propyl-azetidine-2-one.
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([OH:22])[CH:21]=1)[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1)=[O:11])[CH2:4][F:5].CC([Si](C)(C)[O:28][CH2:29][CH2:30][N:31]([CH3:43])[C:32](=[O:42])[C:33]1[CH:38]=[CH:37][C:36](F)=[C:35]([F:40])[C:34]=1F)(C)C.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[F:5][CH2:4][CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([O:22][C:36]2[CH:37]=[CH:38][C:33]3[C:32](=[O:42])[N:31]([CH3:43])[CH2:30][CH2:29][O:28][C:34]=3[C:35]=2[F:40])[CH:21]=1)[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1)=[O:11])[CH2:2][F:1]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(F)c1F
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(OC(CF)CF)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN1CCOc2c(ccc(Oc3cc(OC(CF)CF)cc(C(=O)Nc4ccn(C)n4)c3)c2F)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.1 %

Procedure:
A solution of 3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (100 mg, 0.32 mmol), N-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-2,3,4-trifluoro-N-methylbenzamide (112 mg, 0.32 mmol) and potassium carbonate (89 mg, 0.64 mmol) in DMA (2 mL) was heated in a microwave reactor for 2 hours. Water (20 mL) was added and the solution extracted with ethyl acetate. The ethyl acetate layer was washed with brine (20 mL), dried (MgSO4) and evaporated to a residue which was taken up in DCM (10 mL) and TFA (5 drops) added. The mixture was stirred at RT for 2 hours. The solvent was evaporated to a residue, which was chromatographed by preparative HPLC on C18 reversed phase, eluting with 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA), to give the required product (5 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C@@H:7]([CH2:12][CH2:13][CH3:14])[CH2:6][C@H:5]2[NH:15][CH:16]=[O:17].[C:18](Cl)(=[O:20])[CH3:19].N1C=CC=CC=1>C(Cl)Cl>[C:18]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[C@H:5]([NH:15][CH:16]=[O:17])[CH2:6][C@@H:7]1[CH2:12][CH2:13][CH3:14])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CCC[C@H]1C[C@@H](NC=O)c2cc(Br)ccc2N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC[C@H]1C[C@@H](NC=O)c2cc(Br)ccc2N1C(C)=O
Reaction time: 1 h
Yield: 68 %

Procedure:
[(cis)-6-Bromo-2-propyl-1,2,3,4-tetrahydro-4-quinolinyl]formamide (for a preparation see intermediate 89) (8.0 g, 26.9 mmol) in DCM (100 mL) was added dropwise at room temperature to a mixture of acetyl chloride (6.7 mL, 94.28 mmol) and pyridine (10.85 mL, 134.7 mmol) in DCM (150 mL). The resulting mixture was stirred at this temperature for 1 h then was washed with 1M NaOH aqueous solution, 1M HCl aqueous solution, a saturated NaHCO3 aqueous solution then brine, was dried over MgSO4 and concentrated in vacuovacuo. Purification of the residue by flash chromatography on silica gel (20:1 DCM/MeOH) gave [(cis)-1-acetyl-6-bromo-2-propyl-1,2,3,4-tetrahydro-4-quinolinyl]formamide (6.29 g, 18.5 mmol, 68%) as a light orange solid.
Reaction SMILES: C(O)C.C1N2CN3CN(C2)C[N:5]1C3.N.Cl[CH2:16][C:17]([NH:19][C:20]1[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=1[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)=[O:18]>C(Cl)(Cl)Cl>[C:24]1([C:22]2[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[NH:19][C:17](=[O:18])[CH2:16][N:5]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(CCl)Nc1ccccc1C(=O)c1ccccc1
Agent: N
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C1CN=C(c2ccccc2)c2ccccc2N1
Reaction time: 3 h
Yield: 84.6 %

Procedure:
A mixture of ethanol (300 ml) and hexamethylenetetramine (20 g., 0.143 mol) was stirred, heated to reflux, and saturated with ammonia. 2-Chloroacetamidobenzophenone (18.1 g., 0.066 mol) was added in small increments over 3 to 4 hours while a steady stream of ammonia was bubbled into the reaction mixture. Refluxing was continued for 3 hours after complete addition of 2-chloroacetamidobenzophenone. The flow of ammonia was interrupted and the ethanol removed by distillation in vacuo. The residue obtained was taken up in chloroform (200 ml), and washed with water (100 ml) at 50° C. The chloroform layer was evaporated to dryness at 30° C. and the oily solid obtained was recrystallized from toluene (100 ml) to give 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (13.2 g., 86%), melting at 184°-186° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=O)[NH:33][C:32]=2[CH3:39])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=[C:15]3[C:14]4[C:18](=[CH:19][C:11]([C:4]5[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=5[O:2][CH3:1])=[CH:12][CH:13]=4)[NH:17][C:16]3=[O:20])[NH:33][C:32]=2[CH3:39])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: COc1ccc(-c2ccc3c(c2)NC(=O)C3)c(OC)c1
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C)c(C(=O)NCCN3CCCC3)c2C)c(OC)c1
Yield: 30.7 %

Procedure:
6-(2,4-Dimethoxyphenyl)-1,3-dihydroindol-2-one (51 mg, 0.19 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (50 mg) to give 30 mg (31%) of the title compound as an orange solid.
Reaction SMILES: [BrH:1].C(O)(=O)C.[Cl:6][C:7]1[CH:8]=[C:9]([C:13](=O)[CH2:14][S:15][C:16]#[N:17])[CH:10]=[CH:11][CH:12]=1.O>C(O)(=O)C>[Br:1][C:16]1[S:15][CH:14]=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=2)[N:17]=1
Reactant: Br
Reactant: N#CSCC(=O)c1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: O
Product: Clc1cccc(-c2csc(Br)n2)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A 25% hydrogen bromide/acetic acid (45 ml) solution was added to a solution of 2-(3-chlorophenyl)-2-oxoethyl thiocyanate (4.90 g, 23.2 mmol) in acetic acid (45 ml), and the mixture was stirred at 130° C. for 2 hours and at room temperature for 1 hour. Water (50 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 6.36 g (100%) of the desired product as a solid.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)=[N+]=[N-].O.NN>[Ni].CO>[NH2:1][C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](O)[C@H](N=[N+]=[N-])C[C@@H]12
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](O)[C@H](N)C[C@@H]12

Procedure:
2.0 g 16α-azido-3-methoxy-estra-1,3,5(10)-triene-17α-ol are reduced with 40 ml methanol, 4 ml of 80% hydrazine hydrate and 2 spatula tips Raney nickel in the above described manner. Recrystallization is performed from methanol/ether. Yield: 1.3 g (71%), F: at 145° C. conversion, at 193-198° C. melting; [α]D+44° (pyridine);
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:21][N:22]2[CH2:25][CH:24]([OH:26])[CH2:23]2)=[C:10]([CH:20]=1)[CH2:11][NH:12][C:13](=[O:19])[C@@H:14]1[CH2:18][CH2:17][CH2:16][NH:15]1.[OH:27][C:28]1([C:41](O)=[O:42])[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[OH:27][C:28]1([C:41]([N:15]2[CH2:16][CH2:17][CH2:18][C@H:14]2[C:13]([NH:12][CH2:11][C:10]2[CH:20]=[C:6]([Cl:5])[CH:7]=[CH:8][C:9]=2[CH2:21][N:22]2[CH2:25][CH:24]([OH:26])[CH2:23]2)=[O:19])=[O:42])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=2[C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2
Reactant: O=C(NCc1cc(Cl)ccc1CN1CC(O)C1)[C@@H]1CCCN1
Reactant: O=C(O)C1(O)c2ccccc2-c2ccccc21
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCc1cc(Cl)ccc1CN1CC(O)C1)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21

Procedure:
EDC (49.5, 0.26 mmol) was added to a stirred mixture of N-{5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzyl}-L-prolinamide (55.8 mg, 0.17 mmol), 9-hydroxy-9-H-fluoren-9-ylcarboxylic acid (40.9 mg, 0.18 mmol) and HOAT (11.7 mg, 0.086 mmol) in DMF (1.25 mL). After 16 h the mixture was concentrated and the residue was partitioned between EtOAc and 10% NaHCO3. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica (ammonia saturated CHCl3/MeOH, 98:2) to give the title compound as a glass: HRMS (FAB) calcd C30H31ClN3O4 (M+1) 554.1817, found 554.1855.
Reaction SMILES: [CH3:1][C:2]1([CH3:5])[CH2:4][NH:3]1.[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1>N1C=CC=CC=1.CCOCC>[CH3:1][C:2]1([CH3:5])[CH2:4][N:3]1[S:12]([C:9]1[CH:10]=[CH:11][C:6]([CH3:16])=[CH:7][CH:8]=1)(=[O:14])=[O:13]
Reactant: CC1(C)CN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N2CC2(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.2 %

Procedure:
To a solution of 2,2-dimethylaziridine (5.42 g; 0.076 mole; sold by Polysciences, Inc., Warrington, PA) in pyridine (100 mL) cooled in an ice bath, is added p-toluenesulfonyl chloride (21.81 g; 0.114 mole) in one portion. The reaction is stirred at 0° C. for 2 hours; diluted with ether (400 mL); washed with cold 10% H3PO4 (2×150 mL), with a saturated NaHCO3 solution (3×150 mL) and brine (1×150 mL); and dried over MgSO4. Rotary evaporation of the solution affords a yellowish solid which is crystallized from ethyl acetate to yield the product 2,2-dimethyl-N-p-toluenesulfonyl-aziridine (4.48 g). 1H NMR (CDCl3):1.53 (6H, s), 2.45 (5H, m), 7.2-8.0 ppm (4H, m, aromatics).
Reaction SMILES: F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C.C(OC([N:41]1[C:49]2[C:44](=[C:45]([O:53][CH3:54])[CH:46]=[C:47]([C:50]([OH:52])=O)[CH:48]=2)[CH2:43][CH2:42]1)=O)(C)(C)C.[CH2:55]([O:57][C:58](=[O:67])[C:59]1[CH:64]=[CH:63][C:62]([NH2:65])=[CH:61][C:60]=1[F:66])[CH3:56]>O1CCCC1>[CH2:55]([O:57][C:58](=[O:67])[C:59]1[CH:64]=[CH:63][C:62]([NH:65][C:50]([C:47]2[CH:48]=[C:49]3[C:44]([CH2:43][CH2:42][NH:41]3)=[C:45]([O:53][CH3:54])[CH:46]=2)=[O:52])=[CH:61][C:60]=1[F:66])[CH3:56]
Reactant: COc1cc(C(=O)O)cc2c1CCN2C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1ccc(N)cc1F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NC(=O)c2cc3c(c(OC)c2)CCN3)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27 %

Procedure:
Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (0.874 g, 1.88 mmol, 1.1 equiv.) and diisopropyl ethyl amine (0.46 mL, 3.58 mmol, 2.1 equiv.) were added to a solution of 4-methoxy-2,3-dihydro-indole-1,6-dicarboxylic acid 1-tert-butyl ester (0.500 g, 1.7 mmol, 1 equiv.) in tetrahydrofuran (10 mL) and the mixture was shaken for 5 minutes at room temperature. 4-Amino-2-fluorobenzoic acid ethyl ester (3.433 g 1.88 mmol, 1.1 equiv.) was added and the mixture shaken at room temperature for 16 hours. The solvent was removed under vacuum and the residue dissolved in trifluoroacetic acid (10 mL) and shaken for 1 hour at room temperature. The solvent was removed under vacuum and the residue was purified by column chromatography (SiO2, 1:1 Hept/EtOAc to EtOAc). The fractions were combined to afford crude 2-fluoro-4-[(4-methoxy-2,3-dihydro-1H-indole-6-carbonyl)-amino]-benzoic acid ethyl ester, 0.476 g (27% yield), this material was taken onto the next step without further purification. LC @215 nm; Rt 1.17: 46%, m/z (ES+): 359 (M+H+.).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16]([N:18]([CH3:35])[C@@H:19]([C@@H:31]([CH3:34])[CH2:32][CH3:33])[C@H:20]([O:29][CH3:30])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:17])[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1>CO.[Pd]>[CH3:30][O:29][C@@H:20]([C@@H:19]([N:18]([CH3:35])[C:16](=[O:17])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH2:11])[C@@H:31]([CH3:34])[CH2:32][CH3:33])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CO
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](N)C(C)C

Procedure:
500 mg (1 mmol) of tert-butyl (3R,4S,5S)-4-[{N-[(benzyloxy)carbonyl]-L-valyl}(methyl)amino]-3-methoxy-5-methylheptanoate (intermediate 1) were dissolved in 50 ml of methanol and, after addition of 100 mg of 10% palladium on activated carbon, hydrogenated under standard hydrogen pressure at RT for 1 h. The catalyst was then filtered off and the solvent was removed under reduced pressure. This gave 370 mg (quant.) of the title compound as a virtually colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[OH-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[F:1][C:2]1[CH:3]=[C:4]([NH:11][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(F)cc1NS(=O)(=O)c1ccccc1
Reaction time: 8 h

Procedure:
4-Fluoroanthranilic acid (1.5 g) and sodium hydroxide (0.4 g) were stirred in cold water (100 ml) at ca. 5°. Benzenesulphonyl chloride (1.25 ml) was added and the mixture was stirred overnight, acidified and extracted with dichloromethane. The extracts were washed, dried and evaporated to give 4-fluoro-N-(phenylsulphonyl)anthranilic acid, mp 158°-9°. (Compound 14).
Reaction SMILES: C(C1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)C.[C:36](Cl)(=O)[CH2:37][CH:38]([CH3:40])[CH3:39]>>[CH2:37]([C:36]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH:38]([CH3:40])[CH3:39]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(C)CC(=O)Cl
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(CC(C)C)nc4c(C)cc(C)nc43)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4 of Example 1) and isovaleryl chloride.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=[O:6].[CH3:10][S-:11].[Na+]>CO>[F:1][C:2]([F:9])([F:8])[CH:3]([S:11][CH3:10])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSC(CC(=O)O)C(F)(F)F
Yield: 99.5 %

Procedure:
To a 100 mL round bottom flask was added (E)-4,4,4-trifluorobut-2-enoic acid (8 g, 57.1 mmol) and Methanol (24 mL), the solution was stirred in a water bath, then sodium methanethiolate (10.01 g, 143 mmol) was added in three portions. Vigorous bubbling was observed, the mixture was stirred at 25° C. overnight, NMR showed no more starting material. To the reaction mixture was added 2 N HCl until acidic. The mixture was extracted with chloroform (5×50 mL), combined organic layer was dried over Na2SO4, concentrated in vacuo and further dried under high vacuum until there was no weight loss to give 4,4,4-trifluoro-3-(methylthio)butanoic acid (10.68 g, 56.8 mmol, 99% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 10.88 (s, 1H), 3.53 (dqd, J=10.5, 8.3, 4.0 Hz, 1H), 2.96 (dd, J=16.9, 4.0 Hz, 1H), 2.65 (dd, J=16.9, 10.4 Hz, 1H), 2.29 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.78 (s), 126.61 (q, JC-F=278.8 Hz), 44.99 (q, JC-F=30.3 Hz), 34.12 (d, JC-F=1.7 Hz), 15.95 (s); EIMS m/z 162.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.N1C=CC=CC=1>C(#N)C>[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:14][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(Nc1ccc2oc3c(c2c1)CCCC3)c1ccc(F)cc1
Yield: 65.9 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.50 g, 2.7 mmol), 4-fluorobenzoyl chloride (0.32 mL, 2.7 mmol), and pyridine (0.54 mL, 6.7 mmol) in acetonitrile (30 mL) provided 4-fluoro-N-(6,7,8,9-tetrahydrodibenzo[b,d]furan-2-yl)benzamide (0.55 g) after filtering the precipitate from the reaction mixture. MS (ESI) m/z 310 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[C:7]([CH:18]([OH:20])[CH3:19])=[C:6]1[N:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>ClCCl.[O-2].[O-2].[Mn+4]>[C:18]([C:7]1[C:8]2[N:9]([CH3:17])[C:10](=[O:16])[N:11]([CH3:15])[C:12](=[O:14])[C:13]=2[N:5]([CH2:4][C:3]2[CH:35]=[CH:36][CH:37]=[CH:38][C:2]=2[Cl:1])[C:6]=1[N:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1)(=[O:20])[CH3:19]
Reactant: CC(O)c1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2Cl)c2c(=O)n(C)c(=O)n(C)c12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(=O)c1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2Cl)c2c(=O)n(C)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
Manganese dioxide (0.66 g) was added to a solution of crude tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-(1-hydroxyethyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (167 mg) in dichloromethane (5 ml), and the resulting mixture was stirred overnight at room temperature. Then, the reaction solution was heated to 45° C. and stirred for 3 hours. The reaction solution was filtered through Celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (33 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[N:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][C:2]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)[N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[N:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
A mixture of 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (Intermediate B, 2 g, 6.43 mmol), 1-(bromomethyl)-3-nitrobenzene (1.39 g, 6.43 mmol) and Cs2CO3 (4.2 g, 12.9 mmol) in DMF (40 mL) was stirred at RT for 16 h. The mixture was then diluted with H2O and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with H2O (20 mL) and brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure to afford the title compound as a yellow solid (1.8 g, 56.4%). LC-MS (ES+) C19H13F3N6O4 requires: 446. found: 447 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].[Br:17][C:18]1[CH:19]=[CH:20][C:21](F)=[C:22]([CH:25]=1)[CH:23]=[O:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH2:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[C:22]([CH:23]=[O:24])[CH:25]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOCCNCCCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCN(CCCC(=O)OC(C)(C)C)c1ccc(Br)cc1C=O
Temperature: 90 °C
Reaction time: 60 h
Yield: 25.6 %

Procedure:
In DMF (43.9 ml) was dissolved tert-butyl 4-[(2-ethoxyethyl)amino]butyrate (5.5 g). To the solution was added 5-bromo-2-fluorobenzaldehyde (4.4 g), followed by addition of potassium carbonate (3.6 g). The mixture was stirred at 90° C. for 60 hours and cooled to room temperature. The reaction solution was added to water, the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=6/1→5/1) to give tert-butyl 4-(4-bromo(2-ethoxyethyl)-2-formylanilino]butyrate (2.3 g).