Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:16][CH:17]2[CH2:19][CH2:18]2)C(=O)OC(C)(C)C)[N:5]2[N:20]=[CH:21][C:22]([CH:23]=[O:24])=[C:4]2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:77][C:78]1[CH:79]=[C:80]([CH:82]=[CH:83][C:84]=1[F:85])[NH2:81]>O1CCOCC1.O>[Cl:77][C:78]1[CH:79]=[C:80]([NH:81][C:2]2[CH:7]=[C:6]([NH:8][CH2:16][CH:17]3[CH2:18][CH2:19]3)[N:5]3[N:20]=[CH:21][C:22]([CH:23]=[O:24])=[C:4]3[N:3]=2)[CH:82]=[CH:83][C:84]=1[F:85]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)c1cc(Cl)nc2c(C=O)cnn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1cnn2c(NCC3CC3)cc(Nc3ccc(F)c(Cl)c3)nc12
Temperature: 110 °C

Procedure:
To tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropylmethyl)carbamate (50 mg, 0.14 mmol) in 1 mL of 1,4 dioxane was added cesium carbonate (65 mg, 0.2 mmol), Pd (OAc)2 (4 mg, 0.006 mmol), (+)-BINAP (5 mg, 0.009 mmol), 3-chloro-4-fluoroaniline (31 mg, 0.21 mmol). The reaction mixture was heated in microwave at 110° C. for 20 minutes. The mixture was then cooled to room temperature, water was added, and the product was extracted with ether. The organic layer was then concentrated under reduced pressure and the crude product was dissolved in 1:1 mixture of dichloromethane and trifluoroacetic acid at room temperature for 1 hour. The reaction mixture was concentrated with 10 mL of dichloromethane. To the reaction mixture, ether/hexanes (1:1) was added and the flask was sonicated for 10 minutes then filtered to obtain the yellow precipitate. The precipitate was washed with hexane to yield 5-(3-chloro-4-fluorophenylamino)-7-(cyclopropylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1=460)
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]4[O:32][CH2:33][O:34][C:28]=4[CH:27]=3)[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:35]#[N:36])[CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])C.Cl>C(O)C>[C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]4[O:32][CH2:33][O:34][C:28]=4[CH:27]=3)[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:35]#[N:36])[CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)([OH:7])=[O:5]
Reactant: CCOC(=O)C1CCN(c2nc(NCc3ccc4c(c3)OCO4)c3cc(C#N)ccc3n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc2nc(N3CCC(C(=O)O)CC3)nc(NCc3ccc4c(c3)OCO4)c2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
20 ml of ethanol and 2.0 ml of a 1N aqueous solution of sodium hydroxide were added to 318 mg of 2-(4-ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline. The obtained mixture was stirred at 50° C. for 30 minutes and neutralized with 1N hydrochloric acid. The crystal thus precipitated was recovered by filtration and purified by silica gel column chromatography (chloroform/methanol) to give 118 mg of the title compound.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:14]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:15]1[O:17][CH2:16]1>>[C:8]1([N:7]([CH2:16][CH:15]([OH:17])[CH2:14][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:1](=[O:6])[CH2:2][C:3]([CH3:5])=[O:4])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)CC(=O)Nc1ccccc1
Reactant: c1ccc(OCC2CO2)cc1
Product: CC(=O)CC(=O)N(CC(O)COc1ccccc1)c1ccccc1
Temperature: 170 °C

Procedure:
Acetoacetanilide was mixed with phenyl glycidyl ether in a molar ratio of 1:1.2, and a reaction was allowed to proceed by heating the mixture at 170° C. for 1 hour. Then, the remaining unreacted phenyl glycidyl ether was removed in the same manner as in Reference Example 1, thereby obtaining a reaction product, (D)-2. Reaction product (D)-2 was further subjected to infrared spectrophotometry and gel permeation chromatography in the same manner as in Reference Example 1. This reaction product (D)-2 was a mixture containing, besides the desired compound formed by the reaction of the 1:1 reactants, high molecular weiqht compounds formed through further reactions.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C@@H:16]3[C@@H:11]([C:12]4[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[C:13]=4[CH2:14][CH2:15]3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].C([O-])(O)=O.[Na+]>Br>[CH:1]1([CH2:7][N:8]2[C@@H:16]3[C@@H:11]([C:12]4[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:13]=4[CH2:14][CH2:15]3)[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CC1CCCCC1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CC1CCCCC1
Temperature: 0 °C
Yield: 102.5 %

Procedure:
3.46 g (0.01155 mol) of rac-cis-3-cyclohexylmethyl-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole were dissolved in 0.13 l of 48% aqueous HBr and boiled under reflux for 5 hours. The mixture was poured into an ice-cold aqueous solution of 46.3 g (1.16 mol) of NaOH, whereupon, after the addition of solid NaHCO3, the mixture was extracted three times with CH2Cl2. The organic phase was washed with saturated aqueous NaHCO3 and NaCl solutions, dried with Na2SO4 and then filtered, whereupon the filtrate was concentrated. By chromatography of the residue over silica gel with cyclohexane/ethyl acetate 4:1 there were obtained 3.38 g (100%) of oily rac-cis-3-cyclohexylmethyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-ol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH2:41]([N:44]([CH2:48][C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=1)[CH2:45][CH2:46][CH3:47])[CH2:42][CH3:43].[OH-].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:53][C:52]2[CH:54]=[CH:55][C:49]([CH2:48][N:44]([CH2:45][CH2:46][CH3:47])[CH2:41][CH2:42][CH3:43])=[CH:50][CH:51]=2)=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: CCCN(CCC)Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1
Yield: 29.6 %

Procedure:
Commercially available 4-(t-butoxycarbonylamino-methyl)-benzoic acid (manufactured by Watanabe Chemical Industries, Ltd.) (1.16 g) was dissolved in chloroform (20 ml) and then added with WSCI hydrochloride (1.21 g), HOBt (963 mg), and the compound (865 mg) obtained in Example 15-2, and the whole was stirred overnight at room temperature. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added thereto and the whole was stirred for a while. The solution was subjected to extraction with chloroform and washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off. The residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (545 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([S:17][C:18]4[CH:36]=[CH:35][C:21]5[N:22]=[C:23]([NH:25][C:26](=[O:34])[O:27][C:28]6C=C[CH:31]=[CH:30][CH:29]=6)[S:24][C:20]=5[CH:19]=4)=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1.[OH:37]CC1CCO1.C(N(CC)CC)C>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([S:17][C:18]4[CH:36]=[CH:35][C:21]5[N:22]=[C:23]([NH:25][C:26](=[O:34])[O:27][CH2:28][CH:29]6[CH2:30][CH2:31][O:37]6)[S:24][C:20]=5[CH:19]=4)=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: OCC1CCO1
Reactant: O=C(Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1)OCC1CCO1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
a mixture of 171 mg of phenyl (6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)carbamate, 0.04 cm3 of 2-hydroxymethyloxetane and 0.06 cm3 of triethylamine in 3 cm3 of tetrahydrofuran is heated for 7.5 h in a bath at 80° C. The reaction is left to stand overnight at 20° C. and then the mixture is evaporated to dryness under vacuum. The residue is purified by chromatography on a Merck cartridge of 25 g of silica 15-40 μm by solid deposit, elution being carried out with a dichloromethane/methanol gradient of 100/0 to 96/04. 52 mg of oxetan-2-ylmethyl (6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)carbamate are thus obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].Br[C:34]1[CH:35]=[C:36]([C:40]2[CH:45]=[C:44]([NH:46][CH:47]3[CH2:49][CH2:48]3)[N:43]=[C:42]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=3)[CH:41]=2)[CH:37]=[N:38][CH:39]=1>COCCOC.C(Cl)Cl>[CH:47]1([NH:46][C:44]2[N:43]=[C:42]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=3)[CH:41]=[C:40]([C:36]3[CH:37]=[N:38][CH:39]=[C:34]([C:13]4[CH:14]=[C:15]5[C:10](=[CH:11][CH:12]=4)[CH2:9][NH:8][CH2:17][CH2:16]5)[CH:35]=3)[CH:45]=2)[CH2:49][CH2:48]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1
Reactant: Brc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: c1ccc(-c2cc(-c3cncc(-c4ccc5c(c4)CCNC5)c3)cc(NC3CC3)n2)nc1

Procedure:
To a solution of 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butylester (Intermediate B26) (3 eq, 0.960 mmol, 0.344 g) in dry DME (1 ml) under an inert atmosphere of argon is added 2M Na2CO3 (2 eq, 0.640 mmol, 0.32 ml) followed by (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 1.26) (1 eq, 0.320 mmol, 100 mg) and PdCl2dppf (0.1 eq, 0.032 mmol, 23 mg). The reaction mixture is heated using microwave radiation at 90° C. for 2 hours. The reaction mixture is dissolved in DCM and washed with water. The organic solvent is reduced in vacuo and the residue is purified by reverse phase column chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 420.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][NH2:30])[O:26][C:25]3=[O:31])=[CH:20][C:19]=2[F:32])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(O)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][NH:30][C:33](=[O:35])[CH3:34])[O:26][C:25]3=[O:31])=[CH:20][C:19]=2[F:32])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@H]1CN(c2ccc(NC3CCN(C(=O)OCc4ccccc4)CC3)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NC[C@H]1CN(c2ccc(NC3CCN(C(=O)OCc4ccccc4)CC3)c(F)c2)C(=O)O1

Procedure:
A solution of 450 mg 4-[4-{(5S)-5-aminomethyl-2-oxo-oxazolidin-3-yl}-2-fluoro-phenylamino]-piperidine-1-carboxylic acid benzyl ester (1.01 mmol), 2 ml acetic acid and 0.093 ml (1 mmol) acetic anhydride was stirred at RT for 1 h. The solvents were evaporated.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2].[CH3:12][N:13]=[C:14]=[S:15].O>C(O)C>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:14]([NH:13][CH3:12])=[S:15])=[CH:7][CH:6]=1)=[O:2]
Reactant: CN=C=S
Reactant: Nc1ccc(NNC=O)cc1
Solvent: CCO
Solvent: O
Product: CNC(=S)Nc1ccc(NNC=O)cc1

Procedure:
1-Formyl-2-(4-aminophenyl)hydrazine (1.51 g, 0.01 mole) and methyl isothiocyanate (0.73 g, 0.01 mole) were mixed in ethanol (20 ml) and the mixture was refluxed for 30 minutes. The mixture was chilled in ice, and water was added to precipitate the product. The product came out of solution in an oily form, but solidified upon scratching and standing. The solid material was filtered off and washed thoroughly with ether. The product was dried to give a white crystalline powder. Yield 1.3 g (58%), m.p. 176°-178° C.
Reaction SMILES: F[C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]([CH3:17])[C:5]([C:15]#[N:16])=[C:6]2[C:10]=1[O:9][C:8]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:7]2.C(N(CC)CC)C.[CH3:31][N:32]([CH3:38])[C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1.C(OCC)(=O)C>CS(C)=O.[Cl-].[Na+].O>[CH3:31][N:32]([CH3:38])[C@H:33]1[CH2:37][CH2:36][N:35]([C:2]2[C:3]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:4]([CH3:17])[C:5]([C:15]#[N:16])=[C:6]3[C:10]=2[O:9][C:8]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:7]3)[CH2:34]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)O)nc2c1C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C(C)(C)O)nc2c1C#N
Temperature: 90 °C
Reaction time: 12 h
Yield: 93.3 %

Procedure:
7-Fluoro-2-(1-hydroxy-1-methylethyl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-112) (35 mg, 0.11 mmol) was dissolved in anhydrous dimethyl sulfoxide (2 ml), and at room temperature, triethylamine (24 μl, 0.17 mmol) and (3S)-3-(dimethylamino)pyrrolidine (22 μl, 0.17 mmol) were added. This mixture liquid was stirred at 90° C. for 12 hours, then cooled to room temperature. This was fractionated with ethyl acetate and saturated brine. The aqueous layer was separated, and this was extracted twice with ethyl acetate. The organic layers were combined, this was washed with saturated brine, dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=9:1) to obtain the entitled compound (41.5 mg, 91%) as a white solid. This was further recrystallized from hexane/diethyl ether to obtain a cream powder (27.5 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10])([O-])=O.N[C:12]1[CH:17]=CC=[CH:14][CH:13]=1.C(N1CCCC1=O)O>>[CH2:17]([S:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1])[CH2:12][CH2:13][CH3:14]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1S
Agent: O=C1CCCN1CO
Product: CCCCSc1ccccc1N

Procedure:
2-Butylmercaptoaniline was prepared from -2-nitrothiophenol by a two-step reaction sequence consisting of alkylation followed by reduction corresponding to the procedure described in Example 4. The aniline then was condensed with N-methylol-2-pyrrolidone to yield the desired product.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[F:7][C:8]1[CH:9]=[C:10]([NH:20][C:21]2[N:38]=[C:24]3[CH:25]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:26][C:27](=C)[CH2:28][CH2:29][N:23]3[N:22]=2)[CH:11]=[CH:12][C:13]=1[N:14]1[C:18]([CH3:19])=[N:17][CH:16]=[N:15]1>O.C1COCC1.[Cl-].[Na+].O.[Os](=O)(=O)(=O)=O>[F:7][C:8]1[CH:9]=[C:10]([NH:20][C:21]2[N:38]=[C:24]3[CH:25]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:26][C:27](=[O:2])[CH2:28][CH2:29][N:23]3[N:22]=2)[CH:11]=[CH:12][C:13]=1[N:14]1[C:18]([CH3:19])=[N:17][CH:16]=[N:15]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C1CCn2nc(Nc3ccc(-n4ncnc4C)c(F)c3)nc2C(c2ccc(F)cc2)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncnn1-c1ccc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)cc1F
Reaction time: 1 h
Yield: 77.8 %

Procedure:
A solution of sodium periodate (2.78 g, 13.0 mmol) in water (10 mL) was added over a 10 min period via pipet to a vigorously stirred solution of the N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-9-(4-fluorophenyl)-7-methylene-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine (1.88 g, 4.34 mmol) and osmium tetroxide (110 mg, 0.43 mmol) in THF (10.0 mL). The reaction was stirred for 1 h and then diluted with water (150 mL)/brine (100 mL) and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (1.47 g, 78% yield). The crude product was used in the next step without further purification. LC-MS (M+H)+ 436.3. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.98 (1 H, s), 7.70 (1 H, dd, J=12.5, 2.1 Hz), 7.27-7.34 (1 H, m), 6.96-7.21 (5 H, m), 4.62 (1 H, dd, J=8.9, 3.7 Hz), 4.41-4.56 (2 H, m), 3.36 (1 H, dd, J=14.2, 9.0 Hz), 3.11 (1 H, dd, J=14.2, 3.8 Hz), 2.83-3.01 (2 H, m), 2.40 (3 H, s).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[C:12]=2[O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])=O.[NH4+]>[OH-].[OH-].[Pd+2].C(O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[C:12]=2[O:23][C:24]2[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc2c(Oc3ccc(N)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
Heat a solution of 2-(4-methanesulfonyl-phenyl)-6-methoxy-1-(4-nitro-phenoxy)-naphthalene (1.67 g, 3.7 mmol), ammonium formate (4.7 g, 74 mmol), wet 20% palladium hydroxide on carbon (420 mg, 25 wt %) and absolute ethanol (80 mL) at reflux for 1 hour, then cool to ambient temperature, filter and evaporate to dryness under reduced pressure. Partition the residue with dichloromethane/water. Dry the organic layer with solid magnesium sulfate and chromatograph on silica gel with dichloromethane/methanol mixtures to give 1.15 g of 4-[2-(4-methanesulfonyl-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenylamine (75%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:18]1([S:24]([CH2:27][C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:28]([CH2:27][S:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:26])=[O:25])[CH:29]=2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: Nc1cccc(CS(=O)(=O)c2ccccc2)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=S(=O)(Cc1cccc(Nc2ncnc(Cl)n2)c1)c1ccccc1
Yield: 191.5 %

Procedure:
To a stirred solution of 2,4-dichloro-1,3,5-triazine (150 mg, ABCR GmbH & CO. KG) in THF/i-PrOH (1:1; 1.90 mL) DIPEA (0.35 mL) was added at −40° C. Then a suspension of 3-[(phenylsulfonyl)methyl]aniline (248 mg) in THF/i-PrOH (1:1, 0.94 mL) was added at this temperature. Under stirring the temperature of the reaction mixture was slowly raised over 2 hours to 0° C. The reaction mixture was then concentrated in vacuo to give the crude title compound (691 mg) which was used without further purification.
Reaction SMILES: [CH2:1]([SH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(#N)C>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:29])[S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCCCCCCCCS
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCSC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
In a three necked flask equipped with a dropping funnel, a thermometer and reflux condenser, n-hexadecanethiol (165 g) was dissolved in acetonitrile (1000 ml) in a nitrogen atmosphere. To the solution, p-nitrophenyl isocyanate (100 g) was gradually added, stirred at room temperature for 10 minutes, and then heat-refluxed for 30 minutes. The reaction liquid was cooled to room temperature to allow crystals to precipitate. The crystals were collected by filtering and washed with acetonitrile, to obtain S-n-hexadecyl p-nitrophenylthiocarbamate (250 g) at a yield of 97%.
Reaction SMILES: C([O:8][C:9](=[O:27])[CH2:10][N:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])C1C=CC=CC=1>[Pd].C1COCC1>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:11]([CH2:10][C:9]([OH:27])=[O:8])[C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])=[CH:24][CH:23]=1
Reactant: COc1ccc(CN(CC(=O)OCc2ccccc2)C(=O)CC(C)=O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(CN(CC(=O)O)C(=O)CC(C)=O)cc1
Yield: 103.4 %

Procedure:
Prepared according to the representative procedure (Method C) for preparation of keto-acid intermediate from benzyl ester 54e (0.320 mg, 0.866 mmol), palladium on carbon (35 mg) in a mixture of solvent THF (10 mL) afford keto acid 55e (250 mg, 99%) as a colorless oil. IR (neat) 1723, 1612 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.13 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.0 Hz, 2H), 4.51 (s, 2H), 4.05 (s, 2H), 3.81 (s, 3H), 3.68 (s, 2H), 2.30 (s, 3H) (only major peaks were assigned); LRMS (ESI) Calcd. for C14H17NO5 [M−H] 278, found 278; HRMS (ESI) Calcd. for C14H17NO5 [M−H] 278.1028, found 278.1025.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]([OH:35])([CH3:34])[CH3:33])[CH2:28][CH2:27]1>>[OH:35][C:32]([CH:29]1[CH2:30][CH2:31][N:26]([C:22]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]4[CH:25]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=5)[N:10]=[C:11]4[C:17]=3[CH:18]=2)=[O:23])[CH2:27][CH2:28]1)([CH3:34])[CH3:33]
Reactant: CC(C)(O)C1CCNCC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C(=O)O)ccc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C(=O)N3CCC(C(C)(C)O)CC3)ccc1OCC2

Procedure:
Following the procedure for 109, 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid and 2-(piperidin-4-yl)propan-2-ol gave 113. MS: (ESI+)=465.2. 1H NMR (400 MHz, DMSO) δ 8.40 (d, J=1.6 Hz, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.35 (dd, J=8.4, 1.9 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 5.87-5.69 (m, 1H), 4.56 (s, 4H), 4.15 (s, 1H), 1.75 (s, 2H), 1.48 (d, J=6.6 Hz, 7H), 1.19 (dd, J=23.3, 11.1 Hz, 2H), 1.05 (s, 7H)
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[F:25][C:26]1[CH:27]=[C:28]([NH:38][C:39]([NH2:41])=[NH:40])[CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1>>[F:25][C:26]1[CH:27]=[C:28]([NH:38][C:39]2[N:41]=[CH:3][C:4]3[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=3[N:40]=2)[CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1
Reactant: Cc1cn(-c2ccc(NC(=N)N)cc2F)cn1
Reactant: CCOC(=O)C1CCCC(=CN(C)C)C1=O
Solvent: O=[N+]([O-])O
Product: CCOC(=O)C1CCCc2cnc(Nc3ccc(-n4cnc(C)c4)c(F)c3)nc21

Procedure:
The title compound was prepared from crude ethyl 3-[1-dimethylamino-methylidene]-2-oxo-cyclohexanecarboxylate (165 mg, 0.5 mmol) and N-[3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (134 mg, 0.37 mmol) using in analogous manner the procedure described in example 45b). Obtained as an off-white solid (27 mg, 18%). MS ISP (m/e): 396.4 [(M+H)+]. mp 142-145° C.