Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][NH:14][C:15]1[N:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1.[C:23]([O-])(=[O:25])[CH3:24].[Na+].C(OC(=O)C)(=O)C>O>[C:23]([CH2:13][NH:14][C:15]1[N:20]=[CH:19][C:18]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)=[CH:17][CH:16]=1)(=[O:25])[CH3:24]
Reactant: O=C(O)CNC(=O)c1cccs1
Reactant: CNc1ccc(C=O)cn1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)CNc1ccc(C=C2N=C(c3cccs3)OC2=O)cn1
Temperature: 90 °C
Yield: 28.5 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 6-(methylamino)-3-pyridinecarboxaldehyde (45 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 28 mg of the above-captioned compound.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([N:11]=[C:12](SC)SC)=[N:10][C:5]2=[CH:4][CH:3]=1.Cl.Cl.[NH2:19][CH2:20][C@@:21]1([OH:28])[C@H:26]2[CH2:27][N:23]([CH2:24][CH2:25]2)[CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.C(Cl)(Cl)Cl>[F:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12]3[O:28][C@@:21]4([C@H:26]5[CH2:27][N:23]([CH2:24][CH2:25]5)[CH2:22]4)[CH2:20][N:19]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CSC(=Nc1nc2ccc(F)nc2s1)SC
Reactant: NC[C@]1(O)CN2CC[C@@H]1C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc2nc(NC3=NC[C@@]4(CN5CC[C@@H]4C5)O3)sc2n1
Temperature: 100 °C

Procedure:
To a solution of dimethyl 5-fluorothiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (95 mg, 0.349 mmol) in N,N-dimethylformamide (2 mL) was added (3S*,4R*)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol dihydrochloride (75 mg, 0.349 mmol). The reaction was then treated with cesium carbonate (114 mg, 0.7 mmol). The reaction was heated to 100° C. for 1 hour and then cooled to room temperature. The reaction was diluted with water (20 mL) and chloroform (2×20 mL). The organic phases were combined and concentrated to residue in vacuo. The residue was then triturated in diethyl ether to give (3R*,4R*)—N-(5-fluorothiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine as a precipitate (42 mg, 37%) that was collected via vacuum filtration. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.13 (br. s., 1H) 8.07 (dd, J=8.53, 7.28 Hz, 1H) 7.16 (dd, J=8.53, 1.51 Hz, 1H) 3.85 (d, J=10.29 Hz, 1H) 3.66 (d, J=10.29 Hz, 1H) 2.77-2.98 (m, 2H) 2.71 (td, J=6.65, 4.02 Hz, 2H) 2.58-2.67 (m, 2H) 2.40 (dd, J=10.16, 3.64 Hz, 1H) 1.87-2.00 (m, 1H) 1.53 (t, J=4.39 Hz, 1H). MS (LC/MS) R.T.=0.675 min; (M+H=320.1).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.O1CCC[CH2:12]1.C(NC(C)C)(C)C.[Li].C1CCCCC1.CI>C1COCC1>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[CH3:12]
Reactant: C1CCOC1
Reactant: Brc1csc2ccncc12
Agent: [Li]
Solvent: CI
Solvent: CC(C)NC(C)C
Solvent: C1CCCCC1
Product: Cc1sc2ccncc2c1Br
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 72 %

Procedure:
291 mg of 3-Bromo-thieno[3,2-c]pyridine (1.36 mmol) is dissolved in 3 ml of dry THF and cooled to −78° C. 1.00 ml of lithium diisopropylamine mono(tetrahydrofuran) 1.5M solution in cyclohexane (1.5 mmol) is added to the mixture at −78° C. and stirred at −78° C. for 20 min. 213 mg of methyl iodide (1.5 mmol) is added to the mixture and stirred at −78° C.→room temperature for 1 h. The reaction mixture is quenched by sat. NH4Cl and extracted with CH2Cl2. The separated CH2Cl2 is dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=20:4:1) to give 225 mg of the title compound. Yield 72%. mass spectrum (m/e): 230 (M+1); 1H-NMR (CDCl3): 9.01 (s, 1H), 8.52 (d, 1H, J=5.5 Hz), 7.72 (d, 1H, J=5.5 Hz), 2.61 (s, 3H) ppm.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:10](=[O:15])([O:13][CH3:14])[O:11][CH3:12]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[C:10](=[O:13])([O:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[O:11][CH3:12].[C:10](=[O:15])([O:13][CH2:14][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:11][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCl
Reactant: COC(=O)OC
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCCCCCCCOC(=O)OC
Product: CCCCCCCCOC(=O)OCCCCCCCC
Yield: 74 %
Yield: 5 %

Procedure:
1-Chlorooctane (37.17 g, 0.25 mole), dimethyl carbonate (90.0 g, 1.0 mole), tetra-n-butylphosphonium bromide (3.39 g, 0.01 mole) and N,N-dimethylformamide (200 ml) are heated to 115° C. for 24 hours. After work-up as described for Example 34, distillation gives 34.8 g (74 percent yield based on 1-chlorooctane) of methyl 1-octyl carbonate, b.p. 113° C.-114° C. (17 torr) and 1.9 g (5 percent yield based on n-octyl chloride) of di-1-octyl carbonate, b.p. 129° C.-130° C. (0.5 torr).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][O:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([OH:25])[CH:16]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=3)=[CH:10][CH:9]=2)=[N:4]1)[CH3:2].Cl[C:27]1[CH:32]=[N:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[CH2:1]([C@@H:3]1[CH2:7][O:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([CH:16]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=3)[O:25][C:27]3[CH:32]=[N:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=3)=[CH:10][CH:9]=2)=[N:4]1)[CH3:2]
Reactant: CC[C@@H]1COC(c2ccc(-c3cc(O)cc(O[C@@H](C)COC)c3)[nH]2)=N1
Reactant: CS(=O)(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC[C@@H]1COC(c2ccc(-c3cc(Oc4cnc(S(C)(=O)=O)cn4)cc(O[C@@H](C)COC)c3)[nH]2)=N1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 105.4 %

Procedure:
3-{5-[(4R)-4-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol (272 mg, 0.79 mmol) synthesized in Example (108b) was dissolved in acetonitrile (5.0 mL), and 2-chloro-5-(methylsulfonyl)pyrazine (220 mg, 1.14 mmol) synthesized in Example (97c) and cesium carbonate (640 mg, 1.96 mmol) were added at room temperature, followed by stirring at room temperature for 3.5 hours under nitrogen atmosphere. To this reaction solution, water (20 mL) was added, and extraction was carried out with methylene chloride (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=2%-3%) to afford the desired compound (417 mg, yield ˜100%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:20]#[N:21])[C:10]([CH3:19])=[C:11]([N:14]4[CH:18]=[CH:17][CH:16]=[CH:15]4)[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:29][N:30]([CH3:36])[C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:20]#[N:21])[C:10]([CH3:19])=[C:11]([N:14]4[CH:18]=[CH:17][CH:16]=[CH:15]4)[C:12]=3[N:33]3[CH2:34][CH2:35][C@H:31]([N:30]([CH3:36])[CH3:29])[CH2:32]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-n2cccc2)c(F)c2oc(C3CC3)nc2c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(-n2cccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Temperature: 100 °C
Reaction time: 5.5 h
Yield: 70.6 %

Procedure:
2-Cyclopropyl-7-fluoro-5-methyl-6-(pyrrol-1-yl)-1,3-benzoxazole-4-carbonitrile (I-320) (28 mg, 0.10 mmol) was dissolved in dimethyl sulfoxide (2 ml), then at room temperature, triethylamine (18 μl, 0.13 mmol) and (3S)-3-(dimethylamino)pyrrolidine (17 μl, 0.13 mmol) were added, followed by stirring under nitrogen atmosphere at 100° C. for 5.5 hours. The reaction liquid was cooled to room temperature, then fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was roughly purified by preparative TLC (eluent, chloroform:methanol=92:8, v/v), and the obtained solid was further purified in slurry with diisopropyl ether. This was dried at 60° C. under reduced pressure for 12 hours to obtain the entitled compound (26.5 mg, 71%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:12]3[C:13](=[O:16])[NH:14][CH2:15][C:11]=3[CH:10]=[C:9]([NH:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[N:8]=2)[CH:4]=[N:3]1.[B-](F)(F)(F)[F:33].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.CO.O>C(Cl)Cl>[F:33][C:10]1[C:11]2[CH2:15][NH:14][C:13](=[O:16])[C:12]=2[C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[N:8][C:9]=1[NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29]
Reactant: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)cn1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)NC3)cn1
Yield: 9.6 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (150 mg, 0.352 mmol) and SELECTFLUOR® (150 mg, 0.422 mmol) in DCM (1 mL) and MeOH (1 mL) was stirred at RT overnight. Water was subsequently added and the mixture was extracted with CHCl3 (3×). The organic phases were combined, washed with brine, dried over MgSO4, and evaporated. The residue was purified by preparative HPLC to give the title compound (15 mg, 9.60%). [M+H] calc'd for C22H29FN6O3, 445. found, 445.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)=[CH:3][CH:2]=1.[CH2:13]=[O:14].[OH-].[K+].[CH3:17][O:18]CCO>>[C:1]1([CH3:12])[CH:2]=[CH:3][C:4]([C:7]2[NH:11][C:10]([CH2:13][OH:14])=[C:9]([CH2:17][OH:18])[N:8]=2)=[CH:5][CH:6]=1
Reactant: C=O
Reactant: Cc1ccc(-c2ncc[nH]2)cc1
Reactant: COCCO
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(-c2nc(CO)c(CO)[nH]2)cc1
Yield: 9 %

Procedure:
A mixture of 15.8 g (0.1 mole) of 2-p-tolylimidazole, 24 ml (0.3 mole) of 37% formalin and 2 g of potassium hydroxide was heated for 30 minutes with stirring in the same way as in Example 1, and the reaction mixture was post-treated in the same way as in Example 1 except that methyl cellosolve was used instead of methanol as a recrystallization solvent to afford 2-p-tolyl-4,5-dihydroxymethyl imidazole as a final product in an amount of 2 g (yield 9%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH:21]=[O:22])[C:13]2[C:8](=[CH:9][C:10]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:11]([Cl:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[O:23]1CCCC1>[Ag]=O.O>[CH3:1][O:2][C:3]([C:5]1([C:21]([OH:23])=[O:22])[C:13]2[C:8](=[CH:9][C:10]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)=[C:11]([Cl:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: C1CCOC1
Reactant: COC(=O)C1(C=O)CCc2cc(C3CCCCC3)c(Cl)cc21
Agent: O=[Ag]
Solvent: O
Product: COC(=O)C1(C(=O)O)CCc2cc(C3CCCCC3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.0 g of crude 1-formyl-5-cyclohexyl-6-chloro-1-indanecarboxylic acid methyl ester in 30 of tetrahydrofurane and 3 ml of water is treated with 4 equivalents of silver oxide (manufactured according to Corey et al., J. Amer. Chem. Soc., 90, 5616 (1963)) and the mixture is stirred overnight at room temperature. The reaction solution is then filtered through Celite and the filtrate is partitioned between 150 ml of methylene chloride and 100 ml of 0.1 N hydrochloric acid. The organic phase is washed with twice 150 ml of water, dried over sodium sulphate and evaporated in vacuo. Chromatography of the evaporation residue on silica gel, using benzene/ethyl acetate/glacial acetic acid, 90:30:1, as the eluting agent, yields crude 1-methoxycarbonyl-5-cyclohexyl-6-chloro-1-indanecarboxylic acid which can be purified further by fractional crystallisation from benzene-hexane; melting point 139°-142° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][CH:12]([C:14]([O:16][CH3:17])=[O:15])[N:13]=2)=[CH:5][CH:4]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][CH:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:13]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)C1COC(c2ccc(C(F)(F)F)cc2)=N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)c1coc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 75 °C
Reaction time: 36 h

Procedure:
A solution of methyl 2-[4-(trifluoromethyl)phenyl]-1,3-oxazoline-4-carboxylate (1.33 g, 4.87 mmol) was stirred in toluene (60 ml) at 55° C. until all of the starting material was dissolved. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (5.53 g, 24.365 mmol) was then added in portions, and the resulting solution was stirred at 75° C. for 36 hours. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography, to provide methyl 2-[4-(trifluoromethyl)phenyl]-1,3-oxazole-4-carboxylate, a compound of formula (15). D. Preparation of a Compound of Formula (16)
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17](=[O:26])[C:18](=[CH:22][N:23]([CH3:25])C)[C:19](=O)[CH3:20])=[CH:11][C:10]=3[F:27])[N:7]=[C:6]([C:28]([F:31])([F:30])[F:29])[CH:5]=2)[CH2:3][CH2:2]1.C(O)(=O)C.C(N)=[NH:37].CC[O-].[Na+]>C(O)C>[CH:1]1([C:4]2[N:8]([C:9]3[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:18]4[C:19]([CH3:20])=[N:37][CH:25]=[N:23][CH:22]=4)=[O:26])=[CH:11][C:10]=3[F:27])[N:7]=[C:6]([C:28]([F:30])([F:29])[F:31])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: N=CN
Reactant: CC(=O)C(=CN(C)C)C(=O)Nc1cc(F)c(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ncncc1C(=O)Nc1cc(F)c(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Yield: 5 %

Procedure:
N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3,5-difluorophenyl}-2-[(dimethylamino)methylene]-3-oxobutanamide (700 mg, 1.6 mmol) and formamidine acetate (282 mg, 2.7 mmol) were dissolved in ethanol and added NaOEt (120 mg, 3.4 mmol). The above mixture was refluxed for 3 hr. Ethanol was removed on rotavapour and worked up (H2O/AcOEt) to obtain the crude. Crude was purified by column on 60-120 mesh silica gel using AcOEt and Petether (35:65) as eluent to obtain the title compound (34 mg) as a pale-yellow solid. M.P.: 147-150° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 11.25 (s, 1H), 9.18 (s, 1H), 8.96 (s, 1H), 7.73 (d, J 9.9, 2H), 6.69 (s, 1H), 2.61 (s, 3H), 1.65-1.56 (m, 1H), 0.95-0.86 (m, 2H), 0.80-0.72 (m, 2H). MS (m/z): 424.09 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH2:13]([O:20][C:21](=[O:53])[NH:22][C:23]1[N:52]=[C:26]2[N:27]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=3)[C:28]([CH3:41])=[C:29]([C:39]#[N:40])[C@@H:30]([C:31]3[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=3)[N:25]2[N:24]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1.C1COCC1>[CH2:13]([O:20][C:21](=[O:53])[N:22]([C:23]1[N:52]=[C:26]2[N:27]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:49])[F:50])[CH:43]=3)[C:28]([CH3:41])=[C:29]([C:39]#[N:40])[C@@H:30]([C:31]3[CH:32]=[CH:33][C:34]([C:37]#[N:38])=[CH:35][CH:36]=3)[N:25]2[N:24]=1)[S:9]([CH3:8])(=[O:11])=[O:10])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(C(=O)OCc3ccccc3)S(C)(=O)=O)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas and at room temperature, triethylamine (11.1 mg, 140 mmol, 2.6 eq.) and methanesulfonyl chloride (41 mg, 360 mmol, 10 eq.) were added to a solution of benzyl{(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}carbamate (20 mg, 36 mmol; Example 38) in dry pyridine (2 ml) and THF (2 ml), and the mixture was stirred for 12 h. The reaction mixture was then concentrated under reduced pressure and directly purified by preparative HPLC (Reprosil C18 column, 30×200 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (17.4 mg, 72% of theory).
Reaction SMILES: Cl.[F:2][C:3]1([F:29])[CH2:7][CH2:6][C@@H:5]([C@@:8]([OH:28])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]([O:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH:20]=[NH:21])[CH2:16][CH2:15]2)=[O:10])[CH2:4]1.[Br-:30].[Na+]>O>[BrH:30].[F:29][C:3]1([F:2])[CH2:7][CH2:6][C@@H:5]([C@@:8]([OH:28])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:9]([O:11][CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([CH:20]=[NH:21])[CH2:18][CH2:19]2)=[O:10])[CH2:4]1
Reactant: [Br-]
Agent: Cl
Agent: N=CN1CCC(CCOC(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Agent: [Na+]
Solvent: O
Product: Br

Procedure:
A solution of 50 mg of 2-(1-(iminomethyl)piperidin-4-yl)ethyl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate monohydrochloride in 2 ml of ultrapure water was developed on reversed phase medium pressure liquid chromatography [ODS-AQ 120-S50 (YMC Co.)], and 60 ml of 0.2 M aqueous sodium bromide solution was flowed. After washing with 100 ml of ultrapure water, the title compound was eluted from tetrahydrofuran/water=1/5, and 35 mg thereof was obtained as a colorless solid upon condensation to dry solid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19](C(OC)=O)=[CH:18][C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>CN(C=O)C>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]=[CH:18][C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C1=Cc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC=Cc1ccccc1-3

Procedure:
To a stirred solution of dimethyl 13-cyclohexyl-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate (2.6 g, 6.1 mmol) in DMF (60 mL) was added LiOH (1.45 g, 60 mmol) and the reaction mixture was heated at 60° C. for 2d. The reaction mixture was cooled internally with ice, acidified with 1M aqueous HCl (pH<2) and extracted with EtOAc (350 mL). The organics were washed with H2O (˜150 mL), brine (˜150 mL), dried (MgSO4), filtered and concentrated. The solids were triturated with Et2O/hexanes (1:2) and collected to yield methyl 13-cyclohexyl-7H-indolo[2,1-a][2]benzazepine-10-carboxylate, 6-carboxylic acid (2.06 g, 4.96 mmol. 81%) as a fluffy yellow solid. 1HNMR (500 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.88 (s, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.67–7.55 (m, 4H), 5.58 (br s, 1H), 4.15 (br s, 1H), 3.90 (s, 3H), 2.84–2.75 (m, 1H), 2.10–1.65 (m, 6H), 1.49–1.07 (m, 4H). LCMS: m/e 416 (M+H)+, ret time 1.47 min, column A, 2 minute gradient.
Reaction SMILES: [CH:1]1([CH:10]=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1C2C(=CC=CC=2)C[CH:13]1[CH:21]=[O:22].[CH2:23](O)CO>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH:1]1([CH:10]2[O:22][CH:21]([CH3:13])[CH2:23][O:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: OCCO
Reactant: O=CC1CCc2ccccc21
Reactant: O=CC1Cc2ccccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1COC(C2CCc3ccccc32)O1

Procedure:
A solution of 297 grams of a mixture of 70% indancarbaldehyde and 30% indan-2-carbaldehyde, 300 grams of ethylene glycol, 6 grams of p-toluenesulfonic acid and 300 grams of toluene are heated 2 hours at reflux using a Dean-Stark trap to separate water. The mixture is cooled and washed with 200 milliliters of a 5 weight % sodium carbonate solution. The organic layer is distilled to provide 321 grams of 2-indanyl-4-methyl-1,3-dioxolane (b.p.121° C. at 3 mm).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1.IC.Cl>O1CCCC1.CN(P(N(C)C)N(C)C)C.CCCCCC>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:1])[C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2F)cc1
Reactant: CC(C)NC(C)C
Agent: CN(C)P(N(C)C)N(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: CC(C(=O)O)c1ccc(-c2ccccc2F)cc1
Reaction time: 0.25 h

Procedure:
Diisopropylamine (16.4 ml) was dissolved in tetrahydrofuran (100 ml) and then a hexane solution (30.3 ml, 1.66 M) of n-butyllithium was added under ice-cooling, after which the resulting mixture was stirred for 15 minutes. Subsequently, thereto was added under ice-cooling a solution obtained by dissolving the above carboxylic acid (13.44 g) in tetrahydrofuran (100 ml), and thereafter, hexamethylphosphorus triamide (40 ml) was added, after which the resulting mixture was stirred under ice-cooling for one hour. Further, iodomethane (3.63 ml) was added and the resulting mixture was stirred for 3 hours. To the reaction mixture was added 10% hydrochloric acid (500 ml) and then the solution was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, then dried over sodium sulfate and thereafter concentrated under reduced pressure, to obtain 2-(2'-fluoro-biphenyl-4-yl)-propionic acid (16.64 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]1[C:11](Cl)=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([Cl:15])=[N:14][C:6]=21.O.O1CCCC1.[Cl-].[NH4+]>C(O)C.[Zn]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]1[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([Cl:15])=[N:14][C:6]=21
Reactant: Clc1nc2c3ccc(Br)cc3nn2c(Cl)c1-c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Clc1nc2c3ccc(Br)cc3nn2cc1-c1ccccc1
Temperature: 25 °C
Yield: 58 %

Procedure:
7 g (17.8 mmol) 8-Bromo-2,4-dichloro-3-phenylpyrimido[1,2-b]indazole were suspended in a mixture of 453 mL ethanol, 322 mL water and 173 mL tetrahydrofuran. After addition of 4.5 g (84.4 mmol) ammonium chloride and 7.5 g (114 mmol) zinc the mixture was stirred over night at room temperature. The mixture was filtered via a glass fibre filter, washed with THF and the organic solvents were removed. The residue was treated with a mixture of water and ethyl acetate and the organic phase was separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic extracts were evaporated without prior drying because the product had already precipitated. 3.7 g (57.9%) of the title compound were isolated.