Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:15][C:16]([O:18][C:19]1([CH3:29])[CH:26]2[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2)=[O:17]>C(OCC)C.CN(C)C=O>[CH3:29][C:19]1([O:18][C:16](=[O:17])[CH2:15][O:5][C:1](=[O:4])[CH2:2][OH:3])[CH:26]2[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2
Reactant: O=C(O)CO
Reactant: CC1(OC(=O)CCl)C2CC3CC(C2)CC1C3
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(OC(=O)COC(=O)CO)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
37.6 g (494 mmol) of glycolic acid, 700 mL of DMF, 86.5 g (626 mmol) of potassium carbonate, and 28.3 g (170 mmol) of potassium iodide were charged into a 2 L three-necked flask equipped with a thermometer, a cooling pipe, and a stirrer, followed by stirring at room temperature for 30 minutes. Then, 300 mL of a dimethylformamide solution containing 100 g (412 mmol) of 2-methyl-2-adamantyl chloroacetate was gradually added thereto. The resultant was heated to 40° C., and was then stirred for 4 hours. Following completion of the reaction, 2,000 mL of diethyl ether was added to the reaction mixture, followed by filtration of the resulting mixture. The obtained solution was washed three times with 500 mL of distilled water, followed by crystallization using a mixed solution containing 300 mL of toluene and 200 mL of heptane, thereby obtaining 78 g of an objective compound in the form of a colorless solid (yield: 67%, GC purity: 99%).
Reaction SMILES: [OH:1][P:2]([O-:5])([O-:4])=[O:3].[Ca+2:6].C(=O)([O-])[O-].[Ca+2]>>[O-:3][P:2]([O-:5])([O-:4])=[O:1].[O-:3][P:2]([O-:5])([O-:4])=[O:1].[Ca+2:6].[Ca+2:6].[Ca+2:6]
Reactant: O=P([O-])([O-])O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: O=P([O-])([O-])[O-]
Reaction time: 24 h

Procedure:
β-Tricalcium phosphate was prepared by heating a mixture of dicalcium phosphate anhydrous (DCPA, Baker) and calcium carbonate (CC, Merck) in a molar ratio of 2:1 up to 1050° C. for 24 h, followed by quenching to room temperature. The sintered cake was crushed with pestle and mortar and sieved until it passed through a 355 μm sieve. The material was ground in a ball mill to a medium particle size d50 of 9.8 μm. Monocalcium phosphate monohydrate with a medium particle size d50 of 23.3 μm was purchased from Baker and used as received. Both materials were mixed in equimolar amounts in a coffee grinder for approximately 20-30 s.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[C:21](Cl)(=[O:28])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25]>CCOC(C)=O>[Cl:25][C:24]([Cl:27])([Cl:26])[CH2:23][O:22][C:21](=[O:28])[NH:11][C:9]1[N:8]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:7]=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:10]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reaction time: 0.25 h
Yield: 51.5 %

Procedure:
To a suspension of 3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-amine hydrochloride (2.5 g) in EtOAc (18 ml) was added 2.94 M aqueous NaOH (8 mL) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 15 min. To the reaction mixture was added 2,2,2-trichloroethyl chlorocarbonate (2.79 g), and the resulting mixture was stirred at room temperature for 6 hr. The organic layer was separated and successively washed with brine (10 mL×2), dried over MgSO4, filtered and evaporated in vacuo. The residue was triturated with IPE, and the precipitates produced were collected by filtration to give 2,2,2-trichloroethyl[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]carbamate (1.96 g).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:15](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.O>[CH3:15][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A solution of 4-phenylpiperidine (1.0 g, 6.2 mmol) was dissolved in THF (20 mL) and treated with formaldehyde (2.6 mL of a 37% solution in water). To the stirred reaction mixture was added sodium triacetoxyborohydride (2.63 g, 12.4 mmol). The reaction mixture was maintained at room temperature for 1 h, and then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with 5% aqueous NaHCO3 and brine, then dried over MgSO4. Evaporation of the solvent yielded 1-methyl-4-phenylpiperidine 113 (1.06 g, 97%) as a colorless oil.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH:13]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:11]=[CH:10]2)(=O)C.[OH-].[Na+]>CO.Cl>[NH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH:13]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:11]=[CH:10]2
Reactant: COC(=O)c1ccc2cccc(NC(C)=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc2cccc(N)c2c1
Temperature: 0 °C
Yield: 86.1 %

Procedure:
A stirred solution of 8.0 g (33 mmoles) of 8-acetylamino-2-naphthoic acid, methyl ester (VI) in 50 mL of methanol and 35 mL of 12N HCl was allowed to reflux for 1.5 hours. The reaction mixture was then cooled to 0° C., and pH adjusted to 6.5 with 10N NaOH. Removal of methanol in vacuo followed by collection of precipitate by vacuum filtration followed by washing with H2O and air drying afforded 5.72 g (yield: 80%) of 8-amino-2-naphthoic acid, methyl ester; 1H-NMR: δ8.62 (s, 1H), 7.99 (dd, J=8.5 Hz, 1.4 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.36 (m, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.79 (d, J=7.1 Hz, 1H), 4.35 (bs, 2H), 3.95 (s, 3H); MS (DCI) m/e: 218 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+].O>CN1CCN(C)C1=O>[N:11]([CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[N+:12]=[N-:13]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: N#Cc1ccc(CN=[N+]=[N-])cc1
Yield: 96.7 %

Procedure:
50 g of 4-bromomethylbenzonitrile is dissolved in 350 ml of 1,3-dimethyl-2-imidazolidinone and stirred at 25° for 2 hours with 32.5 g of sodium azide. The mixture is subsequently combined with 500 ml of water under ice cooling, extracted twice with dichloromethane, washed with water, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, thus obtaining 39 g of 4-azidomethylbenzonitrile as a colorless liquid.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]5[S:24][C:23]([NH2:25])=[N:22][N:21]=5)[CH:18]=4)[N:13](S(C4C=CC(C)=CC=4)(=O)=O)[CH:12]=3)[CH:8]=[N:7][CH:6]=2)[CH2:3][CH2:2]1.[OH-].[K+]>O1CCOCC1>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]5[S:24][C:23]([NH2:25])=[N:22][N:21]=5)[CH:18]=4)[NH:13][CH:12]=3)[CH:8]=[N:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(NC4CC4)n3)c3cc(-c4nnc(N)s4)ccc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1nnc(-c2ccc3[nH]cc(-c4cncc(NC5CC5)n4)c3c2)s1
Temperature: 100 °C
Yield: 18.5 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-(6-(cyclopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-thiadiazol-2-amine (97 mg, 0.193 mmol) in p-dioxane (2 mL) followed by 1 M KOH (0.8 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 15 min, then solvent was removed. The residue was purified with RP-HPLC (5-40% ACN in H2O with 0.1% TFA) to give 5-(3-(6-(cyclopropylamino)pyrazin-2-yl)-1H-indol-5-yl)-1,3,4-thiadiazol-2-amine (12.5 mg, 18.6%) as a solid. MS (ESI, pos. ion) m/z: 350 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.80 (1H, br. s.), 8.97 (1H, s), 8.31 (1H, s), 8.22 (1H, d, J=2.7 Hz), 7.62-7.76 (2H, m), 7.52 (2H, d, J=8.4 Hz), 7.27 (1H, br. s.), 2.83 (1H, dt, J=6.9, 3.2 Hz), 0.88-1.00 (2H, m), 0.49-0.60 (2H, m)
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C@@H:23]3[CH2:25][C@H:24]3[NH:26]C(=O)OC(C)(C)C)=[CH:19][CH:18]=2)=[O:15])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34].C(OCC)(=O)C>>[ClH:34].[NH2:26][C@@H:24]1[CH2:25][C@H:23]1[C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:14](=[O:15])[C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(Cc3ccccc3)c2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(Cc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl [trans-2-(4-{[(3-benzylphenyl)carbonyl]amino}phenyl)cyclopropyl]carbamate (125 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give the title compound (54.7 mg).
Reaction SMILES: [NH2:1][C:2]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][C:7]2=[N:6][N:5]=1)=[S:3].[CH3:20][N:21]([CH3:24])[CH:22]=O>>[CH3:20][N:21](/[CH:24]=[N:1]/[C:2]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][C:7]2=[N:6][N:5]=1)=[S:3])[CH3:22]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCn2c(nnc2C(N)=S)C1
Product: CN(C)/C=N/C(=S)c1nnc2n1CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1,1-dimethylethyl 3-(aminocarbonothioyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (I112) (99 mg, 0.349 mmol) in N,N-dimethylformamide (DMF) dimethyl acetal (3 ml, 22.41 mmol) was stirred at room temperature for 1 h. The mixture became red/orange and never went to a clear solution. The DMF dimethyl acetal was evaporated and the product triturated with ether to give an orange solid of desired product in 118 mg.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)[C:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[C:36]([NH3+:40])([CH3:39])([CH3:38])[CH3:37]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][C@@H:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][O:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][CH:30]=3)=[CH:18][CH:17]=2)[C:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[C:36]([NH3+:40])([CH3:39])([CH3:38])[CH3:37]
Reactant: CS(=O)(=O)Oc1ccc(OCCc2ccc(CC(SCCc3ccc(O)cc3)C(=O)[O-])cc2)cc1
Agent: CC(C)(C)[NH3+]
Solvent: CCO
Product: CS(=O)(=O)Oc1ccc(OCCc2ccc(C[C@H](SCCc3ccc(O)cc3)C(=O)[O-])cc2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
Crude tert-Butylammonium 2-{[2-(4-hydroxyphenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]propanoate (11.7 g, 19.8 mmol) was stirred in warm absolute ethanol (53.8 mL) at 71° C. to achieve complete dissolution. The resulting solution was screened into a second vessel through a 1 μm filter, followed by a line wash of warm ethanol (4.7 mL), and the solution allowed to cool to 60° C. Seed crystals (60 mg, 0.5% w/w) were added as a slurry in ethanol (0.5 mL) and the solution held at 60° C. for 30 minutes before cooling to 51° C. at 0.1° C./minute. The solution was held at 51° C. for 3 hours, during which period further seed crystals formed. The slurry was cooled to 46° C. at 0.1° C./minute, and held for 3 hours; then to 41° C. at 0.1° C./minute, and held for 3 hours; then to 31° C. at 0.1° C./minute, and held for 2 hours; then to 17° C. at 0.17° C./minute, and held for at least 5-6 hours. The solid was isolated by filtration, washed by displacement with absolute ethanol (11.7 mL) and dried in a vacuum oven at 50° C. to yield the title compound as a white solid (10.2 g, 87%). HPLC (Rt 9.8 min); chiral HPLC (typically 98% e.e.); mp 137-139° C.; MS (ES+) 534 (M+NH4+, 20%), 517 (M+H+, 30%), 471 (M-CO2H+, 100%). Other data as noted for the Crude stage above.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[S-:11][C:12]#[N:13].[NH4+].BrBr.O>CO>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11][C:12]#[N:13]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: N#CSc1cc(C(=O)O)ccc1N
Temperature: -15 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
4-Aminobenzoic acid (13 g) and ammonium thiocyanate (6.9 g) were suspended in methanol (200 ml) and cooled at −15° C. on an ice bath. A methanol solution (40 ml) containing bromine (4.7 ml) was added slowly dropwise thereto. The mixture was warmed to room temperature and stirred for 2 hours, iced water (500 ml) was added thereto, and precipitated crystals were collected by filtration and washed with water and n-hexane. The product was dried under reduced pressure to give 4-amino-3-thiocyanatobenzoic acid (9.4 g, Y.:53%) as white crystals.
Reaction SMILES: [I-].[C:2]([O:6][C:7](=[O:38])[CH2:8][C@H:9]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:5])([CH3:4])[CH3:3].[CH3:39][C:40]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][C:41]=1[CH:42]=O.C(Cl)Cl.CC(C)([O-])C.[K+]>O1CCCC1.O=[Mn]=O>[C:34]([O:33][C:31]([NH:30][C@H:9]([CH:10]=[CH:42][C:41]1[CH:44]=[C:45]([N+:48]([O-:50])=[O:49])[CH:46]=[CH:47][C:40]=1[CH3:39])[CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:38])=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1ccc([N+](=O)[O-])cc1C=O
Reactant: CC(C)(C)OC(=O)C[C@@H](C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C
Agent: O=[Mn]=O
Agent: CC(C)(C)[O-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])cc1C=C[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Adapting a literature procedure (Jandeleit et al., U.S. Pat. No. 8,168,617 (2012)), tert-butyl(3S)-3-(tert-butoxycarbonylamino)-5-(2-methyl-5-nitro-phenyl)pent-4-enoate (18b) is prepared from [(2S)-4-tert-butoxy-2-(tert-butoxycarbonylamino)-4-oxo-butyl]-triphenyl-phosphonium iodide (18a) (1.30 g, 2.0 mmol), 2-methyl-5-nitro-benzaldehyde (1b) (495 mg, 3.0 mmol) (commercial or prepared in two steps from commercial 2-methyl-5-nitro benzoic acid (i) BH3.SMe2, THF, reflux, ii) MnO2, DCM, room temperature) as described in Example 1) with a commercial ˜1.0 M solution of potassium tert-butoxide (KOtBu) (3.0 mL, 3.0 mmol) in anhydrous tetrahydrofuran (THF) (10 mL) at with gradual warming from 0° (ice bath) to room temperature for 24 hours. Aqueous work and purification by silica gel column chromatography furnish the title compound (18b) as a mixture of geometric isomers ((E)/(Z)-isomers).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH2:14].[Cl:15]NC(=O)CCC(N)=O>C(#N)C>[Cl:15][C:9]1[CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]([NH2:14])=[C:5]([O:4][CH2:3][CH2:2][Cl:1])[CH:10]=1
Reactant: NC(=O)CCC(=O)NCl
Reactant: Nc1c(OCCCl)cccc1[N+](=O)[O-]
Solvent: CC#N
Product: Nc1c(OCCCl)cc(Cl)cc1[N+](=O)[O-]

Procedure:
A solution of 2-(2-chloro-ethoxy)-6-nitro-phenylamine (1a, 30.0 g, 0.14 mol), N-chlorosuccinamide and acetonitrile (1.3 L) was refluxed for 4 hr. The mixture was concentrated under vacuum and the residue was diluted with ethyl acetate (500 mL). The organic layer was washed with water (2×, 250 mL) and brine (250 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to give an orange solid residue. Crystallization from ethyl acetate-hexane gave 33.5 g (95.3%) as orange solid, mp 109-110° C.; MS EI m/e 250/252/254 (M+).
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[F-].[K+].C[Si](C)(C)[C:23]#[C:24][C:25]1([CH3:29])[CH2:28][O:27][CH2:26]1.Br[C:33]1[CH:34]=[C:35]2[C:46]3([N:51]=[C:50]([NH2:52])[CH2:49][O:48][CH2:47]3)[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([C:53]4[C:54]([F:59])=[N:55][CH:56]=[CH:57][CH:58]=4)[CH:44]=3)[O:39][C:36]2=[N:37][CH:38]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C>[F:59][C:54]1[C:53]([C:43]2[CH:44]=[C:45]3[C@:46]4([N:51]=[C:50]([NH2:52])[CH2:49][O:48][CH2:47]4)[C:35]4[C:36](=[N:37][CH:38]=[C:33]([C:23]#[C:24][C:25]5([CH3:29])[CH2:28][O:27][CH2:26]5)[CH:34]=4)[O:39][C:40]3=[CH:41][CH:42]=2)=[CH:58][CH:57]=[CH:56][N:55]=1
Reactant: NC1=NC2(COC1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Reactant: CC1(C#C[Si](C)(C)C)COC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CN(C)C=O
Product: CC1(C#Cc2cnc3c(c2)[C@]2(COCC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)COC1
Temperature: 110 °C
Yield: 13.8 %

Procedure:
A vial charged with Pd(PPh3)4 (0.079 g, 0.068 mmol), copper(I) iodide (0.013 g, 0.068 mmol), 18-crown-6 (0.045 g, 0.170 mmol), potassium fluoride (0.118 g, 2.040 mmol), trimethyl((3-methyloxetan-3-yl)ethynyl)silane (0.229 g, 1.360 mmol), and 3-bromo-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.300 g, 0.680 mmol) was treated with 3 mL DMF, sealed under argon, and heated to 110° C. overnight. The reaction mixture was then poured onto water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification of the crude residue by column chromatography [0-50% (9:1 DCM/MeOH)/DCM] gave (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.079 g, 0.094 mmol, 25.46% yield).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:13][N:14]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH3:40])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)=[O:16])[C@H:9]([O:11][CH3:12])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>C(Cl)Cl>[NH2:7][C@@H:8]([C@H:9]([O:11][CH3:12])[CH3:10])[CH2:13][N:14]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][CH3:40])=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)=[O:16]
Reactant: CCCc1ccc(-c2ccc(N(C[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OC)C(=O)[C@@H]3C[C@H]3c3cnccn3)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1ccc(-c2ccc(N(C[C@@H](N)[C@@H](C)OC)C(=O)[C@@H]3C[C@H]3c3cnccn3)cc2)cc1

Procedure:
A solution of ((1R,2R)-2-methoxy-1-{[(4′-propyl-biphenyl-4-yl)-(trans-2-pyrazin-2-yl-cyclopropanecarbonyl)-amino]-methyl}-propyl)-carbamic acid tert butyl ester (55 mg) in DCM (1 mL) was treated with TFA/DCM (2/2 mL) for 1 h. The mixture was concentrated to give the titled compound as di-TFA salts (65.5 mg). 1H NMR (400 MHz, MeOD) δ ppm 8.5 (d, J=5.3 Hz, 1H), 8.1-8.2 (m, 2H), 7.5 (t, J=8.0 Hz, 2H), 7.4 (dd, J=8.3, 4.5 Hz, 2H), 7.3 (dd, J=8.2, 3.4 Hz, 2H), 7.2 (dd, J=8.1, 1.5 Hz, 2H), 4.2 (ddd, J=14.8, 8.5, 8.3 Hz, 1H), 3.8 (ddd, J=14.7, 7.9, 4.2 Hz, 1H), 3.4 (qd, J=6.1, 5.9 Hz, 1H), 3.2 (s, 3H), 3.2-3.2 (m, 1H), 2.6 (dddd, J=14.8, 6.1, 5.7, 4.2 Hz, 1H), 2.5 (t, J=7.6 Hz, 2H), 2.0 (q, J=8.3 Hz, 1H), 1.7 (dddd, J=8.9, 7.1, 5.6, 3.7 Hz, 1H), 1.6 (d, J=7.6 Hz, 2H), 1.3-1.4 (m, J=8.5, 5.8, 2.9, 2.9 Hz, 1H), 1.1 (dd, J=6.1, 3.0 Hz, 3H), 0.9 (t, J=7.3 Hz, 3H). LRMS (ESI)=459.3, [(M+H)+, Calcd for C28H35N4O2 459.6].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[C:21]([C:22]#[N:23])=[C:20](O)[CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][C:26](=[O:29])[CH:27]=[CH2:28]>CCO.CC1C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C:20]5[C:21]([C:22]#[N:23])([CH2:28][CH2:27][C:26](=[O:29])[CH:25]=5)[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C=CC(C)=O
Reactant: N#CC1=C(O)CCCc2cc3c(cnn3-c3ccc(F)cc3)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: N#CC12CCC(=O)C=C1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
A solution of 1-(4-fluorophenyl)-6-hydroxy-1,7,8,9-tetrahydrocyclohepta[f]indazole-5-carbonitrile (29, R1=4-Fluorophenyl) (30.0 g, 94 mmol) in EtOH (640 mL) was treated with TEA (3.93 mL, 28.2 mmol) and but-3-en-2-one (15.5 mL, 188 mmol) and the mixture was stirred mechanically at rt for about 18 h. The volume of the reaction was reduced to about 300 mL under reduced pressure and the intermediate was filtered off and washed with heptane (50 mL). The solid intermediate is taken up in toluene (1500 mL), treated with pTSA (0.894 g, 4.70 mmol) and heated at reflux with a Dean-Stark trap for about 5 h, then stirred at about 90° C. for about 16 h. The reaction was cooled to rt, washed with sat. aq. NaHCO3 (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield rac-9-(4-fluorophenyl)-3-oxo-1,2,3,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile (30, R1=4-Fluorophenyl) (28.0 g, 72%) as a tan foam. LC/MS, method 3, Rt=2.42 min, 1H NMR (400 MHz, DMSO) δ 8.45 (d, J=0.9 Hz, 1H), 8.20 (s, 1H), 7.84-7.78 (m, 2H), 7.69 (s, 1H), 7.48-7.39 (m, 2H), 6.18 (s, 1H), 3.01-2.59 (m, 6H), 2.46-2.37 (m, 1H), 2.24-2.12 (m, 1H), 2.02-1.87 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=[O:5])C>O1CCOCC1.Cl>[NH:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[NH:12][C@H:9]1[CH2:8][CH2:7][C@H:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1
Reactant: CCOC(=O)[C@H]1CC[C@H](Nc2nc3ccccc3[nH]2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CC[C@H](Nc2nc3ccccc3[nH]2)CC1

Procedure:
A solution of trans 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (K) (500 mg, 1.7 mmol) in dioxane (4 mL) and HCl (6 N, 8 mL) was heated to 60° C. for 16 h. After cooling, concentration of the reaction mixture gave trans 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid as a white solid (M) (420 mg): 1H NMR (300 MHz, CD3OD) δ7.39 (m, 2 H), 7.28 (m, 2 H), 3.57 (m, 1 H), 2.35 (m, 1 H), 2.18 (br t, 4 H), 1.65-1.40 (m, 4 H); mass spectrum m/z 260 [(M+H)+; calcd for C14H18N3O2: 260].