Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[NH2:13][C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)[N:18]=1.[C:30]1([CH:36]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:37][CH2:38][NH:39][CH2:40][CH2:41][CH:42]2[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[C:55]1([CH:36]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:37][CH2:38][N:39]([CH2:40][CH2:41][CH:42]2[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]2)[C:6]([NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=3)[N:18]=2)=[O:7])[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCNCCC(c2ccccc2)c2ccccc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)Nc1ccc(-c2csc(N)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCN(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2nc(-c3ccc(NS(C)(=O)=O)cc3)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DMAP (0.17 g, 1 0.4 mmol), CDI (0.23 g, 1.4 mmol) and N-(4-(2-aminothiazol-4-yl)phenyl)-methanesulfonamide (0.25 g, 0.93 mmol) were mixed together in DCM/DMF and then stirred overnight at room temperature. After 24 hrs a precipitate had formed. tert-butyl 4-(2-(3,3-diphenylpropylamino)ethyl)piperidine-1-carboxylate (0.39 g, 0.93 mmol) was then added and the resulting mixture stirred for a further 15 hrs. The crude mixture was concentrated under reduced pressure and the residue purified by combi-flash to give tert-butyl 4-(2-(1-(3,3-diphenylpropyl)-3-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)ureido)ethyl)piperidine-1-carboxylate 49 as an oily solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH2:7])[CH3:2].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH:20][C:21]1[C:30]([C:31]([OH:33])=[O:32])=[C:29]2[C:24]([CH:25]3[CH2:34][CH:26]3[CH2:27][O:28]2)=[CH:23][CH:22]=1)(=[O:19])=[O:18]>CN1C(=O)CCC1.O>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH:7][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH:20][C:21]1[C:30]([C:31]([OH:33])=[O:32])=[C:29]2[C:24]([CH:25]3[CH2:34][CH:26]3[CH2:27][O:28]2)=[CH:23][CH:22]=1)(=[O:19])=[O:18])[CH3:2]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: CCN(CC)CCCN
Solvent: O
Solvent: CN1CCCC1=O
Product: CCN(CC)CCCNc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 140 °C
Yield: 32.9 %

Procedure:
3-Diethylaminopropyl amine (0.975 g) was added to a solution of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (Intermediate 67, 0.091 g) in NMP (3 mL) and the mixture was heated at 140° C. in a sealed tube for 36 hours. After cooling, the mixture was diluted with water (2 mL) and the solution was purified by preparative HPLC (C18) eluting with a mixture of methanol and water, containing 0.1% formic acid, with a gradient of 10-98% to give (1aRS,7bSR)-5-[2-(3-diethylaminopropylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.039 g) as a white solid.
Reaction SMILES: B(Cl)(Cl)Cl.[CH3:5][NH:6][C:7]([C:9]1[C:13]2[CH:14]=[C:15]([O:23][CH:24](C)C)[C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=2[O:11][C:10]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:8].Cl[CH2:35]Cl>>[CH3:5][NH:6][C:7]([C:9]1[C:13]2[CH:14]=[C:15]([O:23][CH3:24])[C:16]([N:18]([S:19]([CH3:22])(=[O:21])=[O:20])[CH3:35])=[CH:17][C:12]=2[O:11][C:10]=1[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)=[O:8]
Reactant: ClCCl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(OC(C)C)cc12
Agent: ClB(Cl)Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(OC)cc12
Reaction time: 20 h
Yield: 100 %

Procedure:
Preparation of compound 29(a) (2-(4-fluoro-phenyl)-5-hydroxy-6-methanesulfonylamino-benzofuran-3-carboxylic acid methylamide). Boron trichloride (60 mL of 1M dichloromethane) was added for 10 minutes to 2-(4-fluoro-phenyl)-5-isopropoxy-6-methanesulfonylamino-benzofuran-3-carboxylic acid methylamide (7.10 g, 16.9 mmol, which can be prepared according to one of the procedures described in Example 21), in dichloromethane (200 mL). The mixture was stirred for 20 hours, and then carefully quenched with 1N HCl (10 mL). An additional amount of 4N HCl (100 mL) was added, and the reaction mixture was stirred for 24 hours. The precipitated solid was filtered off, washed with water, dried, and triturated with ethyl acetate/hexanes to provide 6.39 g (100%) of the desired product as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][O:8][C:7]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:6]1=2.[CH2:23]([O:25][C:26](=[O:39])[CH:27]([O:36][CH2:37][CH3:38])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[CH2:23]([O:25][C:26](=[O:39])[CH:27]([O:36][CH2:37][CH3:38])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:2][CH2:3][O:4][CH:5]2[C:12]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=3[O:10][CH2:9][O:8][C:7]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:6]2=3)=[CH:33][CH:34]=1)[CH3:24]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: Clc1ccc2c(c1)C(OCCBr)c1cc(Cl)ccc1OCO2
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCOC2c3cc(Cl)ccc3OCOc3ccc(Cl)cc32)cc1)OCC
Temperature: 60 °C
Yield: 52.9 %

Procedure:
To a solution of 12-(2-bromo-ethoxy)-2,10-dichloro-12H-5,7-dioxa-dibenzo[a,d]cyclooctene (404 mg, 1.0 mmol) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (238 mg, 1.0 mmol) in dry toluene (6 mL) was added- potassium carbonate (276 mg, 2.0 mmol) and 18-crown-6 (528 mg, 2.0 mmol). The mixture was heated at 60° C. for 16 h. The mixture was filtered, and concentrated in vacuo. The residue was submitted to flash chromatography using toluene/ethyl acetate (19:1) as eluent to give 297 mg (53%) of the title compound; 1H NMR (300 MHz, CDCl3) δ1.18 (t, 3H), 1.25 (t, 3H), 2.96 (d, 2H), 3.30-3.42 (m, 1H), 3.55-3.65 (m, 1H), 3.90-3.95 (m, 2H), 4.0 (t, 1H), 4.15-425 (m, 4H), 4.55 (d, 1H), 5.87 (d, 1H), 6.18 (s, 1H), 6.88-6.95 (m, 4H), 7.10-7.25 (m, 4H), 7.60 (d, 2H).
Reaction SMILES: [CH:1](=[O:8])[C:2]1C=CC=CC=1.[C:9]([OH:12])(=[O:11])[CH3:10]>C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:2]=[C:1]=[O:8].[CH2:1]=[C:2]1[O:12][C:9](=[O:11])[CH2:10]1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C1CC(=O)O1
Product: C=C=O

Procedure:
106 g of benzaldehyde are dissolved in 150 ml of toluene with 2 g of zinc acetate dihydrate and 1.5 ml of acetic acid in a stirred apparatus, under a nitrogen atmosphere. Ketene gas, which can easily be produced on a laboratory scale by splitting of diketene by means of heat (compare Houben-Weyl, Volume VII/4, page 80; and Org. Syntheses. Coll. Vol. V, page 679) is passed into this solution at 30° to 40° C. in the course of 3 to 4 hours. When 92 to 96% of the benzaldehyde has reacted, determined by analysis by gas chromatography, the addition of ketene is interrupted and the reaction mixture is subsequently stirred for a further brief period and transferred to a VA steel low-pressure autoclave. 4 g of 92% pure sodium hydroxide powder are added and the toluene and excess benzaldehyde are distilled off over a descending condenser into a receiver. The viscous, light-colored residue is then heated at 180° C. for 1 hour and, after cooling to about 100° C., the resulting reaction product is taken up in 700 ml of water and dissolved by adding 140 ml of 20% strength ammonia. After addition of about 20 g of active charcoal, the mixture is stirred at 60° to 70° C. for a further brief period and clarified by filtration and the filtrate is acidified with 30% strength hydrochloric acid until it gives a clearly acid reaction. Cinnamic acid thereby precipitates in white crystals, which are filtered off with suction, washed with a little acidified cold water and dried at 70° C. in a drying cabinet.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](Cl)=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([O:1][C:2]3[C:3]([CH3:12])=[N:4][C:5]4[C:10]([CH:11]=3)=[CH:9][CH:8]=[CH:7][N:6]=4)=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Cc1nc2ncccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCc1ccccc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 69.6 %

Procedure:
3-Hydroxy-2-methyl-[1,8]naphthyridine (400 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (2.25 g), and 4-dimethylaminopyridine (915 mg) were suspended in o-dichlorobenzene (8 ml), and the mixture was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (736 mg, yield 70%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][C:12]3[N:11]=[C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[CH:23]=1.N1C=CC=CC=1.BrN1C(=O)CCC1=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:18])[CH3:19])[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[CH:23]=1
Reactant: CC(C)(C)C(=O)Nc1nc2c(c(=O)[nH]1)-c1cc(Br)ccc1CC2
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)Nc1nc2ccc3ccc(Br)cc3c2c(=O)[nH]1

Procedure:
A mixture of N-(9-bromo-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (1.09 g, 2.9 mmoles) and pyridine (0.28 ml, 3.5 mmoles) in dry benzene (100 ml) was stirred and heated to reflux under a nitrogen atmosphere. N-Bromosuccinimide (0.57 g, 3.2 mmoles) was added in a single portion, and the mixture was vigorously stirred and refluxed for 1.5 hours. After cooling, benzene and excess pyridine were removed under reduced pressure, leaving a light yellow residue which was then triturated with methanol:methylene chloride (1:1), filtered and dried to give N-(9-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide. (0.4 g, 37%) 1H NMR(DMSO-d6, 200 MHz) δ: 1.26(s, 9H, t-butyl); 7.58(d, J=9.0 Hz, 1H, Ar); 7.74(dd, J=8.7, 2.1 Hz, 1H, Ar); 7.98(d, J=8.8 Hz, 1H, Ar); 8.25(d, J=9.0 Hz, 1H, Ar); 9.92(d, J=2.0 Hz, 1H, Ar); 11.35(br s, 1H, NH); 12.35(br s, 1H, NH).
Reaction SMILES: C(OC([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]3[C:29]([Cl:30])=[C:28]4[C:23]([C:24](=[O:38])[C:25]([C:35]([OH:37])=[O:36])=[CH:26][N:27]4[C@@H:31]4[CH2:33][C@@H:32]4[F:34])=[CH:22][C:21]=3[F:39])[CH:17]=2)[CH2:12]1)=O)C1C=CC=CC=1.C(O)C.[OH-].[Na+].O>C(O)(=O)C.[C].[Pd]>[Cl:30][C:29]1[C:20]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[CH2:12][NH:11][CH2:19]3)=[C:21]([F:39])[CH:22]=[C:23]2[C:28]=1[N:27]([C@@H:31]1[CH2:33][C@@H:32]1[F:34])[CH:26]=[C:25]([C:35]([OH:37])=[O:36])[C:24]2=[O:38]
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(Cl)c(-c3ccc4c(c3)CN(C(=O)OCc3ccccc3)C4)c(F)cc2c1=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(Cl)c(-c3ccc4c(c3)CNC4)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 25 ml of acetic acid and 50 mg of 5% palladium carbon was suspended 150 mg of 7-[2-(benzyloxycarbonyl)-isoindolin-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, and the suspension was stirred at room temperature for two hours under a hydrogen stream. The reaction mixture was filtered and thereafter 2 ml of 6N hydrochloric acid was added to the filtrate obtained, after which the mixture was concentrated under reduced pressure. To the residue obtained were added ethanol, and the crystals formed were collected by filtration. To the crystals obtained were added 0.7 ml of ethanol, 0.7 ml of 1N aqueous sodium hydroxide solution and 0.7 ml of water to dissolve the crystals, and thereafter, dilute acetic acid was added to the solution to adjust the pH to 7. The crystals precipitated were collected by filtration, to obtain 45 mg of colorless, crystalline 8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([O:27][S:29]([CH3:28])(=[O:31])=[O:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)OS(C)(=O)=O
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a stirred solution of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate (1.0 g) in pyridine (10 ml) is added dropwise methanesulfonyl chloride (0.92 g) at ice-bath temperature. After stirring for 1 hour at ice-bath temperature, the mixture is stirred for 30 minutes at room temperature, and then cooled. After addition of water (1 ml), the mixture is stirred for 30 minutes at ice-bath temperature, and ice bath is removed. The mixture is stirred for 30 minutes at room temperature, diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The extract is washed successively with 10% hydrochloric acid, water, 0.1N sodium hydroxide solution and water, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate (1.1 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[N:8][C:9]([N:16]([CH2:24][CH3:25])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1Cl)=[O:5])[CH3:2].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C>C(O)C>[CH2:24]([N:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[N:8]=[C:7]([CH3:26])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)[C:10]=1[N+:13]([O-:15])=[O:14])[CH3:25]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(C)nc(N(CC)Cc2ccccc2)c([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(C)nc(N(CC)Cc2ccccc2)c([N+](=O)[O-])c1N1CCN(C)CC1

Procedure:
37.8 g. of 4-chloro-6-[ethyl(phenylmethyl)amino]-2-methyl-5-nitro-3-pyridinecarboxylic acid ethyl ester (0.1 Mol.), 12 g. of N-methylpiperazine (0.12 Mol.) and 15 g. of triethylamine (0.15 Mol.) are refluxed in 200 ml. of ethanol for three hours. After this time, the solvent is distilled off, the residue is dissolved in 100 ml. of water, made alkaline with potassium hydroxide and extracted three times with 100 ml. portions of ethyl acetate. The extract is dried with calcium chloride, the solvent distilled off and the residual 6-[ethyl(phenylmethyl)amino]-2methyl-4-(4-methyl-1-piperazinyl)-5-nitropyridine-3-carboxylic acid, ethyl ester is used without further purification, yield of crude product: 40 g. (90%).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:8])=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: O=C(O)c1cc(F)c(F)cc1Oc1ccc(F)cc1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(F)c(F)cc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 4,5-difluoro-2-(4-fluorophenoxy)benzoic acid (step 1) and methyl 4-[(1S)-1-aminoethyl]benzoate (step 3 of Example 5): MS (ESI) m/z 430 (M+H)+, 428 (M−H)−.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[S:5][CH3:6])#[N:2].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C(O)C>[C:1]([N:3]=[C:4]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[S:5][CH3:6])#[N:2]
Reactant: C1COCCN1
Reactant: CSC(=NC#N)SC
Solvent: CCO
Product: CSC(=NC#N)N1CCOCC1
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A 3 L round bottom flask equipped with a mechanical stirrer was charged with dimethyl cyanodithioimidocarbonate (200 g, 1368 mmol). The solid material was taken up in Ethanol (2279 ml) and stirred until completely dissolved. Morpholine (119 ml, 1368 mmol) was then added to the flask by graduated cylinder and the mechanical stirrer set to a vigorous rate for overnight stirring of the resulting mixture at room temperature. The resulting white precipitate was collected and dried via suction filtration overnight to afford pure white solid methyl N-cyano-4-morpholinecarbimidothioate (212.5 g, 1147 mmol, 84% yield) as a white solid (1H NMR (400 MHz, DMSO-d6) δ ppm 2.70 (s, 3H) 3.61-3.66 (m, 4H) 3.74-3.79 (m, 4H)).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl[CH2:21]Cl>Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:21]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccncc1
Reactant: ClCCl
Agent: Cl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCCCCC2)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A mixture of 4-nitrobenzenesulfonyl chloride (1.78 g, 8.0 mmol), pyridine (0.78 mL, 9.6 mmol), and hexamethyleneimine (0.796 g, 8.02 mmol) in dichloromethane (22 mL) was stirred for 5 hrs at 0° C., diluted with 1N HCl, and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, concentrated, and triturated with diethyl ether to give 1-(4-nitro-benzenesulfonyl)-azepane as a brown solid. The solid was added to a mixture of HCO2NH4 (1.91 g, 30.3 mmol) and 10% Pd/C (catalytic amount) in methanol (20 mL) and ethyl acetate (4 mL), stirred overnight at about 25° C., filtered, concentrated, diluted with water, and extracted with dichloromethane. The isolated organic layer was dried (Na2SO4), filtered and concentrated to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.35 (d, 2H), 7.97 (d, 2H), 3.31 (t, 4H), 1.70-1.79 (m, 4H), 1.56-1.63 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[C:5]([OH:9])=[CH:4][CH:3]=1.C(OC([N:17]1[C:25]2[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=2)[CH:19]=[C:18]1B(O)O)=O)(C)(C)C.C([O-])(O)=O.[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:18]2[NH:17][C:25]3[C:20]([CH:19]=2)=[CH:21][C:22]([F:26])=[CH:23][CH:24]=3)[C:5]([OH:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1I
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2cc(F)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(Cl)nc1-c1cc2cc(F)ccc2[nH]1
Temperature: 100 °C
Yield: 58.2 %

Procedure:
To a degassed solution of 6-chloro-2-iodopyridin-3-ol (1.0 g, 3.91 mmol) and (1-(tert-butoxycarbonyl)-5-fluoro-1H-indol-2-yl)boronic acid (prepared using the method described in Example 1, 1.3 g, 4.66 mmol) in 1,4-dioxane-H2O (20 mL, 10:1), Pd(PPh3)2Cl2 (120 mg) and NaHCO3 (1.0 g, 11.90 mmol) were added under N2. The mixture was heated to 100° C. overnight. The reaction mixture was cooled to room temperature, filtered and washed with EtOAc. The filtrate was washed with H2O, brine, dried over Na2SO4. After concentrated, the residue was purified by column chromatography (PE:EA 5:1) to give the product of 6-chloro-2-(5-fluoro-1H-indol-2-yl)pyridin-3-ol (600 mg, yield: 58.2%). 1H-NMR (DMSO-d6, 400 MHz) δ 11.37 (br s, 1H), 11.03 (s, 1H), 7.51 (dd, J=8.8, 4.8 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.34 (dd, J=10.0, 2.4 Hz, 1H), 7.30 (d, J=1.2 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 6.94˜6.99 (m, 1H). MS (M+H)+: 263/265.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)=[CH:4][C:3]=2[O:2]1.C[Si]([N:39]=[N+:40]=[N-:41])(C)C.C([Sn](=O)CCCC)CCC.C(Cl)Cl>C1(C)C=CC=CC=1.CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]3[CH:27]=[CH:28][C:29]([C:32]4[NH:41][N:40]=[N:39][N:33]=4)=[CH:30][CH:31]=3)=[CH:4][C:3]=2[O:2]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(/C=C/c1ccc(-c2nnn[nH]2)cc1)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Yield: 70 %

Procedure:
To a solution of Example 32 (0.25 g, 0.56 mmol) in 10 mL of toluene were added successively trimethylsilylazide (0.30 mL, 4 equiv.) and dibutyltinoxide (0.06 g, 0.4 equiv.). The resulting mixture was stirred at reflux for two days. T/c monitoring showed formation of a new compound (DCM:MeOH (80.20), Rf=0.35). The reaction mixture was concentrated in vacuo. The resulting yellow gum was dissolved in MeOH and concentrated in vacuo. The residue was partitioned between EtOAc (25 mL) and an aqueous saturated solution of NaHCO3 (25 mL). The organic phase was extracted with an additional portion of an aqueous saturated solution of NaHCO3 (25 mL). The combined aqueous extracts were acidified to pH=2 with HCl (1N) and then extracted with EtOAc (2×25 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated to give a yellow powder that was purified via flash chromatography (SiO2, DCM:MeOH (90:10)). Recrystallization from 2-propanol:iPr2O (1:1) gave the title compound (0.19 g, 70%) as white crystals.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:36]>C(Cl)Cl>[O:36]=[S:4]1[CH2:3][CH2:2][N:1]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:23])([F:24])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5]1
Reactant: O=C(Nc1ccc(N2CCSCC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCS(=O)CC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-thiomorpholin-4-yl-pyridin-3-yl)-amide (30 mg, 0.07 mmol) was dissolved in 3 mL of methylene chloride, and cooled down to −78° C. One equivalent of 3-chloroperoxybenzoic acid (12 mg, 0.07 mmol) was added. The reaction mixture was warmed up to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and then purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0-20% methanol in methylene chloride for 25 min) to gave 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1-oxo-1λ4-thiomorpholin-4-yl)-pyridin-3-yl]-amide as an off-white solid. LCMS calcd for C20H17F3N4O3S (m/e) 450, obsd 451 (M+H).