Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=3)[CH:23]=[CH:22]2)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]1([CH:39]([NH2:42])[CH2:40][CH3:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1([CH:39]([NH:42][C:30]([C:26]2[CH:27]=[C:28]3[C:29](=[CH:24][CH:25]=2)[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]4[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:19][CH:18]=2)[CH:22]=[CH:23]3)=[O:31])[CH2:40][CH3:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(Cn2ccc3cc(C(=O)O)ccc32)cc1
Reactant: CCC(N)c1ccccc1
Product: CCC(NC(=O)c1ccc2c(ccn2Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1)c1ccccc1

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and the 1-phenylpropan-1-amine instead of the (S)-1-(4-bromophenyl)ethanamine.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH2:21]O)=[CH:15][C:14]=1[Cl:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OCC)C.O>ClCCl>[CH2:5]([O:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH2:21][Cl:3])=[CH:15][C:14]=1[Cl:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)cc(Cl)c1OCc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: COc1cc(CCl)cc(Cl)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (2 mL) was added to solution of (4-benzyloxy-3-chloro-5-methoxy-phenyl)-methanol (CAB02170, 2.703 g, 9.7 mmol) in dichloromethane (10 mL). The solution was stirred for 1 h at room temperature, then diethyl ether (50 mL) and water (20 mL) were added. The organic layer was separated, washed with conc. sodium bicarbonate solution (10 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL) and precipitated by addition of hexane (ca. 50 mL). Yield: 2.730 g (95%) white powder. 1H-NMR (400 MHz, CDCl3) δ=3.89 (s, 3H, —OCH3), 4.52 (s, 2H), 5.07 (s, 2H), 6.87 (d, J=2.0 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 7.33-7.43 (m, 3H), 7.53-7.58 (m, 2H). LRMS (FAB+): 91.0 (100), 296.0 (17, [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[Cl:10][CH2:11][C:12](O)=[O:13]>C1COCC1>[Cl:10][CH2:11][C:12]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)=[O:13]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)CCl
Solvent: C1CCOC1
Product: O=C(CCl)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
3,4-Dichloroaniline (8.10 g, 50.0 mmol) was dissolved in THF (50 mL) To the solution was added anhydrous chloroacetic acid (9.40 g, 55.0 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and to the concentrate was added ethyl acetate, (100 mL). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 mL, 20 mL×2), saturated sodium chloride solution (20 mL), successively, dried over magnesium sulfate and concentrated under reduced pressure. To the concentrate was added diisopropyl ether (30 mL) and the resulting precipitates were collected by filtration. The precipitates were washed with diisopropyl ether (10 mL×3), and dried under reduced pressure to give the titled compound (8.08 g) as white crystals. The filtrate was concentrated under reduced pressure. To the concentrate was added diisopropyl ether/hexane (1/1) mixed solvent (30 mL), and the precipitates was collected by filtration. The precipitates were washed with diisopropyl ether/hexane (1/1) mixed solvent (10 mL×3), and dried under reduced pressure to give the titled compound (3.0 g) as white crystals. Yield (11.09 g, 93%, 46.5 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][N:3]=1.[F-].[K+].CC([N:18](C)C)=O>>[NH2:18][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([Cl:1])=[N:3][N:4]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: CC(=O)N(C)C
Agent: [F-]
Agent: [K+]
Product: Nc1nnc(Cl)c2ccccc12
Temperature: 100 °C

Procedure:
A mixture containing 4 mL of 0.5 M 1,4-dichlorophthalazine in DMA, 2 equivalents of amine and 500 mg of KF is heated in a sealed vial at 100° C. overnight. Purification on silica gel and evaporation provides the desired 1-amino-4-chloro-phthalazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].Cl[C:11]([F:16])([F:15])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.CC(OC)(C)C.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([O:9][CH:11]([F:16])[F:15])[CH:4]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1cc(Cl)ccc1Br
Temperature: 100 °C
Yield: 97.9 %

Procedure:
To a solution of 2-bromo-5-chlorophenol (1 g, 4.8 mmol) in DMF/water (45 mL/5 mL) was added sodium chlorodifluoroacetate (1.95 g, 12.0 mmol) and cesium carbonate (3.14 g, 9.64 mmol), and the reaction mixture was heated to 100° C. for 4 hours. The reaction mixture was cooled and diluted with TBME (20 mL) and water (20 mL). The organic layer was collected, washed with saturated aqueous NaHCO3 solution, brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound (1.21 g, 98%), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:10](OC(=O)C)(=[O:12])[CH3:11].N1C=CC=CC=1>Cl>[C:10]([O:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Cl)c(Cl)c1

Procedure:
A solution of 3,4-dichlorophenol (Alfa Aesar, Ward Hill, Mass.) is treated with acetic anhydride and an appropriate base such as pyridine. When the reaction is complete the reaction mixture is diluted with aqueous hydrochloric acid and extracted with an organic solvent. The organic solvent is washed with water, dried over magnesium sulfate, filtered and rotary evaporated to give crude 1-acetoxy-3,4-dichlorobenzene that may be used with or without further purification in the following reaction.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](I)[CH:8]=2)[N:3]=1.[B-](F)(F)(F)[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1P(C1CCCCC1)C1CCCCC1)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(I)ccc2n1
Reactant: CN1CCN(C[B-](F)(F)F)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(Cc2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)CC1

Procedure:
75 mg of (2-amino-6-iodoquinazolin-4-yl)isoindolin-2-ylmethanone are suspended in 2 ml of tetrahydrofuran and 7 μl of water together with 40 mg of potassium 1-methyl-4-trifluoroboratomethylpiperazine, 1 mg of palladium diacetate, 4 mg of ((2,4,6 triisopropyl)phenyl)dicyclohexylphosphine and 176 mg of caesium carbonate, and the mixture is stirred at 80° C. for 48 h. After cooling, the mixture is filtered through kieselguhr, rinsed three times with 5 ml of tetrahydrofuran each time, and the filtrate is evaporated to dry ness in vacuo. The residue is purified by means of preparative HPLC, and the title compound is isolated.
Reaction SMILES: II.[CH2:3]([N:10]1[C:14](=O)[C@H:13]([OH:16])[C@@H:12]([OH:17])[C:11]1=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.B.[Na].[OH-].[K+]>C1COCC1.CO>[CH2:3]([N:10]1[CH2:14][C@H:13]([OH:16])[C@@H:12]([OH:17])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1[C@H](O)[C@@H](O)C(=O)N1Cc1ccccc1
Agent: B
Agent: II
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
A solution of 50.7 g (0.2 mole) iodine in 200 ml THF was added dropwise to a suspension of 22.1 g (0.1 mole) (3R,4R)-1-benzyl-3,4-dihydroxy-2,5-pyrrolidinedione (IIb) and 15.2 g (0.4 mole) sodium boron hydride in 500 ml THF within 1 h at 12°-15° C. The mixture was then heated 2 d under argon on a reflux. After cooling off, 50 ml methanol were added and after the end of the development of gas the mixture was evaporated to dryness. The residue was taken up in 60 ml water and compounded with 15 ml conc. hydrochloric acid until an acidic reaction. After 30 min agitation, 150 ml 20% potash lye were added and [the mixture] extracted twice with 250 ml MTBE each time. After evaporation, 19.2 g colorless, crystalline residue remained. Recrystallization from 60 ml ethyl acetate yielded in 2 fractions 10.4 g (53.9%) (3S,4S)-1-benzyl-3,4-dihydroxypyrrolidine (IIIb).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]OS(C)(=O)=O)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O:20]1[C:24]2([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:23][NH:22][C:21]1=[O:30]>C(#N)C.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:22]2[CH2:23][C:24]3([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[O:20][C:21]2=[O:30])=[N:6][CH:7]=1
Reactant: O=C1NCC2(CCCCC2)O1
Reactant: CS(=O)(=O)OCc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: O=C1OC2(CCCCC2)CN1Cc1ccc(Br)cn1
Temperature: 70 °C
Yield: 57.8 %

Procedure:
Methanesulfonic acid 5-bromo-pyridin-2-ylmethyl ester (85 mg, 0.319 mmol), cesium carbonate (312 mg, 0.957 mmol) and 1-oxa-3-aza-spiro[4.5]decan-2-one (49.5 mg, 0.319 mmol) were mixed in acetonitrile (2 mL). The reaction mixture was heated at 70° C. for 5 hours and then diluted with dichloromethane (8 mL). The mixture was washed with water (3 mL) and brine (3 mL). The combined organic phase was dried over sodium sulfate and concentrated. The residue was purified on silica gel eluting with 10 to 20% ethyl acetate in hexanes to give the product as an off-white solid (60 mg, 58%). 1H NMR (300 MHz, CDCl3): δ 8.6 (d, 1H), 7.81 (dd, 1H), 7.23 (d, 1H), 4.49 (s, 2H), 3.27 (s, 2H), 1.79 (m, 4H), 1.47 (m, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([NH:20][C:21]([C:23]3([NH:29]C(=O)OC(C)(C)C)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])[C:18]#[N:19])=[CH:12][CH:11]=2)=[CH:6][C:5]=1[F:37])(=[O:3])[NH2:2].O>C(#N)C>[NH2:29][C:23]1([C:21]([NH:20][C@H:17]([C:18]#[N:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:1](=[O:3])[NH2:2])=[C:5]([F:37])[CH:6]=3)=[CH:15][CH:14]=2)=[O:22])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc(C(N)=O)c(F)c3)cc2)CCOCC1
Solvent: CC#N
Solvent: O
Product: N#C[C@H](Cc1ccc(-c2ccc(C(N)=O)c(F)c2)cc1)NC(=O)C1(N)CCOCC1
Yield: 120.3 %

Procedure:
(S)-4-Amino-N-(2-(4′-carbamoyl-3′-fluorobiphenyl-4-yl)-1-cyanoethyl)tetrahydro-2H-pyran-4-carboxamide (Example 25, 212 mg) was suspended in acetonitrile (353 μL) and water (6.7 mL) and stirred under nitrogen at room temperature for 17.5 h. The solid was collected by filtration and dried under vacuum to give the titled compound as a solid (205 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:12](=[O:14])[CH3:13])[S:8][C:4]=2[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2ccc(Br)cc2s1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.9 %

Procedure:
6-Bromobenzo[d]thiazol-2-amine (Aldrich, St. Louis, Mo.; 10.02 g, 43.7 mmol) was suspended in DCM (175 mL) to which DMAP (6.107 g, 50.0 mmol) was added. The flask was cooled in an ice water bath under argon, and acetic anhydride (4.60 mL, 48.8 mmol) was added, and the reaction was warmed to RT and stirred overnight. The reaction was washed with 10% HCl and water. The precipitate in the organic phase was filtered. The aqueous washings were extracted with DCM and 10:1 DCM/MeOH. These extracts were concentrated, combined with the filtrate from the above filtration, and concentrated again. The solid was collected (from the filtration as well as the aqueous workup), concentrated, and dried under vacuum to afford the desired N-(6-bromobenzo[d]thiazol-2-yl)acetamide (12.30 g, 45.39 mmol, 88% purity, 91% yield). MS (ESI pos. ion) m/z: 271 (MH+, 79Br), 273 (MH+, 81Br). Calculated exact mass for C9H7BrN2OS: 270 (79Br), 272 (81Br).
Reaction SMILES: [CH:1]([N:4]([CH:14]([CH3:16])[CH3:15])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1)([CH3:3])[CH3:2].[Li]CCCC.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][C:24]=1[O:31][CH3:32].[NH4+].[Cl-]>C1COCC1>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]([OH:28])[C:9]2[CH:10]=[CH:11][C:6]([C:5]([N:4]([CH:14]([CH3:16])[CH3:15])[CH:1]([CH3:3])[CH3:2])=[O:13])=[CH:7][CH:8]=2)=[CH:25][C:24]=1[O:31][CH3:32]
Reactant: COc1cc(C=O)ccc1F
Reactant: CC(C)N(C(=O)c1ccc(I)cc1)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccc(C(=O)N(C(C)C)C(C)C)cc2)ccc1F
Temperature: -78 °C
Yield: 60.3 %

Procedure:
N,N-Diisopropyl-4-iodobenzamide (6.0 g, 18 mmol) was dissolved in THF (200 mL) and cooled to −78° C. under nitrogen atmosphere. n-BuLi (14 mL, 1.3 M solution in hexane, 18 mmol) was added dropwise during 10 min at −65 to −78° C. 4-fluoro-3-methoxybenzaldehyde (2.8 g, 18 mmol) was added dropwise dissolved in THF (5 mL). NH4Cl (aq.) was added after 30 min. After concentration in vacuo, extraction with EtOAc/water, drying (MgSO4) and evaporation of the organic phase, the residue was purified by chromatography on silica (0-75% EtOAc/heptane) to yield the desired product (3.9 g, 60%). 1H NMR (CDCl3) δ 1.0-1.6 (m, 12H), 2.65 (d, J=4 Hz, 1H), 3.4-3.9 (m, 2H), 3.80 (s, 3H), 6.10 (d, J=4 Hz, 1H), 6.76 (m, 1H), 6.95 (m, 1H), 7.04 (m, 1H), 6.76 (m, 1H), 7.25, 7.40 (2d, J=7.5 Hz, 4H).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([C:35]2[CH2:36][CH2:37][O:38][CH2:39][CH:40]=2)([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([C:35]3[CH2:36][CH2:37][O:38][CH2:39][CH:40]=3)([CH3:34])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1NC(CC(C)(C)C2=CCOCC2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C1=CCOCC1
Yield: 99 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 129b (5.5 g, 9.29 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a dark solid (6 g, 99%).
Reaction SMILES: [C:1]1([C:7]2([CH2:16][CH2:17][N:18](C)[CH3:19])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O>[C:1]1([C:7]2([CH2:16][CH2:17][N:18]([C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])[CH3:19])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN(C)CCC1(c2ccccc2)COc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CN(CCC1(c2ccccc2)COc2ccccc21)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
A mixture of 6.0 g (22.5 mole) of 2-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N,N-dimethylethylamine, 3.72 ml (27 mmole) beta,beta,beta-trichloroethyl chloroformate, 12.4 g (90 mmole) anhydrous K2CO3, and 100 ml anhydrous CH2Cl2 was stirred at room temperature overnight. Water was then added to dissolve the inorganics and the layers were separated. The organics were washed with water and dried over MgSO4. Filtration and evaporation gave an oil, which was chromatographed with HPLC using 80% CH2Cl2 /hexane as an eluent to give 6.4 g (66%) of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[C:19]([N:27]3[CH2:32][C@H:31]([CH3:33])[C@@H:30]([OH:34])[C@H:29]([NH:35]C(=O)OC(C)(C)C)[CH2:28]3)=[C:20]3[CH2:26][CH2:25][CH2:24][C:21]3=[N:22][CH:23]=2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:43].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:35][C@H:29]1[C@H:30]([OH:34])[C@@H:31]([CH3:33])[CH2:32][N:27]([C:19]2[C:18]([NH:17][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:43])=[C:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[N:14]=3)=[O:16])=[CH:23][N:22]=[C:21]3[CH2:24][CH2:25][CH2:26][C:20]=23)[CH2:28]1
Reactant: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3)C[C@@H](N)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.5 %

Procedure:
A mixture of tert-butyl {(3R,4R,5S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate (6.0 mg, 0.010 mmol), DCM (0.09 mL) and TFA (0.085 mL, 1.1 mmol) was stirred at room temperature for 20 min. After concentration, the residue was diluted with MeOH, filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the title compound as a white powder (4.6 mg, 92%). LCMS calc. for C26H27F3N5O2 (M+H)+: m/z=498.2. Found: 498.3.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:21]1([C:27]2[S:28][CH:29]=[C:30]([CH:32]=O)[N:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:32][C:30]2[N:31]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:28][CH:29]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1csc(-c2ccccc2)n1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1csc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 2-phenylthiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.93 min.; [M+H]+: 423.12 g/mol.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH2:9][CH2:10][C:5]2=[N:4][N:3]=1
Reactant: Fc1ccc(-c2ccc3nnc(Cl)n3n2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: Fc1ccc(C2=Nn3c(Cl)nnc3CC2)cc1
Reaction time: 1 h
Yield: 87 %

Procedure:
790 mg of zinc powder are added to a mixture of 300 mg of 3-chloro-6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazine in 10 cm3 of glacial acetic acid at 20° C. After stirring for 1 h, the suspension is filtered and the filtrate is concentrated to dryness under vacuum. The oily residue is purified by dry deposit on Biotage Quad 12M (KP-SIL, 60 Å; 32-63 μm), elution being carried out with a 95:5 mixture of dichloromethane/methanol. 263 mg of 3-chloro-6-(4-fluorophenyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine are thus obtained in the form of a yellowy-brown powder, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[H-].[Na+].CS([C:18]1[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=1)(=O)=O>CN(C)C=O>[CH3:27][O:26][C:20]1[CH:21]=[C:22]([O:24][CH3:25])[N:23]=[C:18]([N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[N:4]=[C:3]2[S:2][CH3:1])[N:19]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CSc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(-n2c(SC)nc3ccccc32)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
2-Methylthiobenzimidazole (0.50 g) was dissolved in dimethylformamide (10 ml), and sodium hydride (60% purity, oily) (0.13 g) was added thereto at room temperature. After stirring for 1 hour, 2-methylsulfonyl-4,6-dimethoxypyrimidine (0.67 g) was added at room temperature, followed by stirring for 8 hours. Ice water was added, followed by extraction with ethyl acetate, washing with a saturated sodium chloride aqueous solution and drying over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 0.80 g of the desired product as a white powder (m.p. 135-137° C.).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].I[CH2:13][C:14]([NH2:16])=[O:15]>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:13][C:14]([NH2:16])=[O:15]
Reactant: Cc1cccc(O)c1C
Reactant: NC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCC(N)=O)c1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83 %

Procedure:
2.1 19.95 g of 2,3-dimethylphenol 6 are dissolved in 250 ml of DMF, 6.4 g of NaH (60% suspension in paraffin oil) are carefully added with cooling, and the mixture is stirred at RT for 45 min. 31.4 g of 2-iodoacetamide 2 are then added, and the reaction mixture is stirred overnight. The mixture is subsequently subjected to conventional work-up, giving 23.8 g (83%) of 2-(2,3-dimethylphenoxy)acetamide 7; MS-EI (M+)=179.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]([CH2:20][CH3:21])[C:11](=[O:19])[C:12]([CH3:18])([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:8]=2[CH:7]=1.[I-:24].[Na+].CC(C)=O>O>[CH2:20]([N:10]1[C:11](=[O:19])[C:12]([CH3:18])([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:8]2[CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][I:24])[CH:23]=[CH:22][C:9]1=2)[CH3:21]
Reactant: [I-]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCCl)ccc21
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Temperature: 25 °C
Yield: 99.7 %

Procedure:
7-(3-Chloropropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (2.18 g) and sodium iodide (4.8 g) were added to acetone (50 ml), and heated under reflux for 8.5 hours. The reaction mixture was cooled to room temperature, water was added, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated under reduced pressure to give the title compound(2.76 g) as a colorless oil.