Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.CS([O:11][S:12]([CH3:15])(=[O:14])=[O:13])(=O)=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]([CH3:29])[CH:22]=[C:21]2[C:30]1[N:40]([S:41]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)(=[O:43])=[O:42])[C:33]2=[N:34][CH:35]=[CH:36][C:37]([CH2:38]O)=[C:32]2[CH:31]=1>ClCCl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]([CH3:29])[CH:22]=[C:21]2[C:30]1[N:40]([S:41]([C:44]2[CH:45]=[CH:46][C:47]([CH3:50])=[CH:48][CH:49]=2)(=[O:43])=[O:42])[C:33]2=[N:34][CH:35]=[CH:36][C:37]([CH2:38][O:11][S:12]([CH3:15])(=[O:13])=[O:14])=[C:32]2[CH:31]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: COc1cc2c(-c3cc4c(CO)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc2c(-c3cc4c(COS(C)(=O)=O)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Reaction time: 1 h
Yield: 29.2 %

Procedure:
0.064 g of pyridine and 0.092 g of methanesulfonic anhydride are added to a solution of 0.13 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-yl]methanol in 5 cm3 of dichloromethane, at a temperature in the region of −10° C. The reaction medium is stirred at this same temperature for one hour, and then at room temperature for 24 hours. Ice and 15 cm3 of dichloromethane are added. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. After purification by flash-pack chromatography (SiO2, dichloromethane/methanol 98/02 by volume as eluent), 0.044 g of methanesulfonic acid 2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl ester is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][C@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][N:6]1C(OC)=O)[CH:2]([CH3:4])[CH3:3]>Br>[CH2:1]([C@H:5]1[CH2:10][C@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][NH:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1CC(C)C
Agent: Br
Product: CC(C)C[C@H]1C[C@H](c2cc(=O)[nH]o2)CCN1
Yield: 89.2 %

Procedure:
Racemic trans-methyl 2-isobutyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.39 g, 1.3 mmol) was stirred in HBr (33% in HOAc) for 16 h. The volatiles were concentrated and the residue purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 10 minutes with a flow of 100 mL/minutes. The title compound (0.26 g) was isolated. 1H NMR (600 MHz, d2o) δ 0.76 (d, 3H), 0.79 (d, 3H), 1.14 (m, 1H), 1.33-1.41 (m, 1H), 1.45 (m, 1H), 1.59 (m, 1H), 1.76 (m, 1H), 1.98 (m, 1H), 2.06 (m, 1H), 2.21 (m, 1H), 3.04 (m, 2H), 3.14-3.31 (m, 4H), 5.67 (s, 1H).
Reaction SMILES: [CH3:1][C@H:2]([CH2:7][C:8](OC)=O)[C:3](OC)=O.[NH2:12][C@H:13]([CH3:16])[CH2:14][OH:15]>>[CH3:1][C@@H:2]1[CH2:7][CH2:8][N:12]([C@H:13]([CH3:16])[CH2:14][OH:15])[CH2:3]1
Reactant: COC(=O)C[C@@H](C)C(=O)OC
Reactant: C[C@@H](N)CO
Product: C[C@@H]1CCN([C@H](C)CO)C1

Procedure:
The title compound was synthesized as described in Intermediate 11 using (R)-dimethyl 2-methylsuccinate and (R)-2-aminopropan-1-ol as starting materials. 1H NMR (CDCl3): δ 3.57 (dd, 1H), 3.32 (dd, 1H), 3.02 (br s, 1H), 2.81 (dd, 1H), 2.69 (m, 2H), 2.60 (m, 1H), 2.20 (m, 1H), 2.12 (dd, 1H), 1.98 (m, 1H), 1.32 (m, 1H), 1.04 (m, 6H); MS: 144.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(Br)ccc1F
Product: O=C(O)c1cc(Br)ccc1N1CCOCC1

Procedure:
The title compound was prepared according to the procedure described for example B step 1 from 5-Bromo-2-fluorobenzoic acid and morpholine except that the mixture was heated at 130° C. for 48 hours (77%, white solid), 1-H-NMR (300 MHz, CDCl3) δ=8.45 (d), 7.74 (dxd, 7.33 (d)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:16][O:15][CH2:14][CH2:13][N:12]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:7][CH:6]=1)=O.[BH4-].[Li+].Cl>C1COCC1.CCOC(C)=O>[OH:2][CH2:3][C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]2[CH2:16][O:15][CH2:14][CH2:13][N:12]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc([C@@H]2COCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccc(CO)cc1
Temperature: 0 °C
Yield: 95.1 %

Procedure:
To a solution of tert-butyl (3R)-3-(4-methoxycarbonylphenyl)morpholine-4-carboxylate 9 (6.91 g, 21.50 mmol) in THF (140 mL) was added lithium borohydride (1.873 g, 86.00 mmol) and the resulting mixture then heated under reflux overnight. Additional lithium borohydride (341 mg, 2 eq) was added and the reaction mixture heated under reflux for 2 h. The reaction mixture was cooled in an ice bath and then added ice-water, followed by 2M HCl (10 mL) and stirred until effervescence ceased then diluted with EtOAc (100 mL), mixed and the organic layer separated, washed sequentially with water (1×50 mL), brine (1×50 mL), dried over MgSO4, filtered and concentrated in vacuo to leave the product as a colourless viscous oil (6.0 g, 95% yield); 1H NMR (400.0 MHz, DMSO) d 1.40 (9H, s), 3.01 (1H, m), 3.49 (1H, m), 3.71-3.83 (3H, m), 4.27 (1H, m), 4.47 (2H, m), 4.96 (1H, s), 5.17 (1H, m) and 7.30 (4H, m) ppm.
Reaction SMILES: C(OC([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20]O)[CH:17]=2)[CH2:12]1)=O)C1C=CC=CC=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:43].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.[O-2].[O-2].[Mn+4].O.C(O)(=O)C>[ClH:43].[ClH:43].[ClH:43].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:20][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[CH2:12][NH:11][CH2:19]3)[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: O=C(OCc1ccccc1)N1Cc2ccc(CO)cc2C1
Agent: [Mn+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc3c(c2)CNC3)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 158.9 %

Procedure:
To a suspension of manganese dioxide (15.5 g, 178 mmol) in DCM (100 mL) was added 5-hydroxymethyl-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester (3.35 g, 11.8 mmol) and after 6 h stirring at RT a further addition of manganese dioxide (5 g, 57 mmol) was made. After a further 1 h stirring at RT Celite (7 g) was added and the solution was filtered through a bed of Celite™ giving a clear pale yellow solution. The Celite™ was washed with DCM and the volume of the combined organic solution adjusted to 100 mL by evaporation. N-Methylpiperazine (1.31 mL, 11.8 mmol) and acetic acid (0.68 mL) were added followed by sodium triacetoxyborohydride (4.98 g, 23.5 mmol). The yellow solution was stirred 16 h giving a colourless solution. To the solution was added 2M-HCl (10 mL, 20 mmol) giving an effervescence. After 30 min water (10 mL) and K2CO3 (5.5 g, 39.8 mmol) were added and the organic phase was dried (Na2SO4). After filtration 4M−HCl in dioxan (6 mL) was added with stirring and the suspension was evaporated to dryness. The residue was dissolved in MeOH with warming and after evaporation the solid was washed on a sinter with EtOAc then petrol (bp 40-60° C.) followed by drying in vacuo at 50° C. to give the title compound 3.61 g (70%). 1H NMR (400 MHz, Me-d3-OD): 7.65-7.51 (2H, m), 7.51-7.27 (6H, m), 5.23 (2H, s), 4.83-4.69 (4H, m), 4.49 (2H, s), 3.66 (8H, d), 3.03 (3H, s)
Reaction SMILES: [C:1]([Si:5]([O:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11]I)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[Cu](C#N)C#N.C[Li].[CH2:30]([O:37][C:38]1[CH:39]=[C:40]([CH:56]=[CH:57][CH:58]=1)[CH2:41][C:42]1[C:43](=[O:55])[CH2:44][C@@H:45]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH:46]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CCOCC>[CH2:30]([O:37][C:38]1[CH:39]=[C:40]([CH:56]=[CH:57][CH:58]=1)[CH2:41][C@@H:42]1[C@@H:46]([CH2:11][CH2:10][C@@H:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C@H:45]([O:47][Si:48]([C:51]([CH3:52])([CH3:53])[CH3:54])([CH3:49])[CH3:50])[CH2:44][C:43]1=[O:55])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C(Cc2cccc(OCc3ccccc3)c2)C(=O)C1
Reactant: CCCCC[C@@H](CCI)O[Si](C)(C)C(C)(C)C
Agent: N#C[Cu]C#N
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCCCC[C@@H](CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)[C@@H]1Cc1cccc(OCc2ccccc2)c1)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h

Procedure:
A 25 ml two-necked flask was flame dried and allowed to be cooled. (S)-tert-butyl(1-iodooctan-3-yloxy)dimethylsilane (1.18 g, 3.2 mmol) and 11.8 L ether were added to the reaction flask, followed by dropwise addition of tert-butyl-lithium (3.75 ml, 1.7M in pentane) at −70° C. A homogenous solution of copper cyanide (0.29 g, 3.2 mmol) and methyllithium (1.6 ml, 2M in ether) in 5.8 ml ether was cooled from room temperature to −70° C. and added to the reaction flask while stirring for 30 minutes. Then, a solution of (R)-2-(3-(benzyloxy)benzyl)-4-(tert-butyldimethylsilyloxy)cyclopent-2-enone (0.65 g, 1.6 mmol) in 6.5 ml ether at −70° C. was added to the reaction mixture for 30 minutes. The reaction was quenched with 40 ml saturated ammonium chloride (aq) containing 0.4 ml ammonium hydroxide. The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. Yield of the titled compound was 1.1 g (85%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]([CH3:17])[CH3:16])[CH:8]=2)[N:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][NH2:24]>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:24][CH2:23][C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]([CH3:17])[CH3:16])[CH:8]=2)[N:3]=1
Reactant: NCc1cccs1
Reactant: CN(C)c1ccc2nc(N)c(C#N)c(Cl)c2c1
Solvent: O
Product: CN(C)c1ccc2nc(N)c(C#N)c(NCc3cccs3)c2c1

Procedure:
3 g of 2-amino-3-cyano-4-chloro-6-dimethylaminoquinoline and 6 mL of 2-thienylmethylamine are stirred at 125° C. for 3 hours. The reaction mixture is poured onto 30 mL of water. The precipitated material is filtered off, washed with 20 mL of water. After drying 1.9 g of the title compound is obtained, m.p.: 211° C.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][CH3:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].O1CCOC[CH2:20]1>C=O.[Na+].P(O)(O)[O-]>[CH3:16][N:15]([CH3:20])[C@H:12]1[CH2:13][CH2:14][C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1
Reactant: CN[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Reactant: C1COCCO1
Agent: C=O
Agent: Cl
Agent: [Na+]
Product: CN(C)[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of trans-4-(4-hydroxyphenyl)-N-methylcyclohexanamine, hydrochloride (1.15 g) in dioxane (50 mL), aqueous formaldehyde solution (3.7 mL, 37%) and phosphorous acid monosodium salt (49 mL, 1N) is added concentrated aqueous sodium hydroxide solution until pH is neutral. The solution is stirred at a temperature close to 60° C. for 2 h, cooled to room temperature and brought to pH 7-8 by addition of concentrated aqueous sodium hydroxide solution. Evaporation of dioxane causes precipitation. The precipitate is filtrated and washed with water then diethyl ether to give 1.78 g of trans-N,N-dimethyl-4-(4-hydroxyphenyl)cyclohexanamine as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)=[CH:9][CH:10]=3)[C:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.I[CH2:39][CH2:40][CH3:41]>O>[CH2:39]([O:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)=[CH:9][CH:10]=3)[C:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1)[CH2:40][CH3:41]
Reactant: NC1=NC2(CO1)c1cc(O)ccc1Oc1ccc(-c3cncnc3)cc12
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc2c(c1)C1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A glass vial was charged with 2′-hydroxy-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (prepared as described in Example 2; 53.68 mg, 155 μmol), cesium carbonate (75.7 mg, 232 μmol), DMF (0.62 mL), and 1-iodopropane (16.6 μl, 170 μmol). The mixture was stirred at RT for 18 h, then poured into water (10 mL) and extracted with EtOAc (3×7 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on silica gel (eluting with 0-80% of a 90:10:1 DCM/MeOH/NH4OH solution in DCM) to give 2′-(1-propyloxy)-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine as a white solid. MS m/z=389.2 [M+H]+. Calc'd for C22H21N4O3: 389.2.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].OC(C(F)(F)F)=O.[CH:34]1([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][C:40]2=[O:45])[CH2:38][CH2:37][CH2:36][CH2:35]1>CN1C(=O)CCC1>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:42]4[CH2:43][CH2:44][N:39]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:40](=[O:45])[CH2:41]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reactant: O=C1CNCCN1C1CCCC1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C4CCCC4)C(=O)C3)nn12
Temperature: 180 °C
Reaction time: 5 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 50 mg, 0.145 mmol), KF (84 mg, 1.450 mmol), 1-cyclopentylpiperazin-2-one TFA salt (129 mg, 0.435 mmol) were suspended in NMP (483 μL). The RM was stirred at 180° C. for 5 h. The mixture was purified by preparative UPLC with acetonitrile and water (+0.1% TFA) The fractions were collected and acetonitrile was removed. It was taken up with MeOH and passed through an SPE cartridge of PL-HCO3 MP from polymer lab. The solvent was removed and a brown solid was obtained (tR 1.1 min (conditions 4), MH+=477)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=3)[NH:16][CH:15]=2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]=1.[H-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]=4)[CH:21]=3)[NH:16][CH:15]=2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(O)cc23)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(Oc4ccc([N+](=O)[O-])cn4)cc23)CC1
Temperature: 66 °C
Yield: 78 %

Procedure:
3-(N-t-Butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)-5-hydroxy-1H-indole and 2-chloro-5-nitropyridine were used. Sodium hydride (60% in oil) was the base, tetrahydrofuran was the reaction solvent, the reaction time was heated at reflux (66° C.) for 12 hours, and the chromatographic solvent system was diethyl ether/hexanes [1:3] to afford the title compound (78%) as a yellow foam: 1H NMR (CD3OD) δ8.88 (d, J=2.8 Hz, 1H), 8.39 (dd, J=2.8 and 9.1 Hz, 1H), 7.56 (d, J=2.1 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 7.31 (s, 1H), 6.94-6.88 (m, 2H), 5.98 (br m, 1H), 4.88 (s, NH), 4.00 (br m, 2H), 3.59 (br t, J=5.3 Hz, 2H), 2.50 (br m, 2H), 1.44 (s, 9H); LRMS (m/z, relative intensity) 436 (M+, 4), 379 (68), 363 (16), 335 (29), 57 (100); TLC [methylene chloride ether, 1:1]: Rf =0.5.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][CH2:20][N:19]([S:23]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=4[O:33][CH3:34])(=[O:25])=[O:24])[C:18]=3[CH:35]=2)=[O:13])=[CH:7][CH:6]=1)C.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:32][C:30]1[CH:29]=[CH:28][C:27]([O:33][CH3:34])=[C:26]([S:23]([N:19]2[C:18]3[CH:35]=[C:14]([C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:36])=[O:3])=[CH:6][CH:7]=4)=[O:13])[CH:15]=[CH:16][C:17]=3[O:22][CH2:21][CH2:20]2)(=[O:25])=[O:24])[CH:31]=1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C(=O)O)cc3)cc21
Temperature: 45 °C

Procedure:
A solution of 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo-[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester (0.91 g, 1.72 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL) was treated with 3N NaOH (5 mL, 15 mmol, 8.7 equiv.). The mixture was stirred at 45° C. for 30′. The mixture was then acidified with HCl 3N (5 mL) and the solid which precipitated was filtered, washing with water, and dried under high vacuum. 4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid was obtained as a white solid, 0.85 g (98%). MS (ISP): m/e=501.0 (M−H); δH (300 MHz; d6-DMSO) 12.65 (1H, s), 10.35 (1H, s), 8.05 (1H, d), 7.81-7.88 (5H, m), 7.66-7.71 (2H, m), 7.19 (1H, d), 6.98 (1H, d), 3.96 (2H, m), 3.85 (2H, m), 3.53 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:51])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][C:38]([F:41])([F:40])[CH2:37][C@H:36]3[C:42]([OH:44])=O)=[O:34])[N:28]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=[N:76][C:71]2[CH:72]=[CH:73][CH:74]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCC1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:51])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][C:38]([F:40])([F:41])[CH2:37][C@H:36]3[C:42](=[O:44])[NH:76][CH:71]3[CH2:72][CH2:73][CH2:74]3)=[O:34])[N:28]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CC(F)(F)C[C@H]3C(=O)O)n(-c3ccccc3)n2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CC(F)(F)C[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 4 h

Procedure:
To a solution of 100 mg 4-[(S)-4-tert-Butoxycarbonyl-2-({5-[2-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 5 ml DMF were added 24 μl DIPEA, 53 mg HATU and 12 μl cyclobutylamine. After stirring for 4 h the mixture was dissolved in ethyl acetate and washed with aqueous LiCl (4% w/w) and saturated aqueous NaHCO3. The solvent was evaporated, the residue dissolved in 1.5 ml dichloromethane and treated with 300 μl TFA. After stirring for 34 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 43 mg MS (ES+): m/e=718.
Reaction SMILES: [C:1]([C:3](=[N:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([NH:6][CH2:7][CH2:8][CH3:9])=[O:5])#[N:2].[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)(=O)C>C1(C)C=CC=CC=1>[NH2:2][C:1]1[C:17]2[C:12](=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)[N:11]=[N:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH3:9])=[O:5]
Reactant: CCCNC(=O)C(C#N)=NNc1ccccc1-c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCNC(=O)c1nnc2c(-c3ccccc3)cccc2c1N
Temperature: 25 °C
Yield: 93.9 %

Procedure:
To a suspension of the product of Example A (9.50 g) in dry toluene (150 ml) was added aluminum chloride (14.44 g). The mixture was stirred under nitrogen at reflux (110°) for three hours. The reaction mixture was then cooled to room temperature, and the toluene was decanted from the dark, oily layer into a flask. The oily layer was chilled to 0°, and aqueous sodium hydroxide (1 Liter of 20% w/v solution) was slowly added with stirring to produce a yellow suspension which was stirred with the previously decanted toluene and ethyl acetate (1 Liter) until the precipitate dissolved. The organic layer was separated and the aqueous layer was extracted two times with ethyl acetate (500 ml each time). The extracts were combined, washed with water (1 Liter) and saturated NaCl (500 ml), dried, and evaportated in vacuo to provide 8.92 g (94% yield) of a yellow solid. The solid was purified by flash chromatography over silica gel. Elution with dichloromethane/acetonitrile (95:5) provided the title compound as 7.70 g (81% yield) of an off white solid. Recrystallization from toluene/hexane provided 6.43 g (68% yield) of white crystals m.p. 153°-155°. A second recrystallization from toluene/hexane provided the title compound as white crystals, m.p. 153°-155°. 1H NMR (CHCl3 -d, characteristic peaks only): 1.00 (t, 3H), 1.66 (sextet, 2H), 3.46 (q, 2H), 7.43-7.54 (m, 3H), 7.69-7.88 (m, 5H), 8.60 (br.t, exchangeable, 1H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(Cl)([Cl:20])=O>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([Cl:20])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)Cl)c1

Procedure:
Into a 100 mL round bottom flask a mixture of 5 parts of 3-tert-butyldimethylsilyloxybenzoic acid and 25 mL of thionyl chloride was heated at reflux for 90 mins. The reaction mixture was concentrated under reduced pressure to give an oil, yield 5.77 parts of the following structure.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[S:10]([CH3:13])(=[O:12])=[O:11].O.[NH2:15][NH2:16]>>[NH:15]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[S:10]([CH3:13])(=[O:12])=[O:11])[NH2:16]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1F
Reactant: NN
Solvent: O
Product: CS(=O)(=O)c1cc(C#N)ccc1NN
Yield: 79 %

Procedure:
A suspension of 4-fluoro-3-(methylsulfonyl)benzonitrile (1.96 g, 9.83 mmol) in IMS (30 mL) was treated with hydrazine monohydrate (1.19 mL, 24.8 mmol) and then heated at reflux for 1 hr. The reaction mixture was cooled then filtered and the solid residue was collected and dried in vacuo to afford the title compound as a cream solid (1.64 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13]C(=O)C)(=[O:3])[CH3:2]>Cl>[NH2:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1C(C)=O
Agent: Cl
Product: CC(=O)c1cc([N+](=O)[O-])ccc1N
Temperature: 80 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A mixture of 4 (85.56 g, 0.39 moles) and 6 N HCl (600 mL) was stirred for 2 h at 80° C. The suspension was filtered, washed with water, and air-dried to afford 1-(2-amino-5-nitro-phenyl)ethanone 5 (54.95 g, 79% yield). 1HNMR(400 MHz, DMSO-d6) δ2.61 (s, 3H), 6.86 (d, 1H, J=9.4 Hz), 8.07 (dd, 1H, J=2.6, 9.4 Hz), 8.61 (d, 1H, J=2.6), 8.08-8.61 (bs, 2H); MS m/z 180 (M+).