Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][CH2:29][N:30]([CH3:43])[S:31]([C:34]1[S:35][C:36]([Cl:42])=[C:37]([N+:39]([O-])=O)[CH:38]=1)(=[O:33])=[O:32]>>[Cl:42][C:36]1[S:35][C:34]([S:31](=[O:33])(=[O:32])[N:30]([CH2:29][CH2:28][OH:27])[CH3:43])=[CH:38][C:37]=1[NH:39][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:13]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(CCO)S(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: CN(CCO)S(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-ethyl)-methyl-amide (example B.21) according to general procedure II.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.Cl[C:18]1[CH:27]=[CH:26][N:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([CH2:28][CH3:29])=[N:23]2>>[CH2:28]([C:22]1[N:23]=[C:24]2[C:19]([C:18]([NH:1][C:2]3[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=3[S:9][C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:27][CH:26]=[N:25]2)=[CH:20][CH:21]=1)[CH3:29]
Reactant: CCc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: CCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 4c (131 mg, 0.530 mmol) was reacted with the product from Example 3f (97 mg, 0.503 mmol) for 21 h following the procedure from Example 1g giving the title compound as a hydrochloride salt which was triturated with 5:1 ether/THF giving (210 mg, 98%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.37 (t, J=7.35 Hz, 3H) 2.33 (s, 3H) 3.05 (q, J=7.35 Hz, 2H) 6.29 (d, J=6.99 Hz, 1H) 6.74 (d, J=8.46 Hz, 2H) 7.00 (m, 1H) 7.17-7.29 (m, 4H) 7.84 (d, J=8.83 Hz, 1H) 8.43 (d, J=6.98 Hz, 1H) 9.09 (d, J=8.83 Hz, 1H) 9.90 (s, 1H) 11.12 (br s, 1H) 14.38 (br s, 1H); MS (ESI+) m/z 388 (M−Cl)+; (ESI−) m/z 386 (M−HCl)−.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([CH2:16][NH2:17])[CH2:10][CH2:9][N:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:27][C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C(Cl)Cl>[Cl:27][C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30]([NH:17][CH2:16][C:5]1([CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH2:6][CH2:7][N:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH2:9][CH2:10]1)=[O:31]
Reactant: CCS(=O)(=O)N1CCC(CN)(CC2CC2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1-[4-(cyclopropylmethyl)-1-(ethylsulfonyl)piperidin-4-yl]methanamine (I-5, 250 mg, 1.0 mmol) in CH2Cl2 (10 mL) at 0° C. was treated with i-Pr2NEt (1 mL, 5.7 mmol), 2,4-dichlorobenzoyl chloride (200 μL, 1.43 mmol), and stirred for 15 min before being warmed to room temperature. After 1 h, the reaction was quenched with the addition of 1 M aqueous NaOH (10 mL) and stirred 1 h before being extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried (Na2SO4), concentrated under reduced pressure, and purified by reverse phase HPLC to afford 2,4-dichloro-N-{[4-(cyclopropylmethyl)-1-(ethylsulfonyl)piperidin-4-yl]methyl}benzamide (I-6) as an off-white amorphous solid. Analytical LCMS: single peak (214 nm), 3.328 min. 1H NMR (CDCl3, 300 MHz) δ 7.64 (d, J=8.4 Hz, 1 H), 7.46 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 6.39 (t, J=8 Hz, 1H), 3.63 (d, J=6.3 Hz, 2H), 3.41 (m, 2H), 3.35 (m, 2H), 2.98 (q, J=7.2 Hz, 1H), 1.68 (m, 5H), 1.39 (m, 5H), 0.68 (m, 1H), 0.56 (d, J=8 Hz, 1H). HRMS m/z 433.1091 (C19H26Cl2N2O3S+H+ requires 433.1091).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:38])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[C:30]([CH:35]3[CH2:37][CH2:36]3)=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:35]1([C:30]2[C:29]([C:25]3[CH:24]=[C:23]([C:21]4[CH2:20][C:19](=[O:38])[NH:18][C:9]5[CH:10]=[C:11]([C:14]([F:16])([F:17])[F:15])[CH:12]=[CH:13][C:8]=5[N:7]=4)[CH:28]=[CH:27][CH:26]=3)=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2C2CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cccnc3C3CC3)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M200) (223 mg, 0.413 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (107 mg, 61%).
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35].C([O-])(O)=O.[Na+]>ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]2[NH:16]1
Reactant: CCOC(=O)Cl
Reactant: CC1(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
A solution of (3aR,7aR)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (HCl salt, 99 mg, 0.25 mmol) and diisopropylethylamine (129.3 mg, 1.0 mmol) in dry dichloromethane (5 mL) at 0° C. was added with a solution of 1.0 N ethyl chloroformate in dichloromethane (0.3 mL, 0.3 mmol) dropwise and was stirred at room temperature for 3 h. Saturated NaHCO3 (5 mL) was added followed by dichloromethane (20 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×10 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified with preparative LC/MS (high pH) to give the title compound (48 mg, 49%). 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.99 (s, 3H), 1.21 (t, J=7.03 Hz, 3H), 1.31-1.54 (m, 6H), 1.58-2.00 (m, 9H), 2.06-2.35 (m, 3H), 2.88-3.04 (m, 2H), 3.04-3.18 (m, 2H), 3.29-3.44 (m, 2H), 3.48-3.69 (m, 3H), 4.08 (q, J=7.03 Hz, 2H). MS (M+1): 393.2.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[P:12]([O-:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[OH:9])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOP([O-])OCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 78.3 %

Procedure:
A mixture of p-nitrobenzaldehyde (3.022 g, 20 mmol), diethyl phosphite (2.762 g, 20 mmol), and MgO (2.0 g, 49.6 mmol) in THF (30 mL) was stirred at room temperature for 5 days. The reaction mixture was filtered, the filtrate was concentrated, and residue was purified by silica gel chromatography (EtOAc/hexanes: 1:4) to give 4.53 g of diethyl [(4-nitrophenyl)(hydroxy)methyl]phosphonate (yield: 78%). 1H NMR (CDCl3, 400 MHz): δ=1.27 (m, 6 H), 4.08-4.18 (m, 4 H), 5.18 (d, J=12.0 Hz, 1 H), 7.67-7.70 (m, 2 H), 8.24 (dd, J=0.8, 8.8 Hz, 2 H). MS (ES+): m/z 290.07 [MH+]. HPLC: tR=1.15 min (UPLC TOF, polar—3 min). This material (4.53 g) was hydrogenated in the presence of 10% Pd/C (200 mg) in MeOH (20 mL) under 1 atmosphere for 4 h. The catalyst was filtered off, filtrate was concentrated, and the residue was purified by silica gel chromatography (2% MeOH in DCM) to afford 3.93 g of the title compound (yield: 72%). MS (ES+): m/z 242.08 [MH+—H2O]. HPLC: tR=0.8 min (UPLC TOF, polar—3 min).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=O)[CH3:6])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[S:29])[CH3:6])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)[C@@H](C)N1C(=O)COc2ccc(Br)cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](C)N1C(=S)COc2ccc(Br)cc21
Temperature: 25 °C
Yield: 144.7 %

Procedure:
A solution of (R)-2-(6-bromo-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (82.4 g, 252 mmol) and Lawesson's reagent (61.1 g, 151 mmol) in toluene (900 mL) was heated at reflux for 3 h and then cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give (R)-2-(6-bromo-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (75.2 g, 87%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.19 (d, J=8.8 Hz, 1H), 7.04 (s, 1H), 6.93 (d, J=8.8 Hz, 1H), 6.57 (m, 2H), 4.96-4.87 (m, 2H), 4.29-4.16 (m, 2H), 1.71 (d, J=6.8 Hz, 3H), 1.18 (t, J=6.8 Hz, 3H). SFC (Table 1, Method 29) Rt=3.529 min.; [α]D20=19.25 (C=0.002 g/mL in methanol).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11])[CH3:2].[CH2:12](N)[CH2:13][NH2:14]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[NH:11][CH2:12][CH2:13][N:14]=1)[CH3:2]
Reactant: NCCN
Reactant: CCc1ccccc1CC#N
Product: CCc1ccccc1CC1=NCCN1

Procedure:
2-(2-Ethyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2-ethylphenyl)-acetonitrile and ethylene diamine in analogy to Example 19 b): light yellow powder; MS (ISP): 189.4 ((M+H)+.).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][NH2:11].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:11][CH3:10])=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=Cc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccc(F)cc1
Reaction time: 1 h

Procedure:
To 4-fluorobenzaldehyde (2.48 g) in MeOH was added methylamine (40% aqueous solution, 2.0 mL). The reaction mixture was stirred at RT for 12 h at which time NaBH4 (0.38 g) was added. After stirring for 1 h the reaction was quenched with H2O and extracted with ethyl acetate. The combined extracts were dried, filtered, and concentrated to yield (4-fluorobenzyl)-methylamine (2.30 g) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.[CH2:16]([N:23]=[C:24]=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:24](=[O:25])[NH:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CO
Reactant: O=C=NCc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1COC(=O)NCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 19, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and benzyl isocyanate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[Br:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=1)[C:28](O)=[O:29]>C1COCC1>[Br:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=1)[C:28]([NH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[C:5]([CH3:21])=[CH:4][CH:3]=1)=[O:29]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cncc(Br)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 885.3 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (26.4 mg, 0.009 mmol) and 5-bromonicotinic acid (38 mg, 0.18 mmol) were mixed in THF (2 ml) and the mixture shaken in a varian tube for 5 min at room temperature. Carbodiimde resin (250 mg, 0.27 mmol) was added and shaking continued for 72 h. The solution was filtered off and concentrated under vacuum. The residue was chromatographed on a silica gel flash column eluting with ethyl acetate/hexane (1:2 then 1:1) and the solvent evaporated under vacuum to give 5-bromo-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl1,1′-biphenyl-3-yl)nicotinamide (37 mg, 85%). NMR; δH [2H6]—DMSO 10.50,(1H, s), 9.05,(1H, m), 8.90,(1H, m), 8.62,(1H, t), 8.54,(1H, t), 7.93,(2H, d), 7.70,(1H, dd), 7.66,(1H, d), 7.44,(2H, d), 7.31,(1H, d), 3.16,(2H, t), 2.21,(3H, s), 1.04,(1H, m), 0.43,(2H, m). LCMS: retention time 3.44 min, MH+464/466.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][N:13]1[C:17](=[O:18])[CH:16]=[CH:15][C:14]1=[O:19]>>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([C:15]2[C:14]([N:13]([CH3:12])[C:17](=[O:18])[CH:16]=2)=[O:19])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CN1C(=O)C=CC1=O
Product: CN1C(=O)C=C(c2cccc(C(F)(F)F)c2)C1=O

Procedure:
An 80.6 g portion of 3-aminobenzotrifluoride was reacted with 55.6 g of N-methylmaleimide as described in Example 6, giving 2-(m-trifluoromethylphenyl)-N-methylmaleimide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[C:13]([NH:19][CH3:20])=[CH:12][C:11]=2[F:21])=[CH:4][CH:3]=1>[Ni]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[C:14]([NH2:16])[C:13]([NH:19][CH3:20])=[CH:12][C:11]=2[F:21])=[CH:6][CH:7]=1
Reactant: CNc1cc(F)c(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Agent: [Ni]
Product: CNc1cc(F)c(C(=O)Nc2ccc(Br)cc2)cc1N

Procedure:
The subtitle compound is prepared from N-(4-bromophenyl)-2-fluoro-4-methylamino-5-nitro-benzamide, RaNi and H2 in analogy to example 5c.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O>>[CH:3]1[C:4]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)=[CH:5][CH:6]=[C:1]([OH:7])[CH:2]=1
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Product: Oc1ccc(-c2ccc(O)cc2)cc1
Reaction time: 3 h
Yield: 91 %

Procedure:
The procedures of Example 12 were repeated except that 10.0 g of reaction solution (1) obtained in Example 12, 0.1 g of phenol (solvent) and 0.04 g of sulfuric acid (catalyst) were added to the whole portion of mother liquor (I) obtained in Example 12 and that reaction was performed at 185° C. for 3 hours to produce p,p'-biphenol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30]O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][O:17][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COC(c1ccc(N)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2-(4-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (1.30 g), (S)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g), PPh3 (1.56 g) and molecular sieves 4 Å in THF (100 mL) was added DEAD (0.93 mL) slowly. The reaction was stirred at RT for 5 h and at reflux for overnight. After filtration to remove solids, the filtrate was concentrated and the residue was taken into ether. The organic phase was washed with saturated NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated to give a crude material as a very viscous brown oil which was purified by chromatography through silica gel (400 g, 2:1:7 to 3:1:6 EtOAc/Et3N/hexanes) to afford (S)-2-[1-(4-amino-phenyl)-2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH3:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:19][C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=2[O:32][CH3:33])[CH:24]=1>C1COCC1.C(O)(=O)C>[Cl:19][C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:31]=[CH:30][C:28]([NH:29][C:2]3[N:3]=[C:4]([NH:17][CH3:18])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:27][C:26]=2[O:32][CH3:33])[CH:24]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccccc1

Procedure:
A solution of 2-chloro-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (833 mg, 3.21 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (717.9 mg, 3.21 μmol) in THF (5.6 mL) and acetic acid (5.6 mL) was heated at 85° C. in a 350 mL high-pressure vessel overnight. The solvent was removed in vacuum and the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine, which was contaminated with 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline. The material was triturated with methanol, cooled in the freezer and filtered. The residue was washed with freezing cold methanol and dried to give pure N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (673.5 mg, 47%) as light brown solid. LC-MS (M+H)+=446.9. 1H NMR (500 MHz, CDCl3) δ ppm 7.99 (1H, d, J=1.8 Hz), 7.48 (1H, s), 7.27-7.33 (2H, m), 7.16-7.24 (3H, m), 6.96-7.07 (3H, m), 6.71 (1H, dd, J=8.4, 1.7 Hz), 4.50 (1H, br s), 4.20 (1H, s), 3.48 (3H, s), 3.11 (3H, d, J=4.9 Hz), 2.59-2.79 (3H, m), 2.01-2.13 (1H, m).
Reaction SMILES: [OH:1][C@@H:2]([C@@H:9]([CH2:16]/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].[H][H]>CO.[Pd]>[OH:1][C@@H:2]([C@@H:9]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:21][CH:20]=1)[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)OC(=O)[C@@H](O)[C@@H](C/C=C/c1ccc(OC(F)(F)F)cc1)C(=O)OC(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)OC(=O)[C@@H](O)[C@@H](CCCc1ccc(OC(F)(F)F)cc1)C(=O)OC(C)C
Yield: 99.1 %

Procedure:
To a solution of diisopropyl (2S,3R)-2-hydroxy-3-{(2E)-3-[4-(trifluoromethoxy)phenyl]-2-propenyl}butanedioate (6.98 g; 16.68 mmol; 1.00 eq.) in methanol (105 mL) under N2 atmosphere was added Pd—C (10%; 200 mg; 0.17 mmol; 0.01 eq.). The mixture was then hydrogenated under 2 bars of hydrogen for 14 h at RT. The reaction mixture was then filtered and evaporated to obtain the title compound (6.95 g; 99.1%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]#[N:5].N[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[SH:13]>CCO>[S:13]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:5]=[C:4]1[CH2:3][CH2:2][NH2:1]
Reactant: Nc1ccccc1S
Reactant: N#CCCN
Solvent: CCO
Product: NCCc1nc2ccccc2s1
Temperature: 25 °C

Procedure:
A solution of 50 mg of 3-aminopropionitrile and 596 mg of 2-aminothiophenol in EtOH (15 mL) was heated at reflux for six hrs. After cooling the solution to room temperature, the reaction was concentrated and the residue was purified by silica gel chromatography to afford the title compound as a red oil. MS (M+H)+=179.1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc2ccccc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
To a stirred solution of 2-naphthol (2.9 g) and 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (4 g) in tetrahydrofuran (30 ml) at 0° C. was added triphenylphosphine (5.2 g) and diethyl azodicarboxylate (3.2 ml). The reaction was allowed to warm to room temperature and stirred for 16 h. The solvent was removed in vacuo and the slurry taken up in EtOAc (30 ml) and washed with aqueous sodium hydroxide (1M, 2×30 ml), water (30 ml) and brine (30 ml). The organic extract was diluted with hexane (50 ml), and the precipitates were removed by filtration, and the filtrate dried over magnesium sulphate (1 g). The solvent was removed in vacuo to yield the title compound as a white solid (3.4 g).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][C:8]=12.C([Li])CCC.[CH2:29]([O:36][C:37]([NH:39][C@@H:40]1[C:49]2[C:44](=[CH:45][C:46]([C:50](Cl)=[O:51])=[CH:47][CH:48]=2)[S:43][CH2:42][CH2:41]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O>[CH2:29]([O:36][C:37]([NH:39][C@@H:40]1[C:49]2[C:44](=[CH:45][C:46]([C:50]([NH:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][C:8]=34)=[O:51])=[CH:47][CH:48]=2)[S:43][CH2:42][CH2:41]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(N)ccnc21
Reactant: O=C(N[C@H]1CCSc2cc(C(=O)Cl)ccc21)OCc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(NC(=O)c3ccc4c(c3)SCC[C@@H]4NC(=O)OCc3ccccc3)ccnc21
Reaction time: 0.25 h
Yield: 42.9 %

Procedure:
To a tetrahydrofuran solution of 4-amino-1-[2-(trimethylsilyl)ethoxymethyl]pyrrolo[2,3-b]pyridine (1.32 g) was added dropwise n-butyllithium (1.59 M, 3.17 ml) and the mixture was stirred at the same temperature for 15 min. To this solution was added dropwise a tetrahydrofuran solution (20 ml) of (S)-4-(benzyloxycarbonylamino)thiochromane-7-carboxylic acid chloride (4.20 mmol) obtained by a similar reaction step as in Starting Material Synthetic Example 9 at 0° C. The reaction mixture was stirred at room temperature for 5 hr. Water (100 ml) was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and purified by silica gel column chromatography (hexane-ethyl acetate) to give the objective (S)-4-(benzyloxycarbonylamino)-N-{1-[2-(trimethylsilyl)ethoxymethyl]pyrrolo[2,3-b]pyridin-4-yl}thiochromane-7-carboxamide (1.06 g) as a pale-brown amorphous solid.