Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:7]([CH2:17]O)=[N:8][CH:9]=[CH:10][C:11]=1[N:12]([CH3:16])[CH2:13][CH2:14][OH:15]>ClCCl>[Cl:5][C:6]1[C:7]([CH2:17][Cl:3])=[N:8][CH:9]=[CH:10][C:11]=1[N:12]([CH3:16])[CH2:13][CH2:14][OH:15]
Reactant: CN(CCO)c1ccnc(CO)c1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(CCO)c1ccnc(CCl)c1Cl
Reaction time: 1 h

Procedure:
Thionyl chloride (7.4 ml, 101.5 mmol), dissolved in dichloromethane (50 ml), is added dropwise at 4° C. to a solution of (2-[(3-chloro-2-hydroxymethyl-pyridin-4-yl)-methylamino]-ethanol (10.0 g, 46.1 mmol) in dichloromethane (150 ml). The solution is stirred for 1 h at this temperature, triturated with ice water and neutralized with saturated sodium bicarbonate solution. After separation of the organic layer the aqueous phase is extracted with dichloromethane. The combined organic extracts are washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue is employed without additional purification for the synthesis described in step b).
Reaction SMILES: CC1C=CC2O[C:44](=O)[C:13]3=C(O)[C:15]4[C:16](=[C:17](O[C@@H]5O[C@H](C)[C@H](O)[C@H](O)[C@H]5O[C@H]5O[C@H](C)[C@H](O)[C@H](OC)[C@H]5O)[CH:18]=[CH:19][CH:20]=4)[C:11]4=[C:12]3[C:6]=2[C:7]=1[C:8](O4)=O.[CH3:47][C:48]1[CH:49]=[CH:50][C:51]2[O:93][C:91](=[O:92])[C:59]3=[C:60]([OH:90])[C:61]4[C:62](=[C:63]([O:67][C@@H:68]5[O:73][C@H:72]([CH3:74])[C@H:71]([OH:75])[C@@:70]([OH:77])([CH3:76])[C@H:69]5[O:78][C@H:79]5[O:84][C@H:83]([CH3:85])[C@H:82]([OH:86])[C@H:81]([O:87][CH3:88])[C@H:80]5[NH2:89])[CH:64]=[CH:65][CH:66]=4)[C:57]4=[C:58]3[C:52]=2[C:53]=1[C:54]([O:56]4)=[O:55].CN(C)[CH:96]=[O:97].O1CCOCC1>CS(C)=O.CO.O.C(Cl)(Cl)Cl.C(O)C>[CH3:47][C:48]1[CH:49]=[CH:50][C:51]2[O:93][C:91](=[O:92])[C:59]3=[C:60]([OH:90])[C:61]4[C:62](=[C:63]([O:67][C@@H:68]5[O:73][C@H:72]([CH3:74])[C@H:71]([OH:75])[C@@:70]([OH:77])([CH3:76])[C@H:69]5[O:78][C@H:79]5[O:84][C@H:83]([CH3:85])[C@H:82]([OH:86])[C@H:81]([O:87][CH3:88])[C@H:80]5[NH2:89])[CH:64]=[CH:65][CH:66]=4)[C:57]4=[C:58]3[C:52]=2[C:53]=1[C:54]([O:56]4)=[O:55].[CH:7]1[C:6]2[C:96](=[O:97])[C:15]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:11][C:12]=2[CH:13]=[CH:44][CH:8]=1
Reactant: CO[C@H]1[C@@H](O)[C@@H](C)O[C@H](O[C@H]2[C@H](Oc3cccc4c(O)c5c(=O)oc6ccc(C)c7c(=O)oc(c34)c5c67)O[C@H](C)[C@H](O)[C@@H]2O)[C@@H]1O
Reactant: CN(C)C=O
Agent: CO[C@@H]1[C@@H](N)[C@@H](O[C@H]2[C@H](Oc3cccc4c(O)c5c(=O)oc6ccc(C)c7c(=O)oc(c34)c5c67)O[C@H](C)[C@H](O)[C@]2(C)O)O[C@H](C)[C@@H]1O
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: O=C1c2ccccc2Cc2ccccc21

Procedure:
BBM-2478 A and B were obtained as yellowish-orange crystalline solids. Both components of BBM-2478 are distinguishable from chartreusin by thin layer chromatography (TLC) as shown in Table 5. BBM-2478A is readily soluble in dimethyl sulfoxide, dimethylformamide, dioxane and acidic water, slightly soluble in methanol, ethanol and chloroform and insoluble in other organic solvents. Solubility of BBM-2478B is similar to that of BBM-2478A except that BBM-2478B is insoluble in acidic water. BBM-2478 A and B give positive responses with ferric chloride and anthrone reagents. BBM-2478A shows positive reaction to ninhydrin, while BBM-2478B is negative in the same test. Tollen's and Sakaguchi reactions are negative with both components. The physico-chemical properties of BBM-2478A and B are summarized in Table 6. The UV spectra of the two components are similar, showing maxima at 236, 266, 398 and 422 nm in neutral and acidic solutions and at 240, 268 and 435 nm in alkaline solution. These spectra are closely related to that of chartreusin. The IR spectra of BBM-2478 A and B are illustrated in FIGS. 1 and 2, respectively. The proton (PMR) and 13C-NMR (CMR) spectra of BBM-2478A are shown in FIGS. 3 and 4.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:33])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[CH:18][CH:17]=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][CH3:14].[Br:34]Br>C(Cl)(Cl)Cl>[CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:33])[CH:23]([Br:34])[C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[CH:18][CH:17]=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][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cc2ccc([N+](=O)[O-])cc2)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)C(Br)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 94.9 %

Procedure:
80 g (0.18 mol) of p-n-tetradecyloxy-ω-(p-nitrophenyl)acetophenone prepared as described above was dissolved in 400 cc of chloroform and to the solution 28 g (0.18 mol) of bromine dissolved in 50 cc of chloroform was gradually added dropwise while refluxing with heating. The mixture was washed with water and dried with anhydrous sodium sulfate. Chloroform was distilled off under reduced pressure and 91 g of p-n-tetradecyloxy-ω-bromo-ω-(p-nitrophenyl)acetophenone was obtained after recrystallization from n-hexane. Yield: 95%, Melting Point: 55° to 56° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[C:10]1=[O:19].[OH-:20].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:11](=[O:18])[C:10]([OH:19])=[O:20]
Reactant: O=C1C(=O)N(c2c(Cl)cccc2Cl)c2ccccc21
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 5.8 g of 1-(2,6-dichlorophenyl)indole-2,3-dione (m.p. 174°-175° C.) in 40 ml of ethanol were added 22 ml of a 1 N aqueous sodium hydroxide solution and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated at a bath temperature of not more than 40° C. under a reduced pressure of 5 mmHg. To the residue were added 50 ml of water and the mixture was extracted with 30 ml of ether. The ether extract was separated out. The remaining aqueous layer was acidified with a 5% aqueous hydrochloric acid solution under ice-cooling and the solid thus precipitated was extracted with ether. The ether extract was washed with water and dried over sodium sulfate and concentrated at 10 mmHg without heating. The residue was recrystallized from dichloromethane-hexane to give 6.0 g of 2-(2,6-dichloroanilino)phenylglyoxylic acid as a yellow powder. m.p. 159°-159.5° C. Yield: 97% of theoretical amount
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[N+:16]([O-])([OH:18])=[O:17].C([O-])(O)=O.[Na+]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:3]([C:12]([F:13])([F:14])[F:15])=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:6]([N+:16]([O-:18])=[O:17])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(Br)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)Nc1cc(C(F)(F)F)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To a solution of the acetamide from step (a) above (8.46 g, 30 mmol) in concentrated sulfuric acid (32.5 mL) was added dropwise concentrated HNO3 (4.1 mL, 90%. J. T. Baker) with stirring at 0° C. The resulting solution was stirred at room temperature for 3 h and poured into crushed ice (80 mL). The mixture was carefully neutralized with solid NaHCO3 and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (25% EtOAc/hexane) to give the title compound as a yellow solid. MS (ESI, neg. ion) m/z: 325.0 (M−1).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[C:4](=[O:14])[CH:5]=[C:6]([CH3:13])[O:7]2.N([O-])=O.[Na+].C(=O)(O)[O-].[Na+].[Cu][C:25]#[N:26].[C-]#N.[Na+]>S(=O)(=O)(O)O.O.C(OCC)(=O)C>[CH3:13][C:6]1[O:7][C:8]2[C:9]([CH3:12])=[CH:10][CH:11]=[C:2]([C:25]#[N:26])[C:3]=2[C:4](=[O:14])[CH:5]=1
Reactant: N#C[Cu]
Reactant: Cc1cc(=O)c2c(N)ccc(C)c2o1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(=O)c2c(C#N)ccc(C)c2o1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
0.2 g (1.06 mmol) of 5-amino-2,8-dimethyl-4H-chromen-4-one is dissolved in 5 ml of 45% strength sulfuric acid and cooled to 0° C. A solution of 0.11 g (1.6 mmol) of sodium nitrite in 5 ml of water is then added dropwise in such a way that the temperature does not exceed 5° C. The mixture is stirred at 0° C. for 90 min and then neutralized with sodium bicarbonate. A solution of 0.12 g (1.37 mmol) of copper(I) cyanide and 0.07 g (1.58 mmol) of sodium cyanide in 10 ml of water, cooled to 0° C. and covered with a layer of 50 ml of ethyl acetate, is then added. The mixture is stirred at 0° C. for 45 min. The reaction mixture is then filtered through kieselguhr. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution. After drying over magnesium sulfate, the solvent is removed in vacuo. 0.14 g (67% of theory) of the title compound is obtained.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1.C(O)C.[OH-].[Na+]>CCCCCC>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(-c2ccc(O)cc2)c1
Reactant: OC(CCl)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Product: COc1cccc(-c2ccc(OCC(O)CCc3cccnc3)cc2)c1

Procedure:
Prepared according to the method described in Example 24b) from (±)-α-(chloromethyl)-3-pyridinepropanol (1.90 g), 3'-methoxybiphenyl-4-ol (2.05 g), ethanol (40 ml) and aqueous sodium hydroxide (2.1 M, 5 ml). After the reaction was complete it was concentrated under reduced pressure and the residue partitioned between ethyl acetate and water. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was twice purified by column chromatography over silica eluting with dichloromethane:ethyl acetate as an oil (1.35 g). A white solid was obtained after trituration with ether:hexane.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]2[N:14]=[C:13]([CH2:15][N:16]3[C:24]4[C:19](=[C:20]([NH:25][C:26]([C:28]5[N:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]6=[N:30][CH:29]=5)=[O:27])[CH:21]=[CH:22][CH:23]=4)[C:18]([CH2:37][CH3:38])=[N:17]3)[CH:12]=[CH:11][CH:10]=2)[CH2:4][O:3]1.[ClH:40]>C1COCC1>[ClH:40].[ClH:40].[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]1[N:14]=[C:13]([CH2:15][N:16]2[C:24]3[C:19](=[C:20]([NH:25][C:26]([C:28]4[N:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]5=[N:30][CH:29]=4)=[O:27])[CH:21]=[CH:22][CH:23]=3)[C:18]([CH2:37][CH3:38])=[N:17]2)[CH:12]=[CH:11][CH:10]=1
Reactant: CCc1nn(Cc2cccc(OCC3COC(C)(C)O3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: Cl
Solvent: C1CCOC1
Product: CCc1nn(Cc2cccc(OCC(O)CO)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
To a solution of N-(1-((6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (12 mg, 0.023 mmol) in THF (1 mL) was added hydrogen chloride (0.5 mL, 2.0 mmol; 4M solution in 1,4-dioxane). The mixture was stirred at ambient temperature for 3 hours. The mixture was concentrated under a stream of nitrogen and the residue was dissolved in a mixture of methanol and dichloromethane. A solution of ammonium hydroxide was added to neutralize. The material was purified using preparative thin layer chromatography, eluting with 10% methanol in dichloromethane containing 0.5% ammonium hydroxide. The isolated product was dissolved in a mixture of methanol and dichloromethane and treated with concentrated hydrochloric acid (0.05 mL). The solvent was removed under reduced pressure to give N-(1-((6-(2,3-dihydroxypropoxy)pyridin-2-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (8 mg). MS (APCI), positive scan, m/z=487.2 (M+H).
Reaction SMILES: [NH2:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=2)=[N:5][N:4]=[C:3]1[SH:19].[N:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29](O)=O)=[CH:28][C:23]=2[NH:22][CH:21]=1>P(Cl)(Cl)(Cl)=O>[NH:22]1[C:23]2[CH:28]=[C:27]([C:29]3[S:19][C:3]4=[N:4][N:5]=[C:6]([C:7]5[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=5)[N:2]4[N:1]=3)[CH:26]=[CH:25][C:24]=2[N:20]=[CH:21]1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: COc1cc(-c2nnc(S)n2N)cc(OC)c1OC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(-c2nnc3sc(-c4ccc5nc[nH]c5c4)nn23)cc(OC)c1OC
Yield: 17.5 %

Procedure:
A mixture of 4-amino-3-mercapto-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (80 mg, 0.28 mmol) and 3H-benzo[d]imidazole-5-carboxylic acid (46 mg, 0.28 mmol) in phosphoryl chloride (2 mL) was refluxed for 3 h. The solvent was evaporated and the residue was dissolved in dichloromethane (20 mL). It was neutralized with aqueous sodium carbonate. The organic layer was dried over sodium sulfate, concentrated to give 20 mg (17%) of the title compound as a solid. 1H NMR (CD3OD): 8.55 (s, 1H), 8.35 (s, 1H), 8.01-7.85 (m, 2H), 7.72 (s, 1H), 3.99 (s, 6H), 3.87 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[S:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=3[C:14]=2[CH3:23])(=[O:12])=[O:11])=[CH:5][C:4]=1[N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1>ClCCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[S:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=3[C:14]=2[CH3:23])(=[O:12])=[O:11])=[CH:5][C:4]=1[N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1
Reactant: COc1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)cc1N1CCN(C)CC1
Solvent: ClCCCl
Product: Cc1c(S(=O)(=O)Nc2ccc(O)c(N3CCN(C)CC3)c2)sc2ccc(Cl)cc12

Procedure:
To a suspension of boron tribromide dimethyl sulphide complex (620 mg, 2 mmol) in 1,2 dichloroethane (30 ml) under argon was added 5-chloro-3-methyl-benzo[b]thiophene-2-sulphonic acid[4-methoxy-3-(4-methyl-piperazin-1-yl)phenyl]amide (E17) (0.2 mmol). The reaction mixture was heated to reflux for 12 hrs, cooled, quenched by the addition of water (20 ml) and partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford the title compound (E113). Found MH+ 452/454
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:23][CH2:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([N:31]3[CH2:34][CH2:33][CH:32]3[C:35](O)=[O:36])[CH2:27][CH2:26]2)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:22])([F:21])[F:20])=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl-].[NH4+].C[N:41](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[N+:1]([C:4]1[C:5]([NH:23][CH2:24][C@H:25]2[CH2:26][CH2:27][C@H:28]([N:31]3[CH2:34][CH2:33][CH:32]3[C:35]([NH2:41])=[O:36])[CH2:29][CH2:30]2)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:20])([F:21])[F:22])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C1CCN1[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)C1CCN1[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}cyclohexyl)azetidine-2-carboxylic acid (170 mg, 0.27 mmol) in DMF (1.5 mL) were added ammonium chloride (170 mg, 3.2 mmol), HATU (303 mg, 0.80 mmol) and DIPEA (370 μL, 2.1 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3, water (×3) and brine. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 7 mg of the title compound, m/z 522.6 [M−1]+
Reaction SMILES: [OH:1][C:2]1([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:38])[F:37])[CH:30]=3)=[CH:25][CH:24]=2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[ClH:40]>>[ClH:40].[ClH:40].[N:10]1([CH2:9][CH:8]([C:2]2([OH:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:38])[F:37])[CH:30]=3)=[CH:25][CH:24]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(-c3cccc(OC(F)(F)F)c3)cc2)C2(O)CCCCC2)CC1
Agent: Cl
Product: OC1(C(CN2CCNCC2)c2ccc(-c3cccc(OC(F)(F)F)c3)cc2)CCCCC1

Procedure:
In an analogous manner to Example 135, step 4,1-{2-piperazin-1-yl-1-[3′-(trifluoromethoxy)-1,1′-biphenyl-4-yl]ethyl}cyclohexanol dihydrochloride was prepared from tert-butyl 4-{2-(1-hydroxycyclohexyl)-2-[3′-(trifluoromethoxy)-1,1′-biphenyl-4-yl]ethyl}piperazine-1-carboxylate. MS (ES) m/z 449.3 ([M+H]+); HRMS: calcd for C25H31F3N2O2.2.00 HCl, 520.1871; found (ESI), 449.2389.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[C:7]([O:16][CH2:17][CH3:18])(=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[NH2:10].C(N(CC)CC)C.C(N1C(=O)C2C(=CC=CC=2)NC1=O)CC>C1(C)C(C)=CC=CC=1>[CH2:1]([NH:4][C:5]([NH:10][C:9]1[C:8](=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([O:16][CH2:17][CH3:18])=[O:15])=[O:6])[CH2:2][CH3:3]
Reactant: CCOC(=O)c1ccccc1N
Reactant: CCCN=C=O
Agent: CCCn1c(=O)[nH]c2ccccc2c1=O
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CCCNC(=O)Nc1ccccc1C(=O)OCC
Temperature: 110 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
A solution of propyl isocyanate (34.0 g, 0.40 mol) in xylene (100 ml) is metered, at room temperature, into a solution of ethyl anthranilate (66.1 g, 0.40 mol) in xylene (200 ml). After the addition has ended, the batch is stirred at 110° C. for 2 hours. Triethylamine (5.6 ml, 4.08 g, 0,040 mol) is added. Stirring is continued at 90° C. for a further 2 hours. The desired cyclization product 3-(propyl)-2,4(1H,3H)-quinazolinedione cannot be detected in the reaction solution by thin-layer chromatography. After cooling, the precipitate is filtered off with suction, washed with 3×25 ml of xylene and dried. 67.0 g of ethyl N-(propylcarbamoyl)anthranilate (yield: 66.9% of theory) of melting point 98° to 99° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([NH:22][C:23]([N:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]2[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]12)=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Reactant: CCCCN=C=O
Product: CCCCNC(=O)N1C2=NC(C)(C)N(C)C(=O)N2c2ccccc21

Procedure:
The procedure of Example 10 was used to prepare the title compound from 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one and n-butyl isocyanate. The confirmatory elemental analysis for the product, mp 95°-97° C., is shown in Table III.
Reaction SMILES: [CH:1]([CH:4]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)C(C)(C)C1C)([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=[O:25])C(C)C.C1(C)C=CC=CC=1>[N+](C)([O-])=O>[CH:1]([C:4]([C:12]1[CH:7]=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=1)=[O:25])([CH3:3])[CH3:2]
Reactant: Cc1ccc2c(c1)C(C)(C)C(C)C2C(C)C
Reactant: CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: C[N+](=O)[O-]
Product: Cc1ccc(C(=O)C(C)C)cc1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To prepare 1-isopropyl-2,3,3,5-tetramethylindane, the procedures of Traas et al., U.S. Pat. No. 4,352,748 are substantially followed. Specifically, a solution of aluminum chloride (75 g) in nitromethane (50 ml) is added to a mixture of isobutyroyl chloride (49 g), nitromethane (50 ml) and toluene (100 ml), and stirred for one hour at about 10° C. The reaction mixture is poured over ice and extracted with ether. The ether solution is washed to neutrality, dried and evaporated. The residue is distilled under diminished pressure to obtain p-tolyl isopropyl ketone. The ketone (11 g) is then dissolved in methanol (50 ml), added to a solution of NaBH4 (10 g) in a methanol/water mixture (100 ml; 1:1). The reaction mixture is stirred for one hour, and then poured into water and extracted with ether. The solution in ether is dried on anhydrous magnesium sulfate and evaporated to yield 2-methyl-1-(p-tolyl)propanol-1.
Reaction SMILES: [NH2:1][C@H:2]([C:12]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([Cl:33])=[C:22]3[C:26]=2[N:25]([CH3:27])[N:24]=[C:23]3[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:16][CH:15]=[C:14]([Cl:34])[N:13]=1)[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[CH:5]=1.C(N(CC)CC)C.[F:42][C:43]1([F:60])[C:47]2[N:48]([CH2:55][C:56](O)=[O:57])[N:49]=[C:50]([C:51](F)([F:53])[F:52])[C:46]=2[C@H:45]2[CH2:59][C@@H:44]12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[Cl:34][C:14]1[N:13]=[C:12]([C@@H:2]([NH:1][C:56](=[O:57])[CH2:55][N:48]2[C:47]3[C:43]([F:42])([F:60])[C@@H:44]4[CH2:59][C@@H:45]4[C:46]=3[C:50]([CH:51]([F:53])[F:52])=[N:49]2)[CH2:3][C:4]2[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[CH:5]=2)[C:17]([C:18]2[CH:19]=[CH:20][C:21]([Cl:33])=[C:22]3[C:26]=2[N:25]([CH3:27])[N:24]=[C:23]3[NH:28][S:29]([CH3:32])(=[O:30])=[O:31])=[CH:16][CH:15]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1C(F)(F)[C@@H]1C[C@H]21
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3ccc(Cl)nc3[C@@H](N)Cc3cc(F)cc(F)c3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3ccc(Cl)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of crude (S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-chloropyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide (60A, 400 mg, 0.76 mmol) in DMA (6 mL) was added triethylamine (0.32 mL, 2.28 mmol), 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (30J, 0.61 mmol), then HATU (173.4 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 15 minutes, then additional HATU (86.7 mg, 0.23 mmol) was added. The reaction mixture was stirred at room temperature for an additional 15 minutes. Upon completion, the reaction mixture was concentrated in vacuo and purified by silica gel column chromatography, eluting with 0-100% EtOAc in hexanes to give the title compound (60B). MS (m/z) 790.05 [M+H]+.