Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:8]([N:14]([CH3:24])[CH2:15][CH:16]2[CH2:23][CH2:22][C:19]3([CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:9][C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3].[C-]#N.[K+].C1N2CC[N:30](CC2)[CH2:29]1.O>CS(C)=O>[CH2:1]([O:4][C:5]([C:7]1[C:8]([N:14]([CH3:24])[CH2:15][CH:16]2[CH2:23][CH2:22][C:19]3([CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:9][C:10]([C:29]#[N:30])=[N:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cnc(Cl)nc1N(C)CC1CCC2(CC1)CC2
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCOC(=O)c1cnc(C#N)nc1N(C)CC1CCC2(CC1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the 2-chloro-4-(methylspiro[2.5]oct-6-ylmethylamino)pyrimidine-5-carboxylic acid allyl ester (1.1 mmol) in DMSO (2.0 mL) are added KCN (1.6 mmol), DABCO (0.3 mmol), and H2O (0.2 mL) at room temperature. The reaction mixture is stirred at room temperature for 3 h and the reaction is quenched by the addition of water. The mixture is extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].C[Si](C)(C)[C:23]([F:26])([F:25])[F:24].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH:18]([OH:19])[C:23]([F:26])([F:25])[F:24])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCCN(C)C(=O)c1cc(C=O)cc(C(=O)OCC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Treat a solution of 5-formyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (500 mg, 1.8 mmol) in THF (10 mL) at 0° C. with trimethyl(trifluoromethyl)silane (0.5 M in THF, 5.4 mL, 2.70 mmol) and tetrabutylammonium fluoride (1.0 M in THF, 2.7 mL, 2.70 mmol). Stir at 0° C. for 2 h and quench with saturated aqueous NaHCO3. Extract with ethyl acetate (100 mL), dry (magnesium sulfate) and concentrate to give the crude title product which is used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:11][C:12]2[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])[C@@H:20]([CH3:22])[NH2:21])=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:22][C@H:20]1[NH:21][C:32](=[O:34])[N:18]([C:15]2[CH:16]=[N:17][C:12]([O:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH:2]([CH3:1])[CH3:3])[CH:6]=3)=[CH:13][CH:14]=2)[C:19]1=[O:23]
Reactant: CC(C)Oc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1cccc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a solution of N1-[6-({3-[(1-methylethyl)oxy]phenyl}oxy)-3-pyridinyl]-D-alaninamide (Intermediate 32, 229 mg) and triethylamine (442 mg, 4.38 mmol) in dichloromethane (20 mL) was added a solution of triphosgene (216 mg, 0.73 mmol) in dichloromethane (10 mL) dropwise at 0° C. during 5 minutes. The resulting mixture was stirred at room temperature for 2 hours. The solvent was distilled off and the residue was partitioned between dichloromethane (3 times 50 mL) and water (50 mL). The combined organic layers were washed with brine (3 times 10 mL), dried over sodium sulphate, filtered and concentrated to afford a grey solid, which was purified by silica gel chromatography (PE:EtOAc=2:1) to afford the title compound as a white solid (120 mg).
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.[CH2:43]([S:45]([C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1)(=[O:47])=[O:46])[CH3:44].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:35]2[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=2)=[CH:7][CH:6]=1.[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:51]2[CH:50]=[CH:49][C:48]([S:45]([CH2:43][CH3:44])(=[O:47])=[O:46])=[CH:53][CH:52]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(N)=O)CCOCC1
Product: CCS(=O)(=O)c1ccc(-c2ccc(C[C@H](NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)C(N)=O)cc2)cc1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 2.0 g) in acetonitrile (5 mL) under nitrogen was treated with 4-(trifluoromethyl)phenylboronic acid (0.367 g) and 4-(ethylsulfonyl)phenylboronic acid (0.414 g) followed by aqueous potassium carbonate (3.87 mL) and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (25 mg). The mixture was stirred at 75° C. for 18 h. The reaction mixture was evaporated, dissolved in dichloromethane, evaporated onto silica and purified on a silica column eluting with 50% ethyl acetate in isohexane and then 100% ethyl acetate to afford (S)-tert-butyl 4-(1-amino-1-oxo-3-(4′-(trifluoromethyl)biphenyl-4-yl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate and (S)-tert-butyl 4-(1-amino-3-(4′-(ethylsulfonyl)biphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate as a mixture (1.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3C(=CC(Br)=[CH:9][CH:10]=3)[C:5]([CH2:31][CH2:32][CH:33]([CH3:45])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])([CH2:16][CH2:17][CH:18]([CH3:30])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:4]=2[CH:3]=1.C([Li])CCC.C(N1CCCCC1)=O.[CH2:59]1[CH2:63][O:62][CH2:61][CH2:60]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:59]([CH:63]=[O:62])=[CH:60][C:61]=3[C:5]2([CH2:31][CH2:32][CH:33]([CH3:45])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[CH2:16][CH2:17][CH:18]([CH3:30])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:13][CH:14]=1
Reactant: CC(C)CCCC(C)CCCC(C)CCC1(CCC(C)CCCC(C)CCCC(C)C)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: C1CCOC1
Agent: O=CN1CCCCC1
Agent: [Li]CCCC
Product: CC(C)CCCC(C)CCCC(C)CCC1(CCC(C)CCCC(C)CCCC(C)C)c2cc(Br)ccc2-c2ccc(C=O)cc21
Yield: 72 %

Procedure:
2,7-Dibromo-9,9-bis(3,7,11-trimethyldodecyl)fluorene (Example 7; 21.02 g, 28.25 mmol) was reacted with n-butyllithium (1.6 M, 16.5 mL, 26.4 mmol) in THF at −78° C., and quenched with N-formyl piperidine (4.7 mL, 42.3 mmol). The crude product was chromatographed over silica gel eluting with 15 and 25% toluene-heptane to get the aldehyde product as a liquid, 13.11 g (72% Yield). Mass spec: m/z 692, 694 (M+). Anal Calcd for C44H69BrO: C, 76.16%; H, 10.02%; Br 11.51%. Found: C, 76.39%; H, 9.85%; Br, 11.49%. 1H NMR (CDCl3), δ ppm: 0.51-0.54 (m 4H), 0.67 (tt, 6H), 0.77 (tt, 6H), 0.85 (d, 12H), 0.92-1.26 (m, 30H), 1.47-1.53 (m, 2H), 1.98-2.02 (m 4H), 7.50-7.65 (m, 3H), 7.79-7.87 (m, 3H), 10.05 (s, 1H).
Reaction SMILES: [CH2:1]([C:17]1([CH3:34])[CH2:26][CH2:25][C:24]2[C:19](=[C:20]([CH3:33])[C:21]([CH3:32])=[C:22]([O:28][CH2:29][CH2:30][OH:31])[C:23]=2[CH3:27])[O:18]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][CH2:14][CH2:15][CH3:16].[C:35](=O)([O:44]N1C(=O)CCC1=O)[O:36][N:37]1[C:41](=[O:42])[CH2:40][CH2:39][C:38]1=[O:43].C(N(CC)CC)C.C(#N)C>ClCCl>[CH2:1]([C:17]1([CH3:34])[CH2:26][CH2:25][C:24]2[C:19](=[C:20]([CH3:33])[C:21]([CH3:32])=[C:22]([O:28][CH2:29][CH2:30][O:31][C:35](=[O:44])[O:36][N:37]3[C:41](=[O:42])[CH2:40][CH2:39][C:38]3=[O:43])[C:23]=2[CH3:27])[O:18]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][CH2:14][CH2:15][CH3:16]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CCCCCCCCCCCCCCCCC1(C)CCc2c(C)c(OCCO)c(C)c(C)c2O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCC1(C)CCc2c(C)c(OCCOC(=O)ON3C(=O)CCC3=O)c(C)c(C)c2O1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
Compound 17 (10.5 g, 22 mmol) was dissolved in anhydrous dichloromethane (150 mL). To the solution were added disuccinimidyl carbonate (8.45 g, 33 mmol), triethylamine (20 mL) and acetonitrile (50 mL). The reaction mixture was stirred at room temperature under argon for over night and then evaporated dryness. The residue was dissolved in dichloromethane (300 mL). It was washed with saturated NaHCO3 aqueous solution (3×100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Compound 18 (10.4 g, 77%) was obtained as colorless powder after drying in high vacuum, which was directly used for the next step without further purification.
Reaction SMILES: O(C1C=CC(CCCCN)=CC=1)CCOCCOC.[O:20]([C:34]1[CH:39]=[CH:38][C:37]([CH:40](C(OCC2C=CC=CC=2)=O)[CH2:41][CH2:42][CH2:43][NH2:44])=[CH:36][CH:35]=1)[CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]>>[O:20]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][CH2:43][NH2:44])=[CH:36][CH:35]=1)[CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]
Reactant: COCCOCCOCCOCCOc1ccc(C(CCCN)C(=O)OCc2ccccc2)cc1
Agent: COCCOCCOc1ccc(CCCCN)cc1
Product: COCCOCCOCCOCCOc1ccc(CCCCN)cc1
Yield: 95.9 %

Procedure:
This compound was prepared in a similar fashion to the synthesis of amine 107 from compound 110 (385 mg, 0.78 mmol) to give 266 mg (95%) of compound 111. 1H NMR (300 MHz, CDCl3) δ 1.41-1.54 (m, 2H), 1.60 (br. s, 2H), 2.56 (t, J=7.5 Hz, 2H), 2.70 (t, J=7.0 Hz, 2H), 3.37 (s, 3H), 3.51-3.58 (m, 2H), 3.60-3.77 (m, 10H), 3.84 (m, 2H), 4.10 (t, 5.5 Hz, 2H), 6.83 (d, J=8.3 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]=[C:9]([O:12][CH3:13])[N:8]=[N:7][C:6]=2[N:5]([CH3:14])[C:4](=[O:15])[C:3]=1[C:16]([O:18]C)=O.ClC1N=NC2N(C)C(=O)[C:29]([C:32]([O:34]C)=[O:33])=C(O)C=2C=1.C[O-].[Na+].[NH3:41]>CO>[OH:1][C:2]1[C:11]2[CH:10]=[C:9]([O:12][CH3:13])[N:8]=[N:7][C:6]=2[N:5]([CH3:14])[C:4](=[O:15])[C:3]=1[C:16]([NH:41][CH2:29][C:32]([OH:34])=[O:33])=[O:18]
Reactant: COC(=O)c1c(O)c2cc(OC)nnc2n(C)c1=O
Reactant: N
Reactant: COC(=O)c1c(O)c2cc(Cl)nnc2n(C)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(O)c(C(=O)NCC(=O)O)c(=O)n(C)c2nn1

Procedure:
Methyl 5-hydroxy-3-methoxy-8-methyl-7-oxo-7,8-dihydropyrido[2,3-c]pyridazine-6-carboxylate. The title compound is prepared by reaction of methyl 3-chloro-5-hydroxy-8-methyl-7-oxo-7,8-dihydropyrido[2,3-c]pyridazine-6-carboxylate with sodium methoxide according the procedure described in Bioorg. Med. Chem. Lett., 17, 6206 (2007). Alternatively, the title compound is prepared by reaction of methyl 3-chloro-5-hydroxy-8-methyl-7-oxo-7,8-dihydropyrido[2,3-c]pyridazine-6-carboxylate with ammonia in MeOH solution according to Method 8(a).
Reaction SMILES: C([O:3][C:4](=[O:35])[C@H:5]([OH:34])[CH2:6][C@H:7]([NH:23][C:24]([C:26]1[CH:30]=[C:29]([C:31](=[O:33])[CH3:32])[NH:28][N:27]=1)=[O:25])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)C.[Li+].[OH-].O.CCO>>[C:31]([C:29]1[NH:28][N:27]=[C:26]([C:24]([NH:23][C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[F:22])=[CH:11][CH:10]=2)[CH2:6][C@@H:5]([OH:34])[C:4]([OH:35])=[O:3])=[O:25])[CH:30]=1)(=[O:33])[CH3:32]
Reactant: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(C(C)=O)[nH]n1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)c1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)n[nH]1
Yield: 16.3 %

Procedure:
(2R,4R)-4-[(5-Acetyl-1H-pyrazole-3-carbonyl)amino]-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (75 mg, 150 μmol) was stirred at room temperature with LiOH (10.8 mg, 450 μmol) in water (450 μL, 25 mmol) and EtOH (450 μL, 7.7 mmol), overnight. The solvent was removed and the remaining material was purified by preparative HPLC to yield the title compound (11.6 mg) as a TFA salt.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([C:34](Cl)=[O:35])=[CH:33][C:28]=2[O:27][CH2:26]1>C(OCC)C.CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:34]([C:32]4[CH:31]=[CH:30][C:29]5[O:25][CH2:26][O:27][C:28]=5[CH:33]=4)=[O:35])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc3c(c1)OCO3)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 67 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 1,3-benzodioxol-5-carbonyl chloride, the title compound was synthesized according to Example 1b. Yield: 67%. Melting point: 165-167° C. (Ethyl ether-hexane)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:18])=O)=[N:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[CH3:18])=[N:9][N:8]=2)[CH:7]=1
Reactant: C[C@H]1CCCCN1C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H]1CCCCN1c1nnc2ccc(F)cn12
Temperature: 60 °C
Yield: 82.8 %

Procedure:
To a stirred solution of Intermediate 2c (14.70 g, 58.27 mmol), Ph3P (30.56 g, 116.51 mmol) and Et3N (33 mL, 236.76 mmol) in THF (300 mL) at RT was added hexachloroethane (27.60 g, 116.58 mmol) during 10 min before then heating at 60° C. overnight. The cooled mixture was filtered and concentrated in vacuo to give a residual oil which was dissolved in DCM (200 mL) and extracted into dilute HCl (2M) until most product had been removed from the DCM phase by LCMS. These aqueous extracts were treated with solid NaOH (with cooling) to achieve ˜pH9 and extracted into DCM. Combined DCM extracts were washed with brine, dried (MgSO4), passed through a phase separation cartridge and concentrated in vacuo to give Intermediate 2d (11.30 g, 82%). LCMS (Method 3) Rt 2.99 min, m/z 235 [MH+]. 1H NMR (300 MHz, d6-d6-DMSO): 0.89 (3H, d, J 6.3), 1.40-1.88 (6H, m), 2.85-2.96 (1H, m), 3.18 (1H, dt, J 12.0, 4.5), 3.28-3.35 (1H, m), 7.42 (1H, ddd, J 10.0, 8.0, 2.3), 7.76 (1H, ddd, J 10.0, 4.9, 0.9), 8.31-8.35 (1H, m).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:7][CH:8]=1.[CH:13]1([C:16](=[O:25])[CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1.[Cl-:26].[NH4+]>CCOCC>[ClH:26].[CH:13]1([C:16]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=2)([OH:25])[CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1
Reactant: O=C(CCN1CCCCC1)C1CC1
Reactant: [Cl-]
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: Cl
Product: OC(CCN1CCCCC1)(c1cccc(C(F)(F)F)c1)C1CC1
Temperature: 25 °C

Procedure:
A stirred ether solution of a Grignard reagent prepared from 14.5 g. (0.6 mole) of magnesium, 136 g. (0.6 mole) of 3-bromobenzotrifluoride and 800 ml. of dry ether treated at -20° C. to -30° C. with 53.5 g. (0.296 mole) of crude 1-cyclopropyl-3-piperidino-1-propanone in 200 ml. of ether. After addition the reaction mixture was stirred and allowed to warm to room temperature over one hour. The reaction mixture was treated with 32 g. of ammonium chloride in 170 ml. of water and the ether layer separated. The aqueous fraction was filtered and the solid precipitate was extracted with five 200 ml. portions of ether. The combined ether extracts were dried over magnesium sulfate and concentrated to an oil. Distillation under reduced pressure gave an oil which was converted to the hydrochloride salt. Recrystallization from acetone-ethanol mixture gave 3.6 g. (17%) of pure product which melted at 193°-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[S:26]1[C:34]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]=2[CH:28]=[CH:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:31]1[CH2:32][CH2:33][C:34]2[S:26][CH:27]=[CH:28][C:29]=2[CH2:30]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: c1cc2c(s1)CCNC2
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCc3sccc3C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.81 minutes; C24H20Cl2N4O2S (499.42); mass spectrum: (M−H)−=498/500/502 (chlorine isotope).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1.[Si:14]([O:21][C@H:22]([CH2:27][O:28][CH3:29])[C:23](OC)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1COCC1.CCOC(C)=O>[Si:14]([O:21][C@H:22]([CH2:27][O:28][CH3:29])[C:23]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][N:11]=1)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16]
Reactant: COC[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)OC
Reactant: Cc1ccc(N)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1ccc(C)cn1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyllithium (2.5M in hexanes) (2.04 mL, 3.26 mmol) was added dropwise to a stirred solution of 5-methylpyridin-2-amine (CAS 1603-41-4) (353 mg, 3.26 mmol) in THF (10 mL) cooled to 10° C. under nitrogen. The resulting solution was stirred at ambient temperature for 10 minutes and then added to a solution of (R)-methyl 2-(tert-butyldimethylsilyloxy)-3-methoxypropanoate C5b (810 mg, 3.26 mmol) in THF (10 mL) at 10° C. The resulting solution was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with EtOAc (75 mL) and washed sequentially with saturated ammonium chloride (50 mL), water (25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. Purification by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane provided (R)-2-(tert-butyldimethylsilyloxy)-3-methoxy-N-(5-methylpyridin-2-yl)propanamide (300 mg). 1H NMR (400 MHz, CDCl3) δ 0.15 (3H, s), 0.16 (3H, s), 0.88 (9H, s), 2.12 (3H, s), 3.46 (3H, s), 3.61-3.65 (2H, m), 4.35-4.42 (1H, m), 7.47 (1H, d), 8.19 (1H, d), 8.20 (1H, s), 8.97 (1H, s), m/z (ESI+) (M+H)+=325; HPLC tR=3.08 min.
Reaction SMILES: Cl[C:2](Cl)([CH3:6])[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:15]([NH:23][NH2:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>O.CCOCC>[CH2:15]([NH:23][N:24]=[C:2]([CH3:6])[C:3]([OH:5])=[O:4])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NNCCc1ccccc1
Reactant: CC(Cl)(Cl)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CC(=NNCCc1ccccc1)C(=O)O
Temperature: 90 °C

Procedure:
To a solution of 5.7 g. 2,2-dichloropropionic acid and 2.8 g. potassium carbonate in 40 ml water is added a solution of 6.9 g. phenethylhydrazine hydrochloride and 5.6 g. potassium carbonate in 20 ml water. The mixture is heated with stirring to 90° C., a further solution of 5.6 g. potassium carbonate in 20 ml water is dropped in over 30 minutes and further stirred for 60 minutes at 90° C. Afterwards the still alkaline solution is cooled to ambient temperature, shaken out with ether and acidified with concentrated hydrochloric acid. 2-(phenethylhydrazono)-propionic acid crystallizes out and is recrystallized from toluene. The yield is 3.3 g. (40% of theory); m.p. 74°-76° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH3:7].[CH3:8][CH2:9][CH2:10][CH2:11][Cl:12]>>[Cl-:12].[CH2:11]([N+:4]1[CH:5]=[CH:6][N:2]([CH3:1])[C:3]=1[CH3:7])[CH2:10][CH2:9][CH3:8]
Reactant: CCCCCl
Reactant: Cc1nccn1C
Product: CCCC[n+]1ccn(C)c1C
Product: [Cl-]
Temperature: 70 °C
Yield: 85 %

Procedure:
n-Chlorobutane (55 g) was added slowly to 1,2-dimethylimidazole (50 g) in a 200-milliliter, two-necked round bottom flask fitted with a reflux condenser. This mixture was then stirred with a magnetic stirrer at 70° C. for 1 week. During the week a white solid formed, which slowly turned yellow. The solution was allowed to cool to room temperature. The liquid was decanted away from the yellow solid that remained. The yellow solid washed with diethylether (3×200 mL) and dried under vacuum for 24 hours. The dry yellow solid was dissolved in water (1.5 liters) and decolorizing charcoal (6 g) was added. This mixture was heated to 70° C. for 24 hours, cooled and filtered. The filtrate was pale yellow. The pale yellow filtrate was then treated with decolorizing charcoal (6 g). The mixture was heated for a further 24 hours at 65° C. The solution was cooled to room temperature and filtered. The filtrate was colorless. The water was removed from the colorless filtrate using a lyophilizer. The resulting solid was then heated under a vacuum for 48 hours at 65° C. 1-Butyl-2,3-dimethylimidazolium chloride was obtained as a white solid in a yield of 85%.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:20][CH2:19][CH2:18][C@@H:17]4[C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([O:28][CH2:29][CH:30]5[CH2:34][O:33]C(C)(C)[O:31]5)[CH:22]=4)=[N:12][C:11]=23)=[O:6])[CH2:3][CH2:2]1>O1CCOCC1.Cl.CCN(C(C)C)C(C)C>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:20][CH2:19][CH2:18][C@@H:17]4[C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([O:28][CH2:29][CH:30]([OH:31])[CH2:34][OH:33])[CH:22]=4)=[N:12][C:11]=23)=[O:6])[CH2:3][CH2:2]1
Reactant: CC1(C)OCC(COc2cc(F)cc([C@H]3CCCN3c3ccn4ncc(C(=O)NC5CC5)c4n3)c2)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(NC1CC1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cc(OCC(O)CO)c3)nc12
Reaction time: 0.03 h
Yield: 82.8 %

Procedure:
A solution of N-cyclopropyl-5-((2R)-2-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Example 206, 30 mg, 0.061 mmol) in dioxane (0.5 mL) was charged with two drops of 6N HCl and shaken for two minutes. DIEA (5 drops) was added and the mixture directly purified by reverse phase column chromatography (0-50% acetonitrile/water) to afford N-cyclopropyl-5-((2R)-2-(3-(2,3-dihydroxypropoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (23 mg, 83% yield) as a clear film. MS (apci) m/z=456.1 (M+H).