Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:15]=1[OH:23].I[CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:15]=1[O:23][CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1c(Br)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.23 g of potassium carbonate, 14.6 g of caesium carbonate, 22 ml of dimethylformamide and 1.0 g of 2-bromo-6-nitrophenol are successively introduced into a three-necked round-bottomed flask under argon. The resulting suspension is stirred at ambient temperature for 10 min, and then 0.91 ml of 2-iodopropane is added in one go. The round-bottomed flask is rinsed with 10 ml of dimethylformamide and then the reaction mixture is heated at 40° C. for 48 h. After cooling to ambient temperature, the mixture is treated with 50 ml of water and extracted four times with 30 ml of ethyl acetate. The organic extracts are combined and washed with 30 ml of saturated brine and then 30 ml of water. The organic phase is then dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 30 g silica cartridge, elution being carried out with a 95/5 v/v cyclohexane/ethyl acetate mixture at a flow rate of 30 ml/min, so as to obtain 1.04 g of 1-bromo-2-isopropoxy-3-nitrobenzene in the form of a yellow oil.
Reaction SMILES: C[O:2][C:3]1(OC)[C:9]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=2[OH:18])=[CH:8][C:7](=[O:20])[CH:6]2[CH:4]1[O:5]2.FC(F)(F)C(O)=O>ClCCl.C(=O)(O)[O-].[Na+]>[O:2]=[C:3]1[C:9]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=2[OH:18])=[CH:8][C:7](=[O:20])[CH:6]2[CH:4]1[O:5]2
Reactant: COC1(OC)C(NC(=O)c2cccnc2O)=CC(=O)C2OC21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1=CC(=O)C2OC2C1=O)c1cccnc1O
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of 6a (50 mg, 0.16 mmol) in anhydrous dichloromethane (2 was slowly added trifluoroacetic acid (0.5 mL) at room temperature. After overnight stirring, LC-MS indicated 27% starting material remained. Additional trifluoroacetic acid (0.5 mL) was added and the reaction mixture was stirred an additional 24 hours, at which time it was judged complete. The solution was cooled in an ice bath and diluted with additional dichloromethane (10 mL) before the slow addition of saturated sodium bicarbonate solution until the stirring mixture was alkaline. The mixture was then partitioned and the organic solvents were removed and rinsed with brine. The aqueous layer was extracted twice with ethyl acetate and the organic layer was washed with brine. All organics were pooled and dried over anhydrous magnesium sulfate before filtration and solvent evaporation, giving 7a as a light-yellow solid (30 mg, 71%). LC-MS indicated 80% purity, and the material was used in the next step without further purification.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].C=CC1C=CC=CC=1.[C:16]([O:20]O)([CH3:19])(C)C>O>[C:1]([O:6][CH2:7][CH:16]1[O:20][CH2:19]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC(C)(C)OO
Reactant: C=C(C)C(=O)OC
Solvent: C=Cc1ccccc1
Solvent: O
Product: C=C(C)C(=O)OCC1CO1

Procedure:
An amount of 1155 g of an aqueous latex of a core polymer mainly comprising a styrene-butadiene rubber (containing 375 g of styrene-butadiene rubber particles) as obtained using the procedure described in Example 2 was charged into a 3 L glass vessel followed by addition of 440 g of pure water. A monomer mixture composed of 62 g of methyl methacrylate, 38 g of styrene and 0.1 g of t-butyl hydroperoxide as a monomer mixture that is not the shell forming monomers (A) was added thereto over the course of 120 minutes while stirring at 60° C. in a nitrogen atmosphere to carry out graft polymerization. Following completion of the addition of the monomer mixture, stirring was further continued for 2 hours to complete the reaction. The polymerization conversion rate was 99%. The volume average particle size of the resulting minute polymer particles (CS-1C) in the form of an aqueous latex was 0.1 μm, and a sharp, monodisperse particle size distribution similar to CS-2 of Example 2 was shown.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=S.[OH-].[Na+]>C1COCC1.O>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=1[N:7]=[C:5]1[NH:4][CH2:3][CH2:2][NH:1]1
Reactant: NCCNC(=S)Nc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Clc1cccc(Cl)c1N=C1NCCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
1-(2-Aminoethyl)-3-(2,6-dichlorophenyl)thiourea (200 mg) was dissolved under argon in THF (4 ml), admixed with a solution of sodium hydroxide (102 mg) in water (2 ml) and then a slurry of polystyrene-bound toluenesulfonyl chloride (457 mg, 2.9 mmol/g) in THF (4 ml) was added dropwise within five minutes. After stirring at room temperature for 2 h, further polystyrene-bound toluenesulfonyl chloride (65 mg in 2 ml of THF) was added, followed, after a further hour, by further acid chloride (124 mg in 2 ml of THF). After standing overnight, the reaction mixture was filtered, the resin was slurried twice in dichloromethane and the combined phases were concentrated to dryness. The residue was taken up in water/dichloromethane, the phases were separated and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate, and the solvent was removed under reduced pressure and the residue subsequently dried under high vacuum. 104 mg of the title compound were obtained.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]4)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[Cl:24][C:25]1[C:26]([C:31](O)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1>>[CH3:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([C:7]3[C:6]4[CH2:5][CH2:4][CH2:3][C@@H:2]([NH:1][C:31]([C:26]5[C:25]([Cl:24])=[CH:30][CH:29]=[CH:28][N:27]=5)=[O:32])[C:11]=4[CH:10]=[N:9][CH:8]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:23]
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4N)ccc21
Reactant: O=C(O)c1ncccc1Cl
Product: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4NC(=O)c3ncccc3Cl)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 13, coupling of (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (example 61) with 3-chloro-pyridine-2-carboxylic acid gave the title compound as colorless solid. MS: 447.4 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][C:5](=[O:6])[NH:4][CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].N[C@H](C(O)=O)C[SH:19].C(S)[C@@H](O)[C@H](O)CS.C(O)C(N)(CO)CO.Cl>>[OH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[C@@H:3]2[C@@H:2]([NH:7][C:5]([NH:4]2)=[O:6])[CH2:1][S:19]1)=[O:15]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC1NC(=O)NC1CCCCCC(=O)O
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: O[C@H](CS)[C@H](O)CS
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 95 °C

Procedure:
The enzyme reaction mixture without cell-free extracts contained 100 μM desthiobiotin. 1000 μM SAM, 200 μM L-cysteine, 50 μM deazariboflavin, 0.6 mg/ml (16 μM) BIOB protein, 10 mM DTT and 0.1 M Tris-HCl/pH 7.5 in total volume of 50 μl. The enzyme reaction mixture in a 300 μl glass spitz tube was brought to anaerobic condition by repeating of weak aspiration and argon pressure under dark. The reaction was started by light irradiation from 10 cm distance with 20 W fluorescent bulb at 30° C. After 80 min reaction, reaction was stopped by heating at 95° C., and produced biotin was determined by the microbiological assay 1 ) using Lactobacillis plantarum. (ATCC8014)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([NH:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[N:13][C:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][C:27]3[C:32]([F:33])=[CH:31][C:30]([O:34][CH2:35][CH3:36])=[CH:29][C:28]=3[F:37])[N:18]=2)=[N:15][CH:16]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+].ClCCl.C(O)(C)C>ClCCl>[NH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([NH:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[N:13][C:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][C:27]3[C:28]([F:37])=[CH:29][C:30]([O:34][CH2:35][CH3:36])=[CH:31][C:32]=3[F:33])[N:18]=2)=[N:15][CH:16]=1
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCNC(=O)OC(C)(C)C)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: ClCCl
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCN)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Temperature: 25 °C

Procedure:
28.6 mg of tert-butyl[2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)ethyl]carbamate (4-23, 0.046 mmol, 1.0 eq.) were dissolved in 2 ml of dry dichloromethane. 0.071 ml of trifluoroacetic acid (0.926 mmol, 20.0 eq.) were added at 0° C. The reaction mixture was stirred over night at room temperature. Then a mixture 2 N sodium carbonate and dichloromethane/isopropanol 4:1 was added and the mixture was stirred for 30 min. The phases were separated and the aqueous layer (slightly brown) was extracted twice with dichloromethane/isopropanol 4:1. The combined organic layers were dried over a magnesium sulfate and concentrated in vacuo. The residue was purified by crystallization from ethylacetate to yield 6.8 mg (0.01 mmol, 27.0%) of the analytically pure target compound.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:24]([O:25][CH3:26])=[CH:23][C:22]2[C:21]3[C:16](=[CH:17][C:18]([C:27]([NH:29][C:30]4[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=4[OH:37])=O)=[CH:19][CH:20]=3)[C:15]([CH2:41][CH2:42][CH3:43])([CH2:38][CH2:39][CH3:40])[C:14]=2[CH:13]=1)=[O:11].B(O)(O)O>O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[O:11][C:10]([C:12]3[C:24]([O:25][CH3:26])=[CH:23][C:22]4[C:21]5[C:16](=[CH:17][C:18]([C:27]6[O:37][C:31]7[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:30]=7[N:29]=6)=[CH:19][CH:20]=5)[C:15]([CH2:41][CH2:42][CH3:43])([CH2:38][CH2:39][CH3:40])[C:14]=4[CH:13]=3)=[N:9][C:3]=2[CH:4]=1
Reactant: CCCC1(CCC)c2cc(C(=O)Nc3cc(C)ccc3O)ccc2-c2cc(OC)c(C(=O)Nc3cc(C)ccc3O)cc21
Agent: OB(O)O
Solvent: O
Product: CCCC1(CCC)c2cc(-c3nc4cc(C)ccc4o3)ccc2-c2cc(OC)c(-c3nc4cc(C)ccc4o3)cc21
Temperature: -20 °C
Yield: 47.9 %

Procedure:
A mixture N,N′-bis(2-hydroxy-5-methylphenyl)-9,9-dipropyl-3-methoxyfluorene-2,7-dicarboxamide (76.7 g, 0.133 mol), powdered boric acid (1.8 g) and (750 mL) stirred under argon was slowly heated to reflux allowing water to be distilled. After cooling overnight the resulting mixture was further distilled to remove diethylene glycol dibutyl ether (600 mL). The residual mixture was added to methanol (500 mL) causing precipitation of crude product. The mixture was diluted with water (100 mL) and cooled to −20° C. for 18 h. The mixture was filtered and the solid washed with methanol to afford crude product (51.4 g; m. pt. 205-230° C.). Purification by soxhlet extraction with hexane yielded 2,7-Bis(5-methylbenzoxazol-2-yl)-9,9-dipropyl-3-methoxyfluorene (34.6 g; yield 48%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][N:25]([C:28]([O:30][CH3:31])=[O:29])[CH:24]([C:32]([O:34]C)=[O:33])[CH2:23]4)=[O:21])=[CH:14][C:13]=3[C:36]([F:39])([F:38])[F:37])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].CCO>O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][N:25]([C:28]([O:30][CH3:31])=[O:29])[CH:24]([C:32]([OH:34])=[O:33])[CH2:23]4)=[O:21])=[CH:14][C:13]=3[C:36]([F:37])([F:39])[F:38])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)CCN1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)CC1C(=O)O

Procedure:
The title compound was prepared by hydrolysis of the compound of Example 269 under basic conditions (aq. NaOH/EtOH). 1H NMR (DMSO-d6, 300 MHz) δ 2.60-3.30 (m, 3H), 3.40-3.50 (m, 1H), 3.62 (d, J=12.0 Hz 1H),3.80 (m, 1H), 4.25-4.35 (m, 4H), 4.55 (m, 1H), 7.00 (s, 2H), 7.00-7.06 (m, 1H), 7.25 (m,2H), 7.5 (m, 1H), 7.80 (m, 1H), 8.10 (m, 1H). MS (APCI) m/z 553 (M+H)+. Calcd. Anal. C24H23F3N2O5.1.55 H2O: C, 54.35; H, 4.20; N, 5.07. Found: C, 54.16; H, 4.19; N, 4.96.
Reaction SMILES: PP.C(O)C.[C:6]([NH:9][C:10](=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])(=[O:8])[CH3:7].[H][H]>C(N(CC)CC)C>[C:6]([NH:9][C@H:10]([C:11]([OH:13])=[O:12])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:8])[CH3:7]
Reactant: [H][H]
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Agent: PP
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 1 h
Yield: 82 %

Procedure:
3.1 mg of the complex of the formula [RhCl-1,5-cyclooctadiene]2, 57 mg of the diphosphine of Example 1 and 400 cm3 of ethyl alcohol are introduced under an argon atmosphere into a reactor. The mixture is stirred for 1 hour. 66.62 g of α-acetamidocinnamic acid and 25 microlitres of triethylamine are then added and hydrogen is introduced under a pressure of 1 bar at 25° C. After 4 hours 30 minutes the hydrogenation is complete. After treatment to remove the catalyst similar to that of Example 5, N-acetylphenylalanine is obtained, after extraction, in 97% chemical yield and with an optical rotation [α]D22 of 42.5° (optical yield 82%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH3:31][O:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38]Cl>>[CH3:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:17][C:16]=1[C:3]1[C:2]([O:1][CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:35]([O:34][CH2:33][O:32][CH3:31])[CH:36]=2)=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:14])([CH3:15])[C:5]=2[CH:4]=1
Reactant: COCOc1cccc(CCl)c1
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Product: COCOc1cccc(COc2cc3c(cc2-c2cc(C=CC(=O)O)ccc2OC)C(C)(C)CCC3(C)C)c1
Yield: 89.3 %

Procedure:
In a manner similar to that of Example 1(a), by reaction of 2.5 g (6.12 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in Example 13(f) with 1.26 g (6.73 mmol) of 3-methoxymethoxybenzyl chloride obtained above, 2.90 g (85%) of the expected compound were obtained in the form of a yellow oil.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8](C)=[C:7]([OH:12])[C:6]=1[CH2:13][CH2:14][CH2:15][CH3:16])CCC.[C:17](O)(=[O:20])[CH:18]=[CH2:19].[Cl-].C[NH+](C)C>C1(C)C=CC=CC=1>[CH:16]1[CH:15]=[C:14]([CH2:13][C:6]2[C:7]([OH:12])=[CH:8][CH:9]=[CH:10][CH:5]=2)[C:17]([OH:20])=[CH:18][CH:19]=1
Reactant: C=CC(=O)O
Reactant: CCCCc1ccc(C)c(O)c1CCCC
Agent: C[NH+](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Oc1ccccc1Cc1ccccc1O
Temperature: 98 °C
Reaction time: 50 h

Procedure:
Bisphenol F epoxy resin (Nihon Kayaku Co., Ltd. RE-404P, epoxy equivalent 160 g/eq., amount of hydrolysis 30 ppm) was dissolved in toluene, and added dibutylhydroxy toluene as the polymerization inhibitor therein, then temperature was risen up to 60° C. Thereafter, acrylic acid in 100% equivalent amount to epoxy group was added, further temperature was risen up to 80° C. Then trimethylammonium chloride as the reaction catalyst was added thereto, followed by stirring at 98° C. for about 50 hours. The resultant reaction mixture was washed with water, and toluene was distilled out to obtain epoxy acrylate of bisphenol F (Epoxyacrylate C).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([NH:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:28])[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([NH:29][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[O:28])[CH:24]=2)[NH:19][N:18]=1
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)NC1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1)NC1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.4 %

Procedure:
TFA (0.3 mL, 4.03 mmol) was added to a solution of 1-(3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3-cyclopentylurea (6 mg, 0.013 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (4 mg) as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 8.36 (s, 1H), 7.81 (m, 2H), 7.60 (d, 1H, J=8.8 Hz), 7.46 (m, 3H), 4.11 (t, 1H, J=6.4 Hz), 2.00 (m, 2H), 1.75 (m, 2H), 1.65 (m, 2H), 1.51 (m, 2H); ESI-MS [M+H]+: 361.3.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[C:16]([C:20]1[N:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28](O)=[O:29])=[C:22]([C:31]([F:34])([F:33])[F:32])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17].CN1C(=O)CCC1>C1COCC1>[C:16]([C:20]1[N:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:29])=[C:22]([C:31]([F:34])([F:32])[F:33])[CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: CC(C)(C)c1cc(C(F)(F)F)c(C=CC(=O)O)cn1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(F)(F)F)c(C=CC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cn1
Yield: 62.7 %

Procedure:
3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (41.2 mg, 0.162 mmol) was reacted with 3-(6-tert-butyl-4-trifluoromethyl-pyridin-3-yl)-acrylic acid (1.0 eq, 44.2 mg) DMTMM (1.0 eq, 44.8 mg) and NMP (1.2 eq, 22 μl) in THF to give the title compound (48 mg, 62.6%) after purification by column chromatography (Hex/EtOAc=1/1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](SC)[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.Cl.[CH3:23][O:24][C:25](=[O:31])[C@H:26]([C@@H:28]([CH3:30])[OH:29])[NH2:27]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:27][CH:26]([CH:28]([OH:29])[CH3:30])[C:25]([O:24][CH3:23])=[O:31])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)C(NC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1)C(C)O
Yield: 58.5 %

Procedure:
A solution of 22.0 g of 7-chloro-5-(2-fluorophenyl)-2-methylthio-3H-1,4-benzodiazepine and 20.0 g of L-threonine methyl ester hydrochloride in 200 ml of pyridine was stirred at 75° C. for 5 h. The solvent was removed in a vacuum and the residue was purified by chromatography on 800 g of silica gel with dichloromethane containing 5% methanol. There were obtained 16.3 g (59%) of methyl 2-[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-ylamino]-3-hydroxy-butyrate as a diastereomer mixture which was used without further purification as the starting product for the step described below.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:35]=[CH:34][C:25]2[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.Cl>O1CCOCC1.COCCO>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:21][C:22]2[CH:35]=[CH:34][C:25]3[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CC1(C)CCC(=O)Nc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc21
Temperature: 25 °C
Yield: 19 %

Procedure:
Combined N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (106 mg, 0.312 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (77 mg, 0.377 mmol), 4 N HCl in dioxane (94 ul) and 2-methoxyethanol (3 mL). Heated reaction to 120° C. for 2 hours. Let reaction cool to room temperature and evaporated off solvent. Purified with normal phase chromatography to yield a white solid (30 mg, 19%), N-{(1R,2R)-2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide. mp 170-185° C.; LCMS: m/z=507.33 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.58 (d, 1H, J=9.6 Hz), 7.30 (m, 4H), 6.87 (dd, 1H, J=8.6, 2.3 Hz), 5.79 (m, 1H), 3.80 (m, 1H), 3.27 (m, 1H), 2.78 (m, 3H), 2.31 (m, 2H), 2.13 (m, 4H), 1.78 (m, 2H), 1.36 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.Cl[Sn]Cl>CO.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(N)cnc1Cl
Yield: 102.8 %

Procedure:
2-Chloro-3-methyl-5-nitro-pyridine (2 g, 11.6 mmol) and SnCl2.(H2O)2 (7.86 g, 34.8 mmol) are refluxed in MeOH overnight. After cooled down, the mixture is diluted with ethyl acetate, washed with water, brine, dried over MgSO4, concentrated and purified by column chromatography to afford 6-chloro-5-methyl-pyridin-3-ylamine (1.7 g). To the solution of 6-chloro-5-methyl-pyridin-3-ylamine (1.7 g, 11.6 mmol) in 1N HCl is added the solution of NaNO2 (960 mg, 13.92 mmol) in water (10 ml) slowly at 0° C. After the addition, the solution is stirred for 20 min and then heated to 90° C. for 30 min. The solution is cooled down, quenched with K2CO3, extracted with ether, dried over MgSO4, and purified by column chromatography to afford the titled compound (560 mg) as a yellow solid.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]Br.N.CO.C(Cl)Cl>CC(O)=O>[CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([NH2:15])=[C:14]([Br:16])[C:9]=3[N:8]=[CH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccc2c(c1)ncn2C1CCCC1
Reactant: BrBr
Agent: N
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc2c(ncn2C2CCCC2)c1Br
Yield: 35 %

Procedure:
To a solution of 1-cyclopentyl-5-aminobenzimidazole (1.1 g, 5.5 mmol) in 20 ml of AcOH was added solution of Br2 in. AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 0.54 g (1.9 mmol, 35%) of the product.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[Cl:16][C:17]1[C:18]([O:35][CH3:36])=[C:19]([C:32](=O)[CH3:33])[CH:20]=[C:21]2[C:26]=1[O:25][C:24]([CH3:28])([CH3:27])[CH:23]=[C:22]2[CH:29]([CH3:31])[CH3:30]>>[Cl:16][C:17]1[C:18]([O:35][CH3:36])=[C:19](/[C:32](/[CH3:33])=[C:6](/[F:7])\[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:20]=[C:21]2[C:26]=1[O:25][C:24]([CH3:28])([CH3:27])[CH:23]=[C:22]2[CH:29]([CH3:30])[CH3:31]
Reactant: COc1c(C(C)=O)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Cl)c1OC)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (0.2 mL, 1.07 mmol) and 1-(8-chloro-4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-ethanone (Compound 144, 930 mg, 2.88 mmol) were reacted to give the title compound as a light yellow oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).