Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO.C(Cl)Cl>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[N:10]4[N:9]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: Nc1ccccc1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(Nc3ncc4ccc(Nc5ccccc5)n4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
Into a Microwave vial, (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.12 g, 0.30 mmol), Aniline (0.0470 g, 0.504 mmol), 1,1′-Bis(diphenylphosphino)ferrocene (0.0050 g, 0.0091 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.0051 g, 0.0055 mmol), Sodium tert-butoxide (0.0349 g, 0.363 mmol) were added and purged under an atmosphere of Nitrogen for 10 minutes. Toluene (1.00 mL, 9.39 mmol) was then added and stirred at room temperature for one minute. The reaction was microwaved on 300 watts, 150° C. for 20 minutes. HPLC suggested 50% conversion. DCM and methanol was added and purified via flash column chromatography with DCM and methanol as eluant (10% methanol). The solvent was removed under vacuum to afford a semi-solid. The semi-solid was purified via HPLC with water and ACN as eluant (5 to 45% ACN). The collected fractions afforded N(2)-[4-(4-Methyl-piperazin-1-yl)-phenyl]-N(7)-phenyl-pyrrolo[2,1-f][1,2,4]triazine-2,7-diamine as a yellow solid. MP 152-157° C. LCMS (E/I+) 400.18 (M+H). NMR 1H (DSMO-d6)-8.99 (s, 1H), 8.68 (s, 1H), 8.17 (s, 1H), 7.52 (d, 2H, J=8.96 Hz), 7.22 (t, 1H, J=7.92 Hz), 6.78-6.85 (m, 2H), 6.73 (d, 1H, J=9.00 Hz), 6.56 (d, 1H, J=4.65 Hz), 3.00 (t, 1H, J=4.25 Hz), 2.44 (bs, 4H), 2.23 (s, 3H), 1.16 (s, 9H).
Reaction SMILES: N12CCCN=C1CCCCC2.[Cl-].[Li+].COP([CH:20]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C:21]([O:23][CH3:24])=[O:22])(OC)=O.[F:33][C:34]([F:76])([F:75])[C:35]1[CH:36]=[C:37]([C@H:45]([N:47]([CH3:74])[C:48]([N:50]2[CH2:55][CH2:54][C@:53]([NH:59][S:60]([C:62]([CH3:65])([CH3:64])[CH3:63])=[O:61])([CH2:56][CH:57]=O)[CH2:52][C@@H:51]2[C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][C:67]=2[CH3:73])=[O:49])[CH3:46])[CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1.C([O-])(O)=O.[Na+]>C(#N)C.CCOC(C)=O>[F:76][C:34]([F:33])([F:75])[C:35]1[CH:36]=[C:37]([C@H:45]([N:47]([CH3:74])[C:48]([N:50]2[CH2:55][CH2:54][C@@:53]([CH2:56][CH:57]=[C:20]([O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:27])[CH3:28])[C:21]([O:23][CH3:24])=[O:22])([NH:59][S:60]([C:62]([CH3:65])([CH3:64])[CH3:63])=[O:61])[CH2:52][C@@H:51]2[C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][C:67]=2[CH3:73])=[O:49])[CH3:46])[CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=1
Reactant: COC(=O)C(O[Si](C)(C)C(C)(C)C)P(=O)(OC)OC
Reactant: Cc1cc(F)ccc1[C@H]1C[C@](CC=O)(NS(=O)C(C)(C)C)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: COC(=O)C(=CC[C@@]1(NS(=O)C(C)(C)C)CCN(C(=O)N(C)[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2C)C1)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 7 h
Yield: 72.4 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.185 mL, 1.24 mmol, Aldrich) was added dropwise to a suspension of Lithium chloride (55.6 mg, 1.31 mmol, Aldrich) and Methyl [bis(methyloxy)phosphoryl]{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}acetate (Tetrahedron Lett. 1981, 22, 663-666) (409 mg, 1.31 mmol) in dry Acetonitrile (20 mL) and the mixture was maintained at 0° C. for 1 h. A solution of (2R,4R)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-4-{[(1,1-dimethylethyl)sulfinyl]amino}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-(2-oxoethyl)-1-piperidinecarboxamide (Intermediate 4, 585 mg, 0.898 mmol) in Acetonitrile (5 mL) was added dropwise at 0° C. The mixture was stirred for 7 hours while the temperature was allowed to increase to 25° C. Saturated aqueous NaHCO3 and EtOAc were added to the reaction mixture and the two phases were separated. The combined organic phases were dried (Na2SO4), and evaporated to dryness. The crude was purified by flash chromatography on silica with SP1 (Biotage) system (from 1:0 to 0:1 Cyclohexane/EtOAc) to give the title compound (542 mg, 0.65 mmol, 72% yield) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH2:58])[S:55][C:45]=2[C:46]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[N:47][CH:48]=1>C1COCC1>[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH:58][C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[O:9])[S:55][C:45]=2[C:46]([N:49]2[CH2:50][CH2:51][O:52][CH2:53][CH2:54]2)=[N:47][CH:48]=1
Reactant: O=C(O)C1CCOCC1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)C3CCOCC3)nc12

Procedure:
From tetrahydro-pyran-4-yl-carboxylic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 379 (M+H+, 100).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[CH2:44][CH2:43][N:35]3[C:36]4[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=4[CH:42]=[C:34]3[C:33]2=[O:45])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:29]=[C:22]3[CH2:23][N:24]([CH3:28])[CH:25]([CH3:27])[CH2:26][N:21]3[N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[CH3:28][N:24]1[CH:25]([CH3:27])[CH2:26][N:21]2[N:20]=[C:19]([NH:18][C:16]3[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=[C:12]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([N:32]5[CH2:44][CH2:43][N:35]6[C:36]7[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=7[CH:42]=[C:34]6[C:33]5=[O:45])[C:6]=4[CH2:5][OH:4])[CH:17]=3)[CH:29]=[C:22]2[CH2:23]1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CC(C)N(C)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC1Cn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)cc2CN1C
Temperature: 30 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
To a solution of 250f (75 mg, 0.123 mmol) in THF/i-propanol/water (4/2/2 mL) was added lithium hydroxide (15 mg, 0.62 mmol). The mixture was stirred at 30° C. for 1 h. After the reaction was complete, the mixture was evaporated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 250 as a white solid (40 mg, 57%). MS-ESI: [M+H]+ 569.3. 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J=5.0 Hz, 1H), 7.96 (bs, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.43 (s, 1H), 7.36 (d, J=5.0 Hz, 1H), 6.91 (s, 1H), 5.71 (s, 1H), 5.03 (t, J=3.5 Hz, 1H), 4.65-4.62 (m, 1H), 4.52-4.50 (m, 1H), 4.35-4.33 (m, 1H), 4.17-4.05 (m, 3H), 3.91-3.88 (m, 2H), 3.73-3.71 (m, 1H), 3.71 (s, 3H), 3.55-3.52 (m, 1H), 2.90-2.87 (m, 1H), 2.64-2.58 (m, 4H), 2.43 (s, 3H), 1.93-1.90 (m, 2H), 1.81-1.80 (m, 2H), 1.24 (d, J=6.5 Hz, 3H).
Reaction SMILES: O[CH2:2][C:3]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][C:6]([CH:13]([CH3:15])[CH3:14])=[CH:5][CH:4]=1.N1C=CC=CC=1.CS([Cl:26])(=O)=O>ClCCl>[Cl:26][CH2:2][C:3]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][C:6]([CH:13]([CH3:15])[CH3:14])=[CH:5][CH:4]=1
Reactant: COc1cc(C(C)C)ccc(CO)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(C)C)ccc(CCl)c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
7-hydroxymethyl-4-isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one (2.81 g, 13.5 mmol) and pyridine (1.31 ml, 16.2 mmol) were dissolved in dichloromethane (5 ml) and cooled to 0° C. The solution was stirred while methanesulfonyl chloride (1.25 ml, 16.2 mmol) was added thereto. After stirred at 0° C. for 2 hours, the reaction solution was slowly brought back to room temperature. After 2 hours, the reaction solution was diluted with dichloromethane, washed with aqueous saturated sodium bicarbonate, water and 2N HCl, then dried over sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (1:1)] to give 1.38 g of 7-chloromethyl-4-isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one (yield: 45%) as a pale yellow oil. This oil was solidified when allowed to stand at room temperature.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.Br[C:36]1[CH:41]=[CH:40][N:39]=[C:38]([OH:42])[CH:37]=1>>[OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:15]=[CH:16][C:17]([C:36]3[CH:41]=[CH:40][N:39]=[C:38]([OH:42])[CH:37]=3)=[CH:18][CH:19]=2)[CH3:13])[CH2:7][CH2:6]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: Oc1cc(Br)ccn1
Product: C[C@@H](c1ccc(-c2ccnc(O)c2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-2-hydroxypyridine following a procedure analogous to that described in Example 30 Step 2. LC-MS Method 2 tR=1.019 min, m/z=865.4; 1H NMR (CDCl3) 1.29-1.40 (m, 1H), 1.49 (d, 3H), 1.60-1.72 (m, 1H), 1.83-2.01 (m, 3H), 2.18 (m, 1H), 2.21-2.37 (m, 2H), 2.88 (m, 1H), 3.51 (m, 2H), 5.63 (m, 1H), 6.41 (d, 1H), 6.68 (s, 1H), 6.90 (d, 2H), 7.21-7.33 (m, 7H), 7.39 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[C:6]=1[F:23])[CH3:2].Br[C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH2:32][CH3:33])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([CH2:32][CH3:33])[CH:31]=3)[C:13]=2[CH3:22])[C:6]=1[F:23])[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1F
Reactant: CCc1cncc(Br)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cncc(CC)c3)c3cc(Cl)ccc23)c1F

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-2-fluoro-benzoic acid ethyl ester and 3-bromo-5-ethylpyridine.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:10])[CH:8]=[CH2:9])[CH2:3]1.O=[C:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1.CCN(CC)CC.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[C:7]([NH:6][CH:4]1[CH2:5][N:2]([CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]2)[CH2:3]1)(=[O:10])[CH:8]=[CH2:9]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: C=CC(=O)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)NC1CN(C2CN(C(=O)OC(C)(C)C)C2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.4 %

Procedure:
To a mixture of N-(azetidin-3-yl)acrylamide hydrochloride (500 mg, 3.40 mmol), tert-butyl 3-oxoazetidine-1-carboxylate (684 mg, 4.0 mmol), Et3N (343 mg, 3.40 mmol) and AcOH (100 mg, 0.167 mmol) in DCM (20 mL), NaBH(OAc)3 (2.16 g, 10.2 mmol) was added, and the resulting mixture was stirred at room temperature for 16 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=100:1 to 20:1) to afford the desired product (300 mg, 31% yield).
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][C:29]([C:40]([O:42][CH2:43][CH3:44])=[O:41])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.Cl.O>CO>[OH:1][CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCOC(=O)C(CCC1(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCCCC1)(C(=O)OCC)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C(CCC1(CCO)CCCCC1)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.1 %

Procedure:
To a solution of triethyl 3-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]-1,1,1-propanetricarboxylate (470 mg) in methanol (10 mL)/tetrahydrofuran (5 mL) was added 3N hydrochloric acid (2.5 mL) at room temperature. After stirring the solution at room temperature for 4 hours, water was added to the solution, and it was concentrated under reduced pressure. The solution was extracted with ethyl acetate. The organic layer was washed in turn with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=1:1) to give the title compound (230 mg).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH:13]([CH3:15])[CH3:14])[CH:3]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(I)cc1OC(C)C
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(F)cc2)cc1OC(C)C
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A mixture of methyl 4-iodo-2-isopropoxybenzoate (7.50 g), (4-fluorophenyl)boronic acid (6.56 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (1.44 g), a 2 M aqueous sodium carbonate solution (35.1 mL), tris(dibenzylideneacetone)dipalladium(0) (1.50 g), and toluene (50 mL) was stirred at 100 C for 2 hours in an argon atmosphere. The reaction mixture was allowed to cool to room temperature. Then, the organic layer was separated and passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (6.61 g).
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]2[CH2:11][C:10]([OH:15])([C:12](N)=[O:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:22].[Na+]>C(O)C.O>[C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]2[CH2:11][C:10]([OH:15])([C:12]([OH:22])=[O:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: NC(=O)C1(O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)C1(O)CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
1-(Diphenylmethyl)-3-hydroxyazetidine-3-carboxamide (1.1 g, 3.90 mmol) was treated with 10% sodium hydroxide in ethanol (15 mL) and water (2 mL) at reflux for 2 h and then was concentrated in vacuo. The residue was neutralized with 1 N hydrochloric acid (pH ˜7) and the precipitate was collected by filtration and lyophilized to afford 1-(diphenylmethyl)-3-hydroxyazetidine-3-carboxylic acid (assume 3.90 mmol) which was used without further purification: 1H NMR (400 MHz, d6-DMSO): 7.45-7.40 (m, 4H), 7.31-7.25 (m, 4H), 7.21-7.15 (m, 2H), 4.52 (s, 1H), 3.46 (dd, 2H), 3.02 (dd, 2H); MS (EI) for C17H17NO3: 284 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH3:12])[C:8]([C:13]#[N:14])=[CH:7][C:3]=1C(O)=O.C1CCCCC1>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:7][C:8]([C:13]#[N:14])=[C:9]([S:11][CH3:12])[N:10]=1
Reactant: CSc1nc(N)c(C(=O)O)cc1C#N
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: C1CCCCC1
Product: CSc1nc(N)ccc1C#N
Yield: 55.9 %

Procedure:
A solution of 3 g (14.3 mmol) of 2-amino-5-cyano-6-(methylthio)nicotinic acid in 30 ml of diphenyl ether is stirred at 255° C. for 60 hours. After returning to room temperature, 60 ml of cyclohexane is added and the reaction medium is triturated for 30 minutes. The solid formed is filtered and then rinsed thoroughly with cyclohexane. The solid is redissolved in ethyl acetate and then the organic phase is washed with water, dried on magnesium sulfate, filtered and then evaporated to yield 1.32 g (55%) of 6-amino-2-(methylthio)nicotinonitrile in the form of a brown powder.
Reaction SMILES: C(O[C:6]([N:8]([CH3:19])[C:9]1([CH2:12][CH2:13][C:14](OCC)=[O:15])[CH2:11][CH2:10]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:6][N:8]([CH3:19])[C:9]1([CH2:12][CH2:13][CH2:14][OH:15])[CH2:11][CH2:10]1
Reactant: CCOC(=O)CCC1(N(C)C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C1(CCCO)CC1
Temperature: 5 °C

Procedure:
8.5 g of the product obtained in Step 3 dissolved in 100 ml of tetrahydrofaran are added to 6.9 g of lithium aluminium hydride suspended in 200 ml of tetrahydrofuran. After refluxing for 16 hours, the mixture is cooled to 5° C. and hydrolysed with, in succession, 6.9 ml of water, 6.9 ml of 4N sodium hydroxide solution and then 20.7 ml of water. After customary treatment, chromatography of the residue over silica gel allows the expected product to be isolated (liquid).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[Br:35][CH:36]([CH3:40])[C:37](Br)=[O:38].CCN(CC)CC.CCOC(C)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:25]([NH:31][C:37](=[O:38])[CH:36]([Br:35])[CH3:40])=[CH:26][CH:27]=[CH:28][C:29]=3[CH3:30])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(Br)C(=O)Br
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)C(C)Br)c1
Yield: 66.9 %

Procedure:
Following the procedure described for Example 234, step a, reaction of {[4-(6′-amino-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (65 mg, 0.126 mmol, as prepared in Example 25, step c), racemic 2-bromo-propionyl bromide (19 μL, 0.189 mmol), and Et3N (52 μL, 0.378 mmol) in DCM (2 mL) afforded 55 mg (67%) of the title compound as a glassy solid after chromatography (PTLC, 10% EtOAc in DCM, 2×1500μ SiO2 plate). ESI-MS (m/z): Calcd. for C27H30BrN3O5S3: 652.0 (M+H); found: 653.6, 651.7, 553.9, 552.0 (M−Boc).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[CH3:10][O:9][C:4]1[CH:3]=[C:2]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: COc1cc(Br)ccc1N
Reactant: c1nc[nH]n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(-n2cncn2)ccc1N
Temperature: 110 °C
Yield: 47 %

Procedure:
A mixture of 4-bromo-2-methoxyaniline (208 mg, 1.03 mmol), 1,2,4-triazole (80 mg, 1.13 mmol), Cs2CO3 (0.67 g, 2.06 mmol) and CuI (20 mg, 0.103 mmol) in DMF was heated at 110° C. for 20 h. Further portions of 1,2,4-triazole (0.1 g, 1.44 mmol), Cs2CO3 (0.67 g, 2.06 mmol) and CuI (0.1 g, 0.52 mmol) were added and the mixture was heated a further 72 h at 110° C. The mixture was cooled, diluted with ethyl acetate (20 mL) and washed with water (2×20 mL). The combined aqueous washes were re-extracted with ethyl acetate (20 mL). The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% ethyl acetate/isohexane) gave 2-methoxy-4-(1H-1,2,4-triazol-1-yl)aniline as a light red solid (92 mg, 47%). 1H NMR (400 MHz, CDCl3): δ 8.41 (s, 1H); 8.05 (s, 1H); 7.11 (d, J=2.3, 1H); 6.99 (dd, J=8.3, 2.3, 1H); 6.74 (d, J=8.3, 1H); 3.97 (s, 2H); 3.92 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[NH:28]1[C:32]2=[N:33][CH:34]=[C:35](B(O)O)[CH:36]=[C:31]2[CH:30]=[CH:29]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:35]4[CH:36]=[C:31]5[CH:30]=[CH:29][NH:28][C:32]5=[N:33][CH:34]=4)[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[N:10]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: OB(O)c1cnc2[nH]ccc2c1
Reactant: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(-c4cnc5[nH]ccc5c4)nc3s2)CC1

Procedure:
5-Chloro-2-((4-methylsulfonylpiperazin-1-yl)methyl)-7-morpholinothiazolo[5,4-d]pyrimidine, 1H-pyrrolo[2,3-b]pyridin-5-yl boronic acid (1.2 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate (3 eq) and acetonitrile. The solution was microwaved at 130° C. for 15 minutes. Acetonitrile was added and the solution was filtered. The resulting organic layer was purified by reverse phase silica gel chromatography to give the product 116.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3C(C)=NO[N:16]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CC[C@H](OC(=O)C(F)(F)F)C2)C2[N:39]=[N:38][NH:37][C:35]=2N=1)(C)(C)C.ClCC1N(C)N=NN=1>>[C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:37]([CH3:35])[N:38]=[N:39][N:16]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Reactant: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Agent: Cn1nnnc1CCl
Product: Cn1nnnc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 5-(chloromethyl)-1-methyl-1H-tetrazole and isolated as yellow gum. MS (m/e): 359.3 (MH+).