Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].CC#N.O>CN(C=O)C>[F:27][C:28]([F:37])([F:38])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:11]2[CH2:12][CH2:13][N:8]([CH2:14][C:15]3[N:16]=[N:17][C:18]4[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=4)[N:20]=3)[CH2:9][CH2:10]2)=[CH:31][CH:30]=1
Reactant: Nc1nc(N)c2nc(CN3CCNCC3)nnc2n1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Nc1nc(N)c2nc(CN3CCN(Cc4ccc(C(F)(F)F)cc4)CC3)nnc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.6 %

Procedure:
To a stirred solution of 3-Piperazin-1-ylmethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine TFA salt 5 (50 mg; 0.08 mmol; prepared in EXAMPLE 4) in dry DMF (1.0 mL) was added p-trifluoromethylbenzyl bromide (0.021 mL; 0.14 mmol) followed by potassium carbonate (55 mg; 0.40 mmol). The mixture was allowed to stir for 24 h at room temperature then taken up into CH3CN/H2O/0.1% TFA. The mixture was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 50% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 22 mg of yellow colored 3-[4-(4-Trifluoromethyl-benzyl)-piperazin-1-ylmethyl]-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].[Li].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22].C(Br)CC.C(O)(=O)C>C1COCC1>[CH2:2]([CH:19]1[CH2:20][CH2:21][N:17]([CH2:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=2)[C:18]1=[O:22])[CH2:1][CH3:3]
Reactant: CC(C)NC(C)C
Reactant: O=C1CCCN1CCc1ccccn1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCCBr
Solvent: CC(=O)O
Product: CCCC1CCN(CCc2ccccn2)C1=O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a 2 M lithium diisopropylamine solution in THF of −78° C. is added 1-(2-(pyridin-2-yl)-ethyl)pyrrolidin-2-one and the mixture is stirred for 1.5 h at −78° C. Then 1-propyl bromide is added and the reaction is stirred for another 1.5 h at −78° C. The reaction mixture is allowed to warm up to 0° C. before ice-cold water with acetic acid is added and subsequently extracted 3 times with dichloromethane. The dichloromethane is concentrated in vacuo and the residue is dissolved in dichloromethane, washed with saturated NaHCO3 and brine. Crude 3-propyl-1-(2-(pyridin-2-yl)ethyl)pyrrolidin-2-one is obtained after removal of the solvents in vacuo. The product is purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][CH:31]([CH3:36])[CH2:32][CH2:33][CH2:34]O.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:30][CH:31]([CH3:36])[CH2:32][CH2:33][CH2:34][O:24][C:23]([C:18]1([C:20]([O:22][CH2:7][CH2:2][CH2:3][CH:4]([CH3:8])[CH3:5])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25]
Reactant: CC(C)CCCO
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)CCCOC(=O)C1(C(=O)OCCCC(C)C)Oc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2O1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 4-methylpentanol according to the procedure of Example 30 as a colorless gum (HCl salt); 1H NMR (CDCl3) δ 0.87 (d, J=6.5 Hz, 12H), 1.33 (bs, 3H), 1.10-2.0 (m, 10H), 2.80 (bs, 1H), 3.18 (bs, 2H), 3.48 (bs, 2H), 4.28(m, 4H), 5.60 (bs, 2H), 6.80 (m, 3H), 7.25 (m, 2H), 7.43 (s, 1H), 8.70 (bs, 1H), 10.10 (bs, 1H); IR (KBr): 1765 cm-1 (C=O); MS (CI) m/z 590 (MH+); [α]D25 -24° (c, 1.0, CHCl3). Anal. Calcd. for C32H44ClNO7HCl: C, 61.34; H, 7.08; N, 2.24; Cl, 11.32. Found: C, 60.50; H, 7.36; N, 2.13; Cl, 11.66.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][N:7]=1.[CH3:13][C:14](O)=[O:15]>C(OC(=O)C)(=O)C>[C:14]([O:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][N:7]=1)(=[O:15])[CH3:13]
Reactant: CC(=O)O
Reactant: Nc1ccnc(CSCCO)n1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCCSCc1nccc(N)n1
Reaction time: 16 h

Procedure:
A mixture of 2-(2-hydroxyethylthiomethyl)-4-aminopyrimidine (1.5 g.) in HOAc (5 ml.) and acetic anhydride (5 ml.) was stirred at 25° for 16 hours. The solvent was evaporated in vacuo to give 2-(2-acetoxyethylthiomethyl)-4-aminopyrimidine as a gum which was used without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:11])[CH:7]([OH:10])[CH2:8][CH3:9].C(Cl)Cl>C(N(CC)CC)C>[CH3:1][S:2]([O:11][CH2:6][CH:7]([O:10][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:8][CH3:9])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(O)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(COS(C)(=O)=O)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Into a one liter, four-necked round bottom flask equipped with stirrer, condenser, thermometer, and addition funnel, 57.0 parts of methanesulfonyl chloride, 22.5 parts of 1,2-butanediol and 57.0 parts of methylene chloride were mixed under a nitrogen blanket and cooled to 0° C. using a dry ice-acetone bath. To this 50.5 parts of triethylamine was added over one hour. The reaction was stirred at 0° C. for an additional three hours and allowed to stand for 18 hours at 0° C. The mixture was vacuum filtered and then washed successively with chilled dilute sulfuric acid (twice with 200 part-portions), dilute sodium bicarbonate (three times with 200 part-portions), and water (twice with 200 part-portions), dried over sodium sulfate, filtered, and the solvent removed in vacuo at 35° C. to give the product as a pale yellow liquid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([F:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]([F:11])([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[N:29][NH:30][CH:31]=3)=[CH:3][CH:4]=2)[CH2:9][NH2:10])=[CH:13][CH:14]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: NCC(F)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: NCC(F)(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Reaction time: 0.08 h

Procedure:
2,2-Bis-(4-chloro-phenyl)-2-fluoro-ethylamine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 except that heating was carried out at 100° C. for 5 minutes using 300 W power in a CEM microwave, to obtain the title compound. LCMS (PS-B4) Rt 6.69 min [M−F−]+ 296. 1H NMR (Me-d3-OD) δ 4.04 (2H, d), 7.47-7.55 (6H, m), 7.77 (2H, d), 8.41 (2H, d).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([Cl:25])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:24]=[C:23]([Cl:25])[S:22][C:12]=3[N:13]=2)[CH:17]=1
Reactant: Clc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCc1ccccc1
Product: Clc1cc2c(NCc3ccccc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-3-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-benzylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]2[C:7]3([O:13][CH2:14][CH2:15][C:4]=2[CH:3]=1)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]3.[CH:16]([C:18]1[C:19]([CH3:31])=[N:20][N:21]([C:23]2[C:28]([C:29]#[N:30])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:22]=1)=O>>[F:1][C:2]1[S:6][C:5]2[C:7]3([O:13][CH2:14][CH2:15][C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:16][C:18]1[C:19]([CH3:31])=[N:20][N:21]([C:23]2[C:28]([C:29]#[N:30])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:22]=1)[CH2:9][CH2:8]3
Reactant: Cc1nn(-c2ncccc2C#N)cc1C=O
Reactant: Fc1cc2c(s1)C1(CCNCC1)OCC2
Product: Cc1nn(-c2ncccc2C#N)cc1CN1CCC2(CC1)OCCc1cc(F)sc12
Yield: 32 %

Procedure:
This compound is essentially prepared as described in Preparation 7 by using 2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine] and 2-(4-formyl-3-methyl-pyrazol-1-yl)pyridine-3-carbonitrile. The residue is purified by SCX to give 2-[4-[(2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]pyridine-3-carbonitrile in a 32% yield. MS (m/z): 424 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][C:25]([F:48])([F:47])[CH2:26][C@@H:27]([C:42](OCC)=[O:43])[N:28]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[BH4-].[Li+].CO.O>C1COCC1>[NH2:41][C:38]1[CH:37]=[CH:36][C:35]([S:32]([N:28]([CH:29]([CH3:31])[CH3:30])[C@H:27]([CH2:42][OH:43])[CH2:26][C:25]([F:48])([F:47])[CH2:24][CH2:23][NH:22][C:20](=[O:21])[C@H:6]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:5][C:3]([O:2][CH3:1])=[O:4])(=[O:33])=[O:34])=[CH:40][CH:39]=1
Reactant: CCOC(=O)[C@H](CC(F)(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)N(C(C)C)S(=O)(=O)c1ccc(N)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)N[C@H](C(=O)NCCC(F)(F)C[C@@H](CO)N(C(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
To a solution of the material from Step 11 (50 mg, 0.073 mmol) in THF (726 μL) at 0° C. were added a solution of 2 M lithium borohydride in THF (145 μL, 0.290 mmol) and methanol (11.75 μL, 0.290 mmol). The reaction mixture was stirred at room temperature for 2 hours. TLC showed not complete reaction. Additional 2 equiv of lithium borohydride was added, stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine, dried with MgSO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel using ethyl acetate-hexanes (0:100 to 100:0) to afford 26 mg of the title compound as a colorless foam. LCMS (M+1)=647. 1H NMR (Acetone-d6): δ 7.62 (d, J=8.32 Hz, 2H), 7.46-7.36 (m, 4H), 7.34-7.25 (m, 4H), 7.23-7.15 (m, 3H), 6.76 (d, J=8.32 Hz, 2H), 6.40 (d, J=9.02 Hz, 1H), 5.49 (s, 2H), 4.97 (t, J=10.09 Hz, 1H), 4.42 (d, J=11.05 Hz, 1H), 3.93-3.81 (m, 2H), 3.80-3.69 (m, 2H), 3.66-3.59 (m, 1H), 3.50 (s, 3H), 3.34-3.14 (m, 1H), 3.12-2.95 (m, 1H), 2.46-2.29 (m, 2H), 1.81-1.44 (m, 2H), 1.20 (d, J=8.20 Hz, 6).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH3:24][N:25]1[CH:29]=[C:28]([NH2:30])[CH:27]=[N:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:30][C:28]2[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=2)=[O:21])=[CH:17][N:16]=1
Reactant: Cn1cc(N)cn1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)Nc2cnn(C)c2)cn1
Yield: 41 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 1-methyl-1H-pyrazol-4-ylamine instead of 2-aminoethyl isopropylether, to the title compound (102 mg, 41%) which was obtained as a white solid. MS: m/e=388.1 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41][NH2:42]>CC(N(C)C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:42][CH2:41][C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[NH2:38])=[O:15])[CH:3]=1
Reactant: NCc1ccccc1N
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Product: CCOc1nc(C(=O)NCc2ccccc2N)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 20 mL scintillation vial, 4-amino-5-cyano-6-ethoxy-pyridine-2-carboxylic acid (19 mg, 0.09 mmol) was dissolved in DMA (0.7 mL). Then TBTU (30 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added, followed by the addition of 2-aminobenzylamine (12 mg, 0.11 mmol, 1.2 eq.) in DMA (0.6 mL). Then TEA (9.37 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added. The reaction mixture was shaken at room temperature for 24 hours. The crude mixture was purified using reverse phase HPLC (TFA). 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 1.27 (t, 3H) 4.21-4.37 (m, 2H) 4.45 (q, 2H) 6.33-7.25 (m, 5H). MS (ESI) negative ion 310 (M−H)−.
Reaction SMILES: Br[CH:2]1[C:7](=O)[CH2:6][CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.[C:14](=[S:17])([NH2:16])[CH3:15]>CN(C)C=O>[CH3:15][C:14]1[S:17][C:2]2[CH2:3][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:6][C:7]=2[N:16]=1
Reactant: CCOC(=O)C1CCC(=O)C(Br)C1
Reactant: CC(N)=S
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCc2nc(C)sc2C1
Temperature: 25 °C

Procedure:
A mixture of EXAMPLE 387A (4.4 g) and ethanethioamide (1.33 g) in N,N-dimethylformamide (50 mL) was heated at 140° C. for 20 hours. After it cooled to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica to give the title compound.
Reaction SMILES: [Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=CC=C(C(OC)=O)C=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.FC1C=C(C[C@H](NC(=O)C2C=C(C3OC=CN=3)C=C(C(N(CCC)CCC)=O)C=2)[C@H](O)[C@H]2C[C@@H](OCCC)CN2)C=C(F)C=1.[Si]([O:100][C@H:101]([C@H:136]1[CH2:140][C@@H:139]([O:141][CH2:142][CH2:143][CH3:144])[CH2:138][N:137]1C(OC(C)(C)C)=O)[C@@H:102]([NH:112][C:113](=[O:135])[C:114]1[CH:119]=[C:118]([C:120]2[O:121][CH:122]=[CH:123][N:124]=2)[CH:117]=[C:116]([C:125]([N:127]2[CH2:131][CH2:130][CH2:129][C@@H:128]2[CH2:132][O:133][CH3:134])=[O:126])[CH:115]=1)[CH2:103][C:104]1[CH:109]=[C:108]([F:110])[CH:107]=[C:106]([F:111])[CH:105]=1)(C(C)(C)C)(C)C>Cl.O>[F:110][C:108]1[CH:109]=[C:104]([CH2:103][C@H:102]([NH:112][C:113](=[O:135])[C:114]2[CH:119]=[C:118]([C:120]3[O:121][CH:122]=[CH:123][N:124]=3)[CH:117]=[C:116]([C:125]([N:127]3[CH2:131][CH2:130][CH2:129][C@@H:128]3[CH2:132][O:133][CH3:134])=[O:126])[CH:115]=2)[C@H:101]([OH:100])[C@H:136]2[CH2:140][C@@H:139]([O:141][CH2:142][CH2:143][CH3:144])[CH2:138][NH:137]2)[CH:105]=[C:106]([F:111])[CH:107]=1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N3CCC[C@@H]3COC)cc(-c3ncco3)c2)N(C(=O)OC(C)(C)C)C1
Agent: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)OC)c2)N(C(=O)OC(C)(C)C)C1
Agent: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N(CCC)CCC)cc(-c3ncco3)c2)C1
Agent: Cl
Solvent: O
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N3CCC[C@@H]3COC)cc(-c3ncco3)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Step 12 (B): Preparation of N1-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-5-(oxazol-2-yl)-N3,N3-dipropylisophthalamide. The solution of (2R,4R)-tert-butyl 2-((1S,2S)-2-(3-(benzamido)-5-(oxazol-2-yl)benzamido)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate (step 12 (A), 110 mg) in HCl (4.0 M solution in dioxane, 2 mL) was added 4 drops of H2O and the mixture was stirred at rt for 2 h. The solvent was removed and the mixture was purified by reverse phase HPLC (30×100 mm PHENOMENEX-LUNA S10 column, 42-82% methanol/H2O/0.1% TFA) to give the title compound: 1H NMR (CD3OD, 500 MHz) δ ppm 0.74 (3H, m), 0.97 (3H, m), 1.03 (3H, m), 1.57 (1H, dd, J=5, 15 Hz), 1.63 (1H, m), 1.76 (2H, dd, J=5, 15 Hz), 2.19 (1H, m), 2.54 (1H, m), 2.90 (1H, dd, J=10, 15 Hz), 3.21 (2H, m), 3.35-3.53 (7H, m), 3.85 (1H, m), 4.08 (1H, dd, J=5, 10 Hz), 4.23-4.30 (2H, m), 6.75 (1H, m), 6.92 (2H, m), 7.37 (1H, s), 7.71 (1H, m), 8.06 (1H, s), 8.13 (1H, m), 8.39 (1H, m). MS (ESI) (M+H)+ 613.27.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:29]([C:26]1[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=1)(=[O:31])=[O:30])[CH:7]=[CH:6]2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)n2ccc3c(CN(C)C)c(OC)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 7.6 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 4-methoxybenzene-1-sulfonyl chloride (23 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification using preparative HPLC/UV (System B) afforded the title product (2 mg, 6%) as a white solid. MS (ESI+) for C19H22N2O4S m/z 375 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[CH:9][C:10](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:5]=2[NH:4][C:3]1=[O:19]>[Pd].CCO>[CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:5]=2[NH:4][C:3]1=[O:19]
Reactant: CCOC(=O)/C=C/c1ccc2c(c1)NC(=O)C(C)O2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc2c(c1)NC(=O)C(C)O2
Reaction time: 18 h
Yield: 92 %

Procedure:
In a 100 mL round bottom flask equipped with a magnetic stir bar was added 183 (67 mg, 0.256 mmol), Pd/C (10% by weight, 5 mg) and EtOH (2 mL). The mixture was stirred under a hydrogen atmosphere (balloon) for 18 h. The reaction was filtered and concentrated in vacuo to give the title compound as a white solid (62 mg, 92% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (t, J=7.07 Hz, 3H) 1.39 (d, J=6.82 Hz, 3H) 2.54 (t, J=7.33 Hz, 2H) 2.75 (t, J=7.45 Hz, 2H) 4.04 (q, J=7.24 Hz, 2H) 4.56-4.63 (m, 1H) 6.71 (d, J=1.77 Hz, 1H) 6.76 (dd, J=8.08, 2.02 Hz, 1H) 6.85 (d, J=8.34 Hz, 1H) 10.61 (s, 1H). ESI-MS: m/z 264.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]1[C:9](Cl)=[O:10].C(N(CC)CC)C.CC[O:22]CC>>[Cl:7][C:6]([Cl:8])=[CH:5][CH:4]1[CH:3]([C:9]([OH:22])=[O:10])[C:2]1([CH3:12])[CH3:1]
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Reactant: CCOCC
Solvent: CCN(CC)CC
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Temperature: 25 °C

Procedure:
To a solution of 2.1 grams (0.086 mole) of cyano(6-(3-fluorophenoxy)-2-pyridine)methanol and 2.0 grams (0.0088 mole) of 2,2-dimethyl-3-(2,2-dichloroethenyl)cyclopropane carboxylic acid chloride in 50 milliliters of anhydrous ether was added 3 milliliters of triethylamine. A white precipitate separated out immediately. The reaction mixture was stirred at room temperature for one-half (1/2) hours. The mixture was successively washed with water, dilute hydrochloric acid, dilute sodium hydroxide, dilute sodium bisulfite, dilute hydrochloric acid and water and thereafter dried over anhydrous magnesium sulfate and concentrated under vacuo to give 3.5 grams of crude 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane carboxylic acid:cyano(6-(3-fluorophenoxy)-2-pyridinyl)methyl ester product as a residue. This residue was purified by distillation under reduced pressure to give 3.2 grams of a viscous yellow oil having a refractive index of nD25 =1.5538. The structure of the product was confirmed by its nuclear magnetic resonance spectrum (NMR). In addition, upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 57.91, 3.95 and 6.16 percent, respectively, as compared with the theoretical contents of 57.94, 3.94 and 6.44 percent, respectively, as calculated for the above-named compound (Compound No. 3).
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([C:10]([O:12]CC)=O)[C:5]([O:7]CC)=O.Br.[O:16]1[CH2:21][CH2:20][N:19]([C:22]([NH2:24])=[NH:23])[CH2:18][CH2:17]1>CCO>[F:3][C:4]1[C:5]([OH:7])=[N:23][C:22]([N:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)=[N:24][C:10]=1[OH:12]
Reactant: N=C(N)N1CCOCC1
Reactant: CCOC(=O)C(F)C(=O)OCC
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(N2CCOCC2)nc(O)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.6 %

Procedure:
Sodium hydride (60% in oil, 3.9 g, 96.5 mmol) was washed with hexanes in a round bottom flask under argon and cooled with an ice water bath. EtOH (100 mL) was slowly added. The resulting mixture was warmed to RT and stirred for 30 minutes. To the base mixture, diethyl 2-fluoromalonate (5.7 g, 32.2 mmol) was added, followed by morpholinoformamidine hydrobromide (6.8 g, 32.2 mmol). The mixture was heated to 90-95° C. with stirring under argon. After 12 hours, the reaction was cooled to room temperature and the EtOH was removed in vacuo. The resulting white solid was dissolved in water (25 mL) and acidified with conc. HCl to pH=3-4. A white precipitate formed which was collected on a Büchner filter, washed with water (2×50 mL), air dried on the filter, and dried in vacuo to give 5-fluoro-2-morpholinopyrimidine-4,6-diol (0.87 g, 12%). LC/MS (m/z): 216.0 (MH+), Rt 0.63 minutes.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[CH2:39]([C:43]1[NH:44][C:45]2[CH:51]=[C:50]([N:52]3[C:57](=[O:58])[CH2:56][C:55]([CH3:60])([CH3:59])[CH2:54][C:53]3=[O:61])[CH:49]=[CH:48][C:46]=2[N:47]=1)[CH2:40][CH2:41][CH3:42].CC(C)([O-])C.[K+].O>CS(C)=O>[CH2:39]([C:43]1[N:44]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]([C:20]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:18]=[N:17][N:16]=3)=[CH:5][CH:4]=2)[C:45]2[CH:51]=[C:50]([N:52]3[C:53](=[O:61])[CH2:54][C:55]([CH3:60])([CH3:59])[CH2:56][C:57]3=[O:58])[CH:49]=[CH:48][C:46]=2[N:47]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCCc1nc2ccc(N3C(=O)CC(C)(C)CC3=O)cc2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc2ccc(N3C(=O)CC(C)(C)CC3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.8 g (3.3 mMol) of 4'-bromomethyl-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl are added to a solution of 1.04 g (3.3 mMol) of 2-n-butyl-5-(3,3-dimethylglutarimido)-benzimidazole and 425 mg (3.8 mMol) of potassium tert.-butoxide in 25 ml of dimethylsulphoxide. The mixture is stirred for 3 hours at ambient temperature, then stirred into 150 ml of water, extracted three times with 30 ml of ethyl acetate, then the organic extracts are dried and concentrated by evaporation. The residue obtained is purified by column chromatography (300 g of silica gel; eluant: ethyl acetate/petroleum ether (2:1)).