Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5](CC2C=NC(C)=NC=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.[CH3:31][N:32]1[C:40]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[N:34]=[C:33]1[CH:41]=O>>[CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:41][C:33]2[N:32]([CH3:31])[C:40]3[CH:39]=[CH:38][N:37]=[CH:36][C:35]=3[N:34]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Reactant: Cn1c(C=O)nc2cnccc21
Product: C[C@@H]1CN(Cc2nc3cnccc3n2C)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-methyl-1H-imidazo[4,5-c]pyridine-2-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 10.83 (brs 1H), 9.01 (s, 1H), 8.41 (d, J=15.8 Hz, 1H), 7.98 (s, 1H), 7.30 (d, J=4.98 Hz, 1H), 4.79-4.75 (m, 1H), 4.13-4.06 (m, 3H), 4.00-3.96 (s, 4H), 3.60-3.52 (m, 2H), 3.30 (t, J=8.7 Hz, 1H), 3.07 (d, J=9.9 Hz, 1H), 2.92-2.89 (m, 1H), 2.82-2.77 (m, 1H), 2.48-2.45 (m, 1H), 2.36-2.27 (m, 2H), 2.19-2.17 (m, 1H), 1.89-1.79 (m, 2H), 1.23 (d, J=6.6 Hz, 3H). MS: (M+H m/z 449.2).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:36]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[N:36]1([C:42]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[O:17][C:18]5[C:23]([C:24](=[O:26])[CH:25]=4)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=5[N:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)=[O:15])=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Reactant: O=C(Cl)N1CCOCC1
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCN(C(=O)N5CCOCC5)CC4)cc3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 431 and commercially available morpholine-4-carbonyl chloride (Aldrich) via the parallel synthesis described above. MS−base peak at m/z=591 by positive ion CI.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:52])[CH2:48][CH2:49][CH2:50][CH3:51])[CH:43]=[CH:44][CH:45]=2)=[N:8]1>Cl.O1CCOCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:52])[CH2:48][CH2:49][CH2:50][CH3:51])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: CCCCC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCC(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
N-(3-{1-Perhydro-2H-pyran-2-yl-5[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenyl)pentanamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature for 4 h. After neutralization with aqueous NaHCO3, the crude product was extracted in ethyl acetate and purified by preparative HPLC (0.046 g, 51.5% yield over 2 steps): 1H NMR (CD3OD) δ 8.65 (t, 1H), 8.23 (br s, 1H), 8.07 (t, 1H), 8.0 (dd, 1H), 7.66 (dd, 2H), 7.60 (dd, 1H), 7.41 (t, 1H), 2.34 (t, 2H), 1.63 (quintet, 2H), 1.35 (sextet, 2H), 0.90 (t, 3H); ES-MS (m/z) 361 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[CH:19]=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(O)C>[C:1]1([C:7]2[C:8]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:35](=[O:37])[CH3:36])=[CH:22][CH:21]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[CH:19]=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)NCc1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 4-3 (0.02 g, 0.06 mMol) and triethylamine (0.02 mL, 0.2 mMol) in absolute ethanol (0.5 mL) was added acetic anhydride (0.02 mL, 0.2 mMol). The reaction was complete after 10 minutes and was purified directly on a C18 reverse phase HPLC to give 18-1 as a solid. LC/MS (M+1) calculated: 394.5; observed: 394.2
Reaction SMILES: C(OC([CH:8]([NH2:37])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]1[C:19](=[O:20])[CH2:18][N:17]([N:21]=[CH:22][C:23]2[O:27][C:26]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=3)=[CH:25][CH:24]=2)[C:16]1=[O:36])=[O:14])=O)(C)(C)C>Cl.C(O)(=O)C>[ClH:34].[NH2:37][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]1[C:19](=[O:20])[CH2:18][N:17]([N:21]=[CH:22][C:23]2[O:27][C:26]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=3)=[CH:25][CH:24]=2)[C:16]1=[O:36])=[O:14]
Reactant: CC(C)(C)OC(=O)C(N)CCCCC(=O)N1C(=O)CN(N=Cc2ccc(-c3ccc(Cl)c(Cl)c3)o2)C1=O
Agent: Cl
Solvent: CC(=O)O
Product: NCCCCCC(=O)N1C(=O)CN(N=Cc2ccc(-c3ccc(Cl)c(Cl)c3)o2)C1=O
Reaction time: 2 h

Procedure:
The 3(t-butoxycarbonyl-aminohexanoyl)-1-{[5-(3,4-dichlorophenyl)furfurylidene]amino}hydantoin (29 g, 0.052 mole) was added to 3% hydrochloric acid/acetic acid (650 ml) and stirred for 2 hours. The mixture was filtered and the collected solid was washed with nitromethane and ether, then heated to boiling in nitromethane and filtered again, yielding 10 g (38%, 28% overall), m.p. 205°-207°.
Reaction SMILES: [CH2:1]([C:8]1([C:23]([OH:25])=O)[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][C:28](=[O:34])[C@H:29]([C@@H:31]([CH3:33])[OH:32])[NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:16]([O:15][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C:8]1([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:23](=[O:25])[NH:30][C@@H:29]([C@H:31]([OH:32])[CH3:33])[C:28]([O:27][CH3:26])=[O:34])=[O:14])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: O=C(OCc1ccccc1)N1CCCC1(Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)C1(Cc2ccccc2)CCCN1C(=O)OCc1ccccc1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
To a suspension of compound 3 (1.0 g, 2.94 mmol), L-threonine methyl ester (471 mg, 3.53 mmol) in DMF (20 mL) was added HATU (1.12 g, 2.94 mmol) and DIPEA (1.58 mL, 8.84 mmol) at 5° C. The reaction mixture was stirred at RT for 16 h. It was diluted with EtOAc (150 mL) and washed with water (2×30 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography 50% EtOAc/Hexane as eluent to yield compound 4 (1.0 g, 74%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([F:29])=[C:12]([CH:28]=2)[CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C@@H:15]2[CH3:27])[CH:5]=[CH:4][N:3]=1.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH2:40])[CH:34]=[C:35]([F:37])[CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:38][CH2:39][NH:40][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([F:29])=[C:12]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C@@H:15]3[CH3:27])[CH:28]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cc(-c2ccnc(Cl)n2)ccc1F
Reactant: NCCc1cc(F)cc(F)c1
Product: C[C@H]1CNCCN1Cc1cc(-c2ccnc(NCCc3cc(F)cc(F)c3)n2)ccc1F

Procedure:
Intermediate 166 from above was coupled with 2-(3,5-difluorophenyl)ethanamine following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 442. 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.31 ppm) δ 8.8 (d, 1H) 8.4 (d, 1H) 8.3 (d, 1H) 7.7 (d, 1H), 7.5 (t, 1H), 7.0 (d, 2H) 6.7 (d, 1H), 3.8-3.7 (m, 3H) 3.6-3.5 (m, 8H), 3.0 (t, 2H), 1.7 (d, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](I)[CH:3]=1.[Cu](C#N)[C:14]#[N:15].[Cl-].[NH4+].N>CN1CCCC1=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]#[N:15])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1I
Reactant: N#C[Cu]C#N
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(Br)cc1C#N
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a mixture of methyl 4-bromo-2-iodobenzoate (3.52 g) described in Preparation Example 74 and copper cyanide (1.16 g) was added N-methylpyrrolidone (21 mL), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was cooled, a solution of saturated aqueous ammonium chloride solution and aqueous ammonia (1:1) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a solution of saturated aqueous ammonium chloride solution and aqueous ammonia (1:1), saturated aqueous ammonium chloride solution, and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated to give the title compound (2.39 g).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]3[CH2:18][CH2:17][CH2:16][C@H:15](O)[C:10]=3[CH:11]=2)[CH2:6]1)=[O:4].C1C=CC(P([N:36]=[N+:37]=[N-:38])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1.Cl>C1(C)C=CC=CC=1>[N:36]([C@H:15]1[C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][C:9]=2[CH2:18][CH2:17][CH2:16]1)[CH2:6][N:5]([C:3](=[O:4])[C:2]([F:21])([F:20])[F:1])[CH2:14][CH2:13]3)=[N+:37]=[N-:38]
Reactant: O=C(N1CCc2cc3c(cc2C1)CCC[C@@H]3O)C(F)(F)F
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=N[C@@H]1CCCc2cc3c(cc21)CCN(C(=O)C(F)(F)F)C3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-2,2,2-trifluoro-1-(6-hydroxy-3,4,6,7,8,9-hexahydrobenzo[g]isoquinolin-2(1H)-yl)ethanone (3.0 g, 10 mmol) in 30 mL of toluene at −10° C. was added DPPA (2.6 mL, 12 mmol). To this stirred solution was then added DBU (1.8 mL, 12 mmol) dropwise while keeping the temperature below 0° C. After stirring at room temperature overnight, 7 mL of 10% HCl was added and the resulting solution was evaporated to dryness and directly submitted to flash chomatography (SiO2, hexane/EtOAc=100:10 to 100:15 to 100:20) to afford (R)-1-(6-azido-3,4,6,7,8,9-hexahydrobenzo[g]-isoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone as a colorless oil which was directly used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[C:10]1([Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:7])=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
To a stirred solution of 6-chloronicotinaldehyde (1.0 g, 7.1 mmol) in anhydrous tetrahydrofuran (10 mL) was added phenylmagnesium bromide solution (3M in diethyl ether, 2.6 mL, 7.8 mmol) dropwise at −78° C. under argon. After the reaction mixture was stirred at −78° C. for 10 min and 0° C. for 20 min, saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×10 mL). The combined ethyl acetate extracts were dried (Na2SO4) and concentrated to give (6-chloropyridin-3-yl)(phenyl)methanol (1.5 g, 6.8 mmol, 96% yield) as a yellow liquid. MS found: (M+H)+=220.09.
Reaction SMILES: C[O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br.CO.C(=O)([O-])O.[Na+]>ClCCl>[OH:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)Cc1coc2c(OC)cccc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1coc2c(O)cccc12
Temperature: -78 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
Methyl (7-methoxybenzofuran-3-yl)acetate (12.37 g) was dissolved in dichloromethane (50 ml) and the solution was cooled to −78° C. To this solution, boron tribromide (1.0 M, 120 ml) was added dropwise for 50 minutes. Thereafter, the temperature was raised to room temperature and the reaction solution was stirred at this temperature for 3 hours. After completion of the reaction, the reaction solution was cooled to −78° C. and methanol (100 ml) was added thereto. After neutralizing the reaction mixture by adding sodium hydrogen carbonate, the resulting solution was filtered. The filtrate was concentrated and poured into water layer (300 ml) and the resultant was extracted twice with ether (150 ml). After combining the organic layers, the resultant was washed with saturated brine and dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=2/1) using silica gel to obtain the desired compound (10.53 g, yield: 91%).
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([F:26])[CH:14]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[C:35]([CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[NH:33][CH:32]=[CH:31]2>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:31]2[C:30]3[C:34](=[C:35]([CH2:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH:36]=[C:28]([F:27])[CH:29]=3)[NH:33][CH:32]=2)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([F:26])[CH:14]=1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Reactant: N#CC1CC1C(O)c1ccc(Cl)cc1F
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc(Cl)cc3F)C3CC3C#N)c[nH]c12

Procedure:
471 mg (2.13 mmol) of indium(III) chloride and 0.25 ml (3.19 mmol) of trifluoroacetic acid were added to 400 mg (1.77 mmol) of the compound from Example 165A and 483 mg (2.13 mmol) of the compound from Example 87A under argon in 18 ml of dichloromethane, and the mixture was heated under reflux for 3 days. It was concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) and another RP18 separation with acetonitrile/water 55:45 to result in 131 mg (17% of theory) of diastereomer 1 and 127 mg (17% of theory) of diastereomer 2 of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][CH:9]1[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].B#B.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][CH:9]1[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: B#B
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1CO
Temperature: 25 °C

Procedure:
To a stirred solution of 21.6 g. (0.10 mol.) of N-t-butoxycarbonyl-DL-proline in 100 ml. of dry tetrahydrofuran at room temperature is added 50 ml. of a 1 molar diborane solution in tetrahydrofuran at such a rate that the temperature of the reaction mixture is maintained at 25°-30°. After the addition is complete, the reaction mixture is stirred at room temperature for an additional hour. Water is then cautiously added to the reaction mixture, the tetrahydrofuran is removed in vacuo, the residue is diluted with ether, and this solution is washed thoroughly with 5% aqueous sodium hydroxide. The ether solution is dried and concentrated in vacuo to obtain 1-(t-butoxycarbonyl)-2-pyrrolidinemethanol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][F:18])=[CH:11][CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[S:20]([NH2:30])(=[O:29])([C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)=[O:21]>C(O)(C)C.C(O)(C(F)(F)F)=O>[NH2:30][S:20]([C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][F:18])=[CH:11][CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)=[CH:26][CH:27]=1)(=[O:21])=[O:29]
Reactant: FCCCc1ccc(Nc2nc(Cl)ncc2F)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: NS(=O)(=O)c1ccc(Nc2ncc(F)c(Nc3ccc(CCCF)cc3)n2)cc1
Temperature: 100 °C

Procedure:
2-Chloro-5-fluoro-N4-[4-(3-fluoropropyl)phenyl]-4-pyrimidineamine (100 mg) and sulfanilamide (100 mg) were suspended in isopropanol (1 mL) and TFA (5 drops). The solution was heated at 100° C. overnight. The solution was evaporated and purified by flash column chromatography (2.0 M NH3/MeOH in dichloromethane=1-3%) and recrystallized from ethyl acetate to give N2-(4-aminosulfonylphenyl)-5-fluoro-N4-[4-(3-fluoropropyl)phenyl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 1.89-2.02 (m, 2H), 2.67 (t, J=8.1 Hz, 2H), 4.38 (t, J=5.7 Hz, 1H), 4.53 (t, J=5.7 Hz, 1H), 7.11 (br, 2H), 7.19 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 7.65 (d, J=8.1 Hz, 2H), 7.80 (d, J=8.7 Hz, 2H), 8.12 (d, J=3.9 Hz, 1H), 9.38 (br, 1H), 9.57 (br, 1H); 19F NMR (282 MHz, DMSO-d6): δ −201.79; LCMS: purity: 91.96%; MS (m/e): 420.74 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=C)[CH2:10][CH:9]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22](C3C=CC4C(=CC=C(C5NC(C6CCCN6C(=O)C(NC(OC)=O)C(C)C)=NC=5)C=4)C=3)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:56][O:57][C:58](=[O:88])[NH:59][CH:60]([C:64]([N:66]1[CH2:70][C:69](=[CH2:71])[CH2:68][CH:67]1[C:72]1[NH:73][C:74]([C:77]2[CH:86]=[CH:85][C:84]3[C:79](=[CH:80][CH:81]=[C:82](Br)[CH:83]=3)[CH:78]=2)=[CH:75][N:76]=1)=[O:65])[CH:61]([CH3:63])[CH3:62].C(OC(N1CCCC1C1NC(C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=CN=1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:82]3[CH:81]=[CH:80][C:79]4[C:84](=[CH:85][CH:86]=[C:77]([C:74]5[NH:73][C:72]([CH:67]6[CH2:68][C:69](=[CH2:71])[CH2:70][N:66]6[C:64](=[O:65])[CH:60]([NH:59][C:58]([O:57][CH3:56])=[O:88])[CH:61]([CH3:63])[CH3:62])=[N:76][CH:75]=5)[CH:78]=4)[CH:83]=3)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C1CC(c2ncc(-c3ccc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: C=C1CC(c2ncc(-c3ccc4cc(Br)ccc4c3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1
Agent: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Product: C=C1CC(c2ncc(-c3ccc4cc(-c5ccc(-c6cnc(C7CCCN7C(=O)OC(C)(C)C)[nH]6)cc5)ccc4c3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1

Procedure:
This compound was synthesized using the same method used to make 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester using (1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-4-methylene-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.200 g, 0.391 mmol) and 2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.223 g, 0.508 mmol) to give 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-methylene-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.040 g, 0.054 mmol). LCMS-ESI+: calc'd for C43H49N7O5: 743.38 (M+); Found: 744.73 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:13])[C:9](=O)[CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N:20]#[C:21][NH2:22].[OH-].[Na+]>O1CCCC1.O>[NH2:22][C:21]1[O:11][CH:10]=[C:9]([CH:8]([C:6]2[CH:5]=[CH:4][C:3]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:2]([F:1])[CH:7]=2)[CH3:13])[N:20]=1
Reactant: N#CN
Reactant: CC(C(=O)CO)c1ccc(-c2ccccc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1coc(N)n1
Reaction time: 8 h

Procedure:
To 3-(2-Fluoro-4-biphenylyl)-2-oxo-1-butanol (3.57 g, 13.8 mmol) in tetrahydrofuran (35 ml) was added cyanamide (3.65 g, 77.6 mmol) in water and 2N-sodium hydroxide to pH 10. After the addition, the mixture was stirred overnight, then cyanamide (3.65 g, 77.6 mmol) was added to the reaction mixture to pH 10, the mixture was stirred overnight. The reaction mixture was extracted with ether and the extracts were washed with water, dried over and evaporated under reduced pressure to a residue, which was chromatographed to afford 2-Amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)oxazole as crystalline material (1.05 g, 27% yield): mp 150.5°-151.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[CH:12][C:11]([C:21]3([OH:31])[CH2:30][CH2:29][C:24]4(OCC[O:25]4)[CH2:23][CH2:22]3)=[N:10]2)=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1.Cl>[OH:31][C:21]1([C:11]2[CH:12]=[C:13]([C:14]3[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:10]=2)[CH2:30][CH2:29][C:24](=[O:25])[CH2:23][CH2:22]1
Reactant: COc1ccc(-n2nc(C3(O)CCC4(CC3)OCCO4)cc2-c2ccc(C)nc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C3(O)CCC(=O)CC3)cc2-c2ccc(C)nc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of 8-(1-(4-methoxyphenyl)-5-(6-methylpyridin-3-yl)-1H-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol (Reference Example 31) (128.8 mg, 0.30 mmol) in tetrahydrofuran (0.6 mL), 6 M hydrochloric acid (1.2 mL) was added, and the obtained solution was stirred at room temperature for 3 hours. The reaction solution was cooled in ice, and 50% aqueous sodium hydroxide solution was added dropwise thereto at 0° C. until it became basic. Thereafter, the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the title compound (109.5 mg, 0.29 mmol, 96%) as an amorphous product.