Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>>[Cl:19][C:17]1[CH:18]=[C:13]([CH:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[N:7]=2)=[O:9])[CH3:12])[CH:14]=[N:15][C:16]=1[O:20][CH2:21][C:22]([F:24])([F:23])[F:25]
Reactant: CC(C)C(=O)Cl
Reactant: CC(NC(=O)c1ccnc(N)n1)c1cnc(OCC(F)(F)F)c(Cl)c1
Product: CC(C)C(=O)Nc1nccc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (20 mg, 0.05 mmol, Step-1 of Example 210, single enantiomer) and isobutyryl chloride (28 mg, 0.27 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH2:11]([N:18]1[CH:22]=[C:21]([CH3:23])[C:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:19]1[C:31]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[CH2:11]([N:18]1[C:19]([C:31]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[O:32])=[C:20]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:21]([CH3:23])=[C:22]1[CH:4]=[O:5])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cn(Cc2ccccc2)c(C(=O)N2CCOCC2)c1-c1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N2CCOCC2)n(Cc2ccccc2)c1C=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
To an ice-cold solution of DMF (0.441 mL, 5.70 mmol) in DCM (5 mL) was added POCl3 (0.425 mL, 4.56 mmol). After stirring the reaction mixture at 0° C. for 15 min, a solution of (1-benzyl-3-(4-chlorophenyl)-4-methyl-1H-pyrrol-2-yl)(morpholino)methanone [obtained via standard EDI/HOAt coupling of ACI-02 with morpholine] (900 mg, 2.28 mmol) in DCM (1 mL) was dropwise added. The reaction was stirred for 30 min, then the ice-bath was removed and stirring was continued at room temperature for 1 h. The reaction mixture was cooled to 0° C., then saturated aqueous NaHCO3 was added while vigorously stirring, until the mixture was neutralised. The mixture was extracted with DCM, washed with brine and concentrated. The residue was dissolved in i-PrOH and precipitated with H2O. The precipitate was filtered, washed with i-PrOH/H2O (1:1, 2×) and MeOH (2×) and dried on for a couple of hours to give the desired product (761 mg, 79%).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH3:24][C:25]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[C:26]=1[NH2:27]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:27][C:26]4[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:25]=4[CH3:24])=[O:3])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: Cc1cc(C)c(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)c(C)c1

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (75.0 mg) and 2,4,6-trimethylaniline (71.6 μL) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(2,4,6-trimethylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (29.1 mg).
Reaction SMILES: C(OCC)(=O)C.[CH3:7][O:8][CH:9]([CH2:18][O:19][CH2:20][CH2:21][CH:22]([CH3:39])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:38])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:10][S:11]([CH2:14][CH2:15][CH2:16][OH:17])(=[O:13])=[O:12].[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(N(CC)CC)C>[CH3:7][O:8][CH:9]([CH2:18][O:19][CH2:20][CH2:21][CH:22]([CH3:39])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:38])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:10][S:11]([CH2:14][CH2:15][CH2:16][O:17][S:41]([CH3:40])(=[O:43])=[O:42])(=[O:13])=[O:12]
Reactant: COC(COCCC(C)CCCC(C)CCCC(C)CCCC(C)C)CS(=O)(=O)CCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(COCCC(C)CCCC(C)CCCC(C)CCCC(C)C)CS(=O)(=O)CCCOS(C)(=O)=O

Procedure:
To 100 ml of ethyl acetate are added 4.5 g of 3-[(2-methoxy-3-(3,7,11,15-tetramethylhexadecyloxy)propyl)sulfonyl]propanol and 1.54 ml of triethylamine, to which is further added 0.85 ml of methanesulfonyl chloride dropwise at room temperature with stirring. After being stirred at room temperature for 3 hours, the reaction mixture is washed with water, dilute hydrochloric acid, an aquoues sodium bicarbonate and water. After drying, the solvent is distilled off to leave 5.16 g of the captioned compound as an oily substance.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CN(C=O)C>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH:12]=[CH:11]2)=[O:4]
Reactant: O=C(CCl)Nc1cccc2ccc(O)cc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)Oc1ccc2cccc(NC(=O)CCl)c2c1
Reaction time: 16 h

Procedure:
To a solution of the crude alcohol from Step A (50.3 mmol) in 150 mL of DMF at 0° C. was added triethylamine (15.0 mL, 108 mmol), followed by dropwise addition of methanesulfonyl chloride (6.0 mL, 77.5 mmol). After 16 hours, additional portions of triethylamine (7.0 mL, 50 mmol) and methanesulfonyl chloride (3.0 mL, 39 mmol) were added. After 4 hours, the solution was concentrated in vacuo and partitioned between EtOAc and saturated NH4Cl solution. The organic layer was extracted with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide a dark purple solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH2:9][CH2:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[CH3:37][O:38][C:39](Cl)=[O:40]>>[CH3:37][O:38][C:39]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=2)[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([OH:19])=[O:18])=[CH:24][CH:25]=2)=[N:6][CH:7]=1)=[O:40]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(N)cn2)cc1
Reactant: COC(=O)Cl
Product: COC(=O)Nc1ccc(N(CCc2ccc(OC(C)(C)C(=O)O)cc2)Cc2ccc(C(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(5-aminopyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and methylchloroformate.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:21])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1)[N:9]=[CH:8]2.CCOC(C)=O>CN(C=O)C>[OH:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([NH:13][C:10]2[N:9]=[CH:8][C:7]3[C:12](=[C:3]([OH:2])[C:4]([CH3:21])=[CH:5][CH:6]=3)[N:11]=2)[CH2:19][CH2:18]1
Reactant: COc1c(C)ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1O
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a solution of trans-4-[(8-methoxy-7-methylquinazolin-2-yl)amino]cyclohexanol (16.7 g, 0.058 mol) in DMF (280 mL) was added NaSEt (11.9 g, 0.142 mol) in one portion at room temperature. The reaction mixture was stirred at 120° C. for 3 h. TLC (EtOAc) indicated the reaction was complete. DMF was removed in vacuo. The residue was taken up with water (200 mL), and the aqueous solution was adjusted to pH 6 with 1 N aq. HCl. The precipitate was filtered, washed with water (60 mL×2) and dried in vacuo to give the title compound (15.1 g, 95%) as an off-white solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:35]([OH:37])=[O:36])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24]C(OCC3C=CC=CC=3)=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:35]([OH:37])=[O:36])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-Nε-benzyloxycarbonyl-L-lysine (502 mg, 1.00 mmol) was dissolved in TFA/CH2Cl2 (3 mL/3 mL) and stirred at room temperature for 1 h. The volatiles were removed in vacuo to afford the title compound quantitatively as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].[CH:14](OCC)(OCC)OCC>FC(F)(F)C(O)=O>[CH3:14][NH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6]
Reactant: C=CCOC(=O)c1cccc(N)c1
Reactant: CCOC(OCC)OCC
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)c1cccc(NC)c1
Yield: 17 %

Procedure:
Allyl 3-aminobenzoate (5 g, 28.2 mN) was dissolved in triethyl orthoformate (50 ml) and trifluoroacetic acid (5 drops) was added. The solution was stirred and refluxed up through 3a molecular sieves for 5 hours. Solvent was removed, and the residue dissolved in ethanol (50 ml), followed by the addition of acetic acid (8.08 ml) and sodium cyanoborohydride (6.85 g, 0.108 M) in several portions. The mixture was stirred at ambient temperature for 16 hours, and solvent removed. The residue was dissolved in diethyl ether, washed with water, brine, and dried over MgSO4. Crude product was purified by chromatography on silica, eluting with a gradient from dichloromethane to dichloromethane/ethyl acetate (95:5), to give allyl 3-methylaminobenzoate (0.93 g, 17%). Nmr (CDCl3): δ 2.88 (s, 3H); 4.81 (dt, 2H); 5.23-5.45 (m, 2H); 5.94-6.13 (m, 1H); 6.83 (dd, 1H); 7.25 (dd, 1H); 7.33 (t, 1H); 7.43 (dm, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[N:23]=[C:22]([C:24](OC)=[O:25])[CH:21]=[CH:20][N:19]=3)[CH2:10][CH2:9]2)[CH:7]=1.[NH2:30][CH2:31][CH2:32][NH:33][C:34]1[NH:35][CH:36]=[CH:37][C:38](=[O:40])[N:39]=1>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[N:23]=[C:22]([C:24]([NH:30][CH2:31][CH2:32][NH:33][C:34]4[NH:35][CH:36]=[CH:37][C:38](=[O:40])[N:39]=4)=[O:25])[CH:21]=[CH:20][N:19]=3)[CH2:12][CH2:13]2)[CH:7]=1
Reactant: COC(=O)c1ccnc(NCCCN2CCN(c3cc(Cl)ccc3OC)CC2)n1
Reactant: NCCNc1nc(=O)cc[nH]1
Solvent: CCCCO
Product: COc1ccc(Cl)cc1N1CCN(CCCNc2nccc(C(=O)NCCNc3nc(=O)cc[nH]3)n2)CC1

Procedure:
1.89 g of (4.5 mmols) of methyl 2-[[3-[4-(5-chloro-2-methoxyphenyl)piperazin-1-yl]propyl]amino]-pyrimidine-4-carboxylate and 0.77 g (5 mmols) of 2-[(2-aminoethyl)amino]pyrimidin-4(1H)-one in 5 ml of n-butanol are introduced into a 25 ml, round bottomed flask. The mixture is heated at the reflux temperature of the solvent for 15 hours and then the solvent is evaporated under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[C:20]3[C:19]([O:21][CH3:22])=[CH:18][CH:17]=[C:16]([C:23](OC4C=CC([N+]([O-])=O)=CC=4)=[O:24])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[C:12]([Cl:35])[CH:13]=3)=[CH:5][CH:4]=1.[Cl:38][C:39]1[CH:40]=[N:41][CH:42]=[C:43]([Cl:46])[C:44]=1[NH2:45].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:38][C:39]1[CH:40]=[N:41][CH:42]=[C:43]([Cl:46])[C:44]=1[NH:45][C:23]([C:16]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:35])[CH:13]=3)[N:8]([CH2:7][C:6]3[CH:36]=[CH:37][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:20]=2[C:19]([O:21][CH3:22])=[CH:18][CH:17]=1)=[O:24]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1ccc(Cn2c3ccc(Cl)cc3c3c(C(=O)Oc4ccc([N+](=O)[O-])cc4)ccc(OC)c32)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c3ccc(Cl)cc3c3c(C(=O)Nc4c(Cl)cncc4Cl)ccc(OC)c32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
To a solution of 4-Nitrophenyl 9-(4-methoxy benzyl)-6-chloro-1-methoxy-4-carbazole carboxylate (95 mg, 0.232 mmoles) in dry DMF (5 ml) under nitrogen atmosphere, 3,5-dichloro-4-amino pyridine (37.8 mg, 0.232 mmoles) was added followed by sodium hydride (60% suspension, 20.0 mg, 0.464 mmoles) and the reaction mixture was stirred at room temperature for two hours. Ice pieces were added to the reaction mixture, diluted with water (15 ml) and neutralized with 1N HCl. The precipitated product was filtered, washed with water and dried under vacuum to give 60 mg of the title compound as an off white solid, m. p: 257-258° C.
Reaction SMILES: [NH2:1][CH:2]([C:7]([NH2:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4]>O>[NH2:1][C@@H:2]([C:7]([NH2:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)C(N)C(N)=O
Solvent: O
Product: CC(C)(C)[C@@H](N)C(N)=O

Procedure:
In accordance with the process described in JP Patent Application Laying Open (Kokai) No. 62-55097, Enterobacter cloacae N-7901 (FERM BP-873) was cultured. 1 L of culture solution was centrifuged, and the wet cells were then suspended in distilled water to prepare a 800 g cell suspension. 200 g of D,L-tert-leucine amide was dissolved in this suspension, and the solution was then allowed to react at 40° C. for 52 hours. After the reaction, cells were removed by centrifugation and 970 g of an aqueous solution containing 10% by mass each of L-tert-leucine and D-tert-leucine amide was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[C:15]([O:19][C:20]([N:22]1[CH2:25][CH:24]([CH:26]=[O:27])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CCCCCCC.C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:25][CH:24]([CH:26]([OH:27])[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Reactant: COc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COc1ccc(C(O)C2CN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2.2 g (11.8 mmol) 4-bromoanisole in 30 mL dry heptane under nitrogen was added 8.02 mL (1.6 M in hexane, 12.83 mmol) n-butyl lithium dropwise, and the mixture was stirred at room temperature for 30 minutes. The solution was then cooled to −78° C. and a solution of 2.0 g (10.7 mmol) 3-formyl-azetidine-1-carboxylic acid tert-butyl ester (route 18, step a) in 30 mL dry THF was added. The resultant mixture was allowed to warm to room temperature, quenched with 50 mL 1 M sodium bicarbonate and extracted with DCM (2×50 mL). The combined organic layers were dried over Na2SO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 4:1 to 1:1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C([O-])(O)=O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(=O)=O>O.C1(C)C=CC=CC=1>[C:16]([N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
N-Benzyloxycarbonyl)-trans-4-hydroxy-L-proline. Trans-4-hydroxy-L-proline 1 (10.0 g, 76.3 mmol) and NaHCO3 (16.0 g, 190 mmol) were dissolved in H2O (165 mL), then a solution of benzyl chloroformate (12.5 mL, 15.0 g, 87.7 mmol) in toluene (40 mL) was added over a period of 15 minutes. After stirring at room temperature for 16 h, CO2 evolution had ceased and the two phases were separated. Excess benzyl chloroformate was removed from the aqueous phase by washing with ether (4×50 mL). Cooling of the aqueous phase in an ice bath, followed by acidification to pH 2 with concentrated HCl, caused the oily product to precipitate. This oil was extracted into ethyl acetate by repeated washings (5×50 mL) of the aqueous layer. Further acidification of the aqueous layer produced no more precipitate, indicating thorough removal of the product. The combined organic extracts were dried (MgSO4) and concentrated to a viscous oil, which crystallized upon standing at room temperature to provide 19.9 g (98%) of N-CBZ-trans-4-hydroxy-L-proline: mp 106°-107° C. (lit.19 mp 106°-107° C.); [α]24D-77.5° (c 1.03, CHCl3) [lit.19 [α]20D-72° (c 1.0 CHCl3)].
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:4]=2[N:3]=1.[Br-].[CH:19]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:21])[CH3:20]>>[CH2:16]([C:14]1[CH:13]=[CH:12][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:15]=1)[N:10]=[CH:9][CH:8]=[CH:7]3)[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1nc2cc(C=O)ccc2c2cccnc12
Agent: [Br-]
Product: CC(C)Cc1ccc2c(c1)nc(N)c1ncccc12

Procedure:
8-Isobutylbenzo[f][1,7]naphthyridin-5-amine was prepared from 5-aminobenzo[f][1,7]naphthyridine-8-carbaldehyde (from Example 87) with isopropyl(triphenyl)phosphonium bromide following the procedures described for Example 91 (wittig reaction) and Example 92 (reduction). 1H NMR (acetone-d6): δ 8.98 (dd, 1H), 8.88 (dd, 1H), 8.35 (d, 1H), 7.82 (dd, 1H), 7.44 (d, 1H), 7.18 (dd, 1H), 6.73 (br s, 2H), 2.63 (d, 2H), 2.04-1.94 (m, 1H), 0.94 (d, 6H). LRMS [M+H]=252.1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1csc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c12
Reactant: c1c[nH]cn1
Product: Cc1csc2nc(-n3ccnc3)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC(OCC)=O.CCN(CC)CC.[F:30][C:31]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:32]=1[C:33](=[NH:36])[NH:34][NH2:35]>C1COCC1>[F:30][C:31]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:32]=1[C:33](=[NH:36])[NH:34][NH:35][C:14](=[O:16])[C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:10]([CH3:11])([CH3:12])[CH3:13]
Reactant: N=C(NN)c1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)NNC(=N)c1cc(F)ccc1F)C(C)(C)C
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
The N-Boc-D-tert-butylglycine (7.5 g, 32.4 mmol) was converted to a mixed anhydride by adding ethyl chloroformate (3.41 mL, 35.6 mmol), Et3N (6.8 mL, 48.6 mmol) in anhydrous THF (65 mL, 0.5 M) at −5° C. to 0° C. The mixture was stirred at −5° C. for 30 min. The resulting solid was filtered off and additional anhydrous THF was added to wash the precipitate. The resulting reaction solution was then added to a THF solution of 2,5-difluorobenzimido-hydrazide (5.53 g, 32.4 mmol) at −5° C. Then the reaction was gradually warmed to room temperature and stirred for overnight. Once the reaction was complete, the mixture was partitioned between EtOAc and H2O. The organic layer was separated and washed with H2O, brine, then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give the crude product, which was purified on silica gel column (50% EtOAc in Hexanes) to afford (R)-tert-butyl 1-(2-((2,5-difluorophenyl)(imino)methyl)hydrazinyl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (67%). Rf=0.4 (50% EtOAc in Hexanes). LC/MS (uplc): MH+ 385.3, 0.65 min.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:18])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[F:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1F.Cl.CCO>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[O:18][C@@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Fc1cc(F)c(F)cc1F
Reactant: CCCC[C@@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCC[C@@H](Oc1cc(F)c(F)cc1F)[C@H]1CCNC1
Temperature: 90 °C

Procedure:
(S)-3-((R)-1-Hydroxypentyl)pyrrolidine-1-carboxylic acid t-butyl ester (40.0 mg, 155 μmmol) was dissolved in DMF (100 mL, 12.9 mmol). While stirring, 60% sodium hydride in oil (0.4:0.6, sodium hydride:mineral oil, 18.6 mg, 311 μmmol) was slowly added, and the mixture was stirred for 15 minutes. 1,2,4,5-Tetrafluorobenzene (52.1 μL, 466 μmmol) was added. The mixture was then heated at 90° C. for 3 hours. The reaction was quenched with MeOH (1 mL), and the solvent was removed under reduced pressure. 1.25M HCl in EtOH (2.0 mL, 2.5 mmol) was added, and the mixture was stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (19.2 mg, 97% purity). MS m/z: [M+H]+ calcd for C15H20F3NO, 288.15; found 288.2.
Reaction SMILES: [CH:1]([N:4]1C=C(CCNC(NC2SC(C3C=C(C)N=C(SC)N=3)=C(C)N=2)=O)N=[CH:5]1)([CH3:3])[CH3:2].C(C1O[C:35]([CH2:37][CH2:38][NH:39][C:40]([NH:42][C:43]2[S:44][C:45]([C:49]3[CH:54]=[C:53]([CH3:55])[N:52]=[C:51]([S:56]([CH3:59])(=[O:58])=[O:57])[N:50]=3)=[C:46]([CH3:48])[N:47]=2)=[O:41])=[N:34][CH:33]=1)C>>[CH:1]([N:4]1[CH:5]=[C:35]([CH2:37][CH2:38][NH:39][C:40]([NH:42][C:43]2[S:44][C:45]([C:49]3[CH:54]=[C:53]([CH3:55])[N:52]=[C:51]([S:56]([CH3:59])(=[O:57])=[O:58])[N:50]=3)=[C:46]([CH3:48])[N:47]=2)=[O:41])[N:34]=[CH:33]1)([CH3:3])[CH3:2]
Reactant: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(S(C)(=O)=O)n3)s2)o1
Reactant: CSc1nc(C)cc(-c2sc(NC(=O)NCCc3cn(C(C)C)cn3)nc2C)n1
Product: Cc1cc(-c2sc(NC(=O)NCCc3cn(C(C)C)cn3)nc2C)nc(S(C)(=O)=O)n1

Procedure:
This material is prepared from 1-[2-(1-isopropyl-1H-imidazol-4-yl)-ethyl]-3[4-methyl-5-(6-methyl-2-methylsulfanyl-pyrimidin-4-yl)-thiazol-2-yl]-urea by the same protocol described for 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(2-methanesulfonyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-urea (Example 41).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C@@H:31]([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)[CH2:20][O:21][C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C@@H:31]([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1cc(F)c(Oc2ccnc(C(F)(F)F)c2)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3cc(F)c(Oc4ccnc(C(F)(F)F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.