Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.Br.C(OP([N:14]1[CH2:27][CH2:26][N:25]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:24][CH2:23][CH2:22][CH:21]([F:40])[CH2:20][CH2:19][CH2:18][N:17]([S:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[N+:50]([O-:52])=[O:51])(=[O:43])=[O:42])[CH2:16][CH2:15]1)(=O)OCC)C>C(OCC)C>[F:40][CH:21]1[CH2:22][CH2:23][CH2:24][N:25]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-:39])=[O:38])(=[O:29])=[O:30])[CH2:26][CH2:27][NH:14][CH2:15][CH2:16][N:17]([S:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[N+:50]([O-:52])=[O:51])(=[O:42])=[O:43])[CH2:18][CH2:19][CH2:20]1
Reactant: CCOP(=O)(OCC)N1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCCC(F)CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCCC(F)CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.3 %

Procedure:
Acetic acid (15 ml), saturated with anhydrous hydrogen bromide (gas) was added to [11-fluoro-1,7-bis(2-nitro-benzenesulfonyl)-1,4,7-triaza-cyclotetradec-4-yl]-phosphonic acid diethyl ester (560 mg, 0.77 mmol) contained in round-bottomed flask closed by glass stopper. The resulting mixture was allowed to stir for 18 hours at room temperature and then diethyl ether (50 ml) was added. The white precipitate which formed was allowed to settle to the bottom of the flask and the diethyl ether solution was decanted off. This white solid was re-dissolved in methanol, stirred with K2CO3 (solid) for 30 mins then diluted with 100-ml ethyl acetate, and the solids were removed by filtration. Evaporation of the filtrates gave the title compound (454 mg, 100%) as white foam.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.C1(C)C=CC(S(O)(=O)=[O:19])=CC=1.[NH:23]1C[CH2:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[CH2:26]1[C:1]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][CH2:3][C:2]=2[NH:23][C:24](=[O:19])[CH2:25]1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1CCc2ccccc2C1
Solvent: Cc1ccccc1
Product: O=C1CCC2=C(CCc3ccccc32)N1

Procedure:
2-Tetralone (25 g, 171 mmol) was added to a solution of p-toluenesulfonic acid (3.2 g, 16.8 mmol) and pyrrolidine (15 g, 211 mmol) in toluene (250 ml) and the solution was heated under reflux with a Dean-Stark apparatus. When no more water was distilled off, the solvent was removed to afford the enamine as an yellow oil. Acrylamide (46 g, 647 mmol) was added in one portion to the stirred oil, and the resulting mixture was heated at 100° C. for 2 hours. Water (100 ml) was added to the reaction mixture and pH was adjusted to 3-4 with concentrated hydrochloric acid. The solution was extracted with chloroform and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate, and dried to afford 1,4,5,6-tetrahydro-2H-benzo[f]quinolin-3-one (28 g, 140 mmol, 82%) as white crystals.
Reaction SMILES: [CH:1]([P:5]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:6][CH2:7][CH2:8][OH:9])([CH2:3][CH3:4])[CH3:2].[OH:14]CCCP(C(CC)C)C(CC)C.OO.C=CCC>C(O)(C)C.C(=S)=S>[CH:1]([P:5](=[O:14])([CH2:6][CH2:7][CH2:8][OH:9])[CH2:10][CH2:11][CH2:12][OH:13])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)P(CCCO)CCCO
Reactant: CCC(C)P(CCCO)C(C)CC
Agent: C=CCC
Agent: OO
Solvent: S=C=S
Solvent: CC(C)O
Product: CCC(C)P(=O)(CCCO)CCCO

Procedure:
The residual product is believed to contain both s-butyl bis(3-hydroxypropyl) phosphine and 3-hydroxypropyl di-s-butyl phosphine. It is dissolved in an equal volume of isopropanol and oxidized with 30% hydrogen peroxide in an equal volume of isopropanol as described above in Example I until a negative carbon disulfide reading is obtained. The solution of oxidized phosphine is concentrated under reduced pressure to yield a syrupy yellow liquid weighing 555.6 g (99.2% yield on oxidation or a yield of 62.5% based on the starting butene).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li:9]CCCC.CCCCCC>C1COCC1>[Li:9][C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: C#Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]C#Cc1ccccc1
Temperature: 25 °C
Yield: 45 %

Procedure:
A solution of fresh LiC≡CPh was prepared by reacting 0.057 mL of phenylacetylene (0.525 mmol) and 0.298 mL of 1.5M nBuLi in hexane solution (0.462 mmol) in 15 mL of dry THF at −78° C. for 0.5 hour. The resulting solution was added drop wise via cannula to a solution of 160 mg of Ir(ppy)2(CNtBu)OTf (0.22 mmol) in 10 mL of dry THF at −78° C. The mixture was reacted for 1 h at −78° C. and the temperature was raised to RT over 2 hours. The solvent was removed under reduced pressure and the crude was extracted with diethylether. 67.8 mg of Ir(ppy)2(CNtBu)(CCPh) is obtained (45% yield).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=4)[NH2:19])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C([N:25]([CH2:28]C)CC)C.ClC(Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.[NH4+].[OH-]>C1COCC1.C(Cl)Cl>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:17]=[C:18]([NH:19][C:28]([NH2:25])=[O:33])[CH:20]=[CH:21][CH:22]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Reactant: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccc(N)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccc(NC(N)=O)c1
Reaction time: 0.25 h

Procedure:
To a solution of 3-[(1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]aniline (16 mg, 0.055 mmol, from Example 43, Step 1) in THF (1.6 mL) and DCM (0.64 mL) were added triethylamine (23 μL, 0.16 mmol) and triphosgene (16 mg, 0.055 mmol, Aldrich). The mixture was stirred for 15 minutes, then NH4OH solution (43 μL, 14.8 N) was added. After stirring for 30 minutes, the product was precipitated as a yellow solid, re-dissolved in MeOH and filtered, then purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (5.5 mg, 30%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:21])[C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:5]=[O:6].O.[BH4-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([F:21])[C:9]=1[O:10][Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)[Si](Oc1c(F)cc(C=O)cc1F)(C(C)C)C(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)[Si](Oc1c(F)cc(CO)cc1F)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
35.0 g (111 mmol) of 3,5-difluoro-4-triisopropylsilanyloxybenzaldehyde are introduced into 150 ml of water and 40 ml of methanol, cooled to 0° C. and, after addition of 8.42 g (222 mmol) of sodium borohydride in portions, stirred at RT overnight. The mixture is cautiously acidified with 1 N hydrochloric acid and extracted with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulfate, and the solvent is distilled out in vacuo. Chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 4:1) results in 29.5 g (93.2 mmol, 84% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O.[Si](C#N)(C)(C)C.[N:26]1([C:31](N2C=CN=C2)=[O:32])C=CN=[CH:27]1>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:14]([C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[F:11])[CH2:27][NH:26][C:31]3=[O:32])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=Cc1ccccc1F
Agent: C[Si](C)(C)C#N
Product: O=C1NCC(c2ccccc2F)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 2-fluorobenzaldehyde (0.496 g, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (1.04 mL, 7.5 mmol), di-(imidazol-1-yl)methanone (0.662, 4.08 mmol) as described in method 2.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:13])=O>C(Cl)Cl>[Br:1][C:2]1[O:6][C:5]([C:7]([Cl:13])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Br)o1
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Br)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., to a stirred solution of 5-bromofuran-2-carboxylic acid (3.00 g, 15.7 mmol) in DCM (30 mL) was added dropwise oxalyl dichloride (4.50 mL, 47.1 mmol). Then the resulted mixture was stirred at room temperature for 2 h. TLC and LC-MS showed no starting material. The volatile was removed under reduced pressure and the residual yellow solid was used without further purification (3.20 g, quant.)
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[CH2:26]([O:28][C:29](=[O:34])[C:30]([NH:32][OH:33])=N)[CH3:27]>>[CH2:26]([O:28][C:29]([C:30]1[N:2]=[C:1]([N:3]2[CH2:4][CH2:5][CH:6]([N:9]([CH:23]3[CH2:25][CH2:24]3)[C:10](=[O:22])[C:11]3[CH:12]=[CH:13][C:14]([C:17]4[O:21][CH:20]=[N:19][CH:18]=4)=[CH:15][CH:16]=3)[CH2:7][CH2:8]2)[O:33][N:32]=1)=[O:34])[CH3:27]
Reactant: CCOC(=O)C(=N)NO
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: CCOC(=O)c1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and hydroxyamino-imino-acetic acid ethyl ester following a procedure analogous to that described in Example 1. LC (method 3): tR=1.77 min; Mass spectrum (ESI+): m/z=452 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([N:9]2[N:18]=[C:17]3[C:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH2:29][O:30]C6CCCCO6)[CH:27]=5)[CH:20]=[CH:19][C:16]=43)=[CH:10]2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.CO>C(OCC)C>[CH:1]([N:4]1[C:8]([N:9]2[N:18]=[C:17]3[C:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH2:29][OH:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=43)=[CH:10]2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(-c3cnn(CCOC4CCCCO4)c3)cc1OCC2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(-c3cnn(CCO)c3)cc1OCC2
Yield: 95.9 %

Procedure:
2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene 45 (134 mg, 0.27 mmol) was dissolved in diethyl ether (5 mL) and treated with 1M HCl in diethyl ether (1 mL) then methanol (5 mL). After 30 min the reaction mixture was concentrated to dryness and the resultant residue triturated in diethyl ether to give 176 as a pale cream solid (105 mg, 86%). 1H NMR (400 MHz, DMSO-d6): δ 8.32 (s, 1 H); 8.23 (s, 1 H); 8.19 (d, J=8.23 Hz, 1 H); 8.03 (s, 1 H); 7.96 (s, 1 H); 7.39 (dd, J=8.24, 1.74 Hz, 1 H); 7.29 (d, J=1.68 Hz, 1H); 5.46-5.36 (m, 1 H); 4.34 (t, 2 H); 4.17 (t, J=5.61 Hz, 2 H); 3.78 (t, J=5.58 Hz, 2 H); 3.13 (t, J=4.91 Hz, 2 H); 1.52 (d, J=6.57 Hz, 6 H). 1 Exchangeable proton not observed. LCMS: RT=10.68 min, M+H+=406
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:28]([NH:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3ccnc(Cl)c3)n2)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)ccn2)c1

Procedure:
The title compound was prepared from 2′-chloro-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example E.27) (0.403 g, 1.0 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.334 g, 1.3 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.375 g, 65%). MS (ISP) 580.3 [(M+H)+]; mp 196° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:20]=2[NH:19][C:18]1=[O:29]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:20]=2[NH:19][C:18]1=[O:29])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: NC1CCc2ccc(Cl)cc2NC1=O
Product: CC(C)(CC(=O)NC1CCc2ccc(Cl)cc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step F by the procedure described in Example 1, Step F. 1H NMR (300 MHz, CDCl3): 1.35 (s,6H), 1.42 (s,9H), 1.95 (m,1H), 2.4-2.8 (m,5H), 4.51 (m,1H), 5.22 (br s,1H), 6.73 (d,7 Hz,1H), 7.02 (s,1H), 7.14 (br s,2H), 8.21 (br s,1H). FAB-MS: calculated for C20H28ClN3O4 409; found 410 (M+H,55%).
Reaction SMILES: Br[C:2]1[C:3]([Cl:11])=[CH:4][C:5]2[CH2:9][CH2:8][O:7][C:6]=2[CH:10]=1.FC1(F)OC2C=C(C)C([C:22]3[CH:23]=[CH:24][C:25]([NH:28]C(=O)C4C=CC=CC=4F)=[N:26][CH:27]=3)=CC=2O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:11][C:3]1[C:2]([C:22]2[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=2)=[CH:10][C:6]2[O:7][CH2:8][CH2:9][C:5]=2[CH:4]=1
Reactant: Clc1cc2c(cc1Br)OCC2
Reactant: Cc1cc2c(cc1-c1ccc(NC(=O)c3ccccc3F)nc1)OC(F)(F)O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2cc3c(cc2Cl)CCO3)cn1
Temperature: 85 °C
Yield: 75.5 %

Procedure:
A mixture of 6-bromo-5-chloro-2,3-dihydrobenzo[b]furan (18) (233 mg, purity ca 60%, ca 0.6 mmol), 2-aminopyridine-5-boronic acid pinacol ester (6) (220 mg, 1 mmol), bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (36 mg, 10% mol), Pd(PPh3)4 (58 mg) and K3PO4 (212 mg, 1 mmol) in 2 ml ACN, 2 ml dioxane, 0.5 ml H2O was bubbled with argon before heated at 85° C. for 4 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine. Org. phase was dried over Na2SO4, concentrated and then subjected to prep HPLC purification to give 5-(5-chloro-2,3-dihydrobenzo[3,4-b]furan-6-yl)-2-pyridylamine (19) (111.8 mg, yield: 75.5%, purity>95%) as yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[CH2:14][CH2:13][CH2:12][O:11][C:10]=12)=[O:5])C.O>O1CCCC1.C(O)C.[OH-].[Li+]>[N:8]1[N:9]2[C:10]([O:11][CH2:12][CH2:13][CH2:14]2)=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=1
Reactant: CCOC(=O)c1cnn2c1OCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cnn2c1OCCC2
Yield: 98.2 %

Procedure:
A solution of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester (9.67 g, 49.3 mmol) in tetrahydrofuran (150 mL), ethanol (50 mL) and 1M of lithium hydroxide in water (148 mL, 148 mmol) was stirred at 60° C. for 2 days. After cooling, the volatiles were removed. The residue was transferred to an Erlenmeyer flask and ice was added. The reaction was acidified to pH 2 with 10M HCl. The aqueous layer was extracted several times with 3/1 chloroform/IPA. The combined organic layers were dried (Na2SO4), filtered, concentrated to afford the acid as a solid (8.14 g, 98%). 1H NMR (400 MHz, DMSO-d6) δ7.57 (s, 1H), 4.37 (t, 2H, J=5.29 Hz), 4.07 (t, 2H, J=6.11 Hz), 2.20-2.15 (m, 2H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:19][CH:20]([CH:28]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:20]([CH:28]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:19][N:18]([CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]([O:10][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:12])[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCC(NC(=O)OC(C)(C)C)C(CCCCCCO)CN(CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCC(NC(=O)OC(C)(C)C)C(CCCCCCOS(C)(=O)=O)CN(CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulphonyl chloride (1.25 ml, 16.21 mmol) was added to a stirred solution of B6 (9.67 g, 13.5 mmol) in dry dichloromethane (100 ml) containing triethylamine (2.82 ml, 20.26 mmol) at 0° C. The flask was stirred at 0° C. for 1 hr, then overnight at room temperature. The solvent was removed and the residue chromatographed (silica—50% ethyl acetate in hexane) to yield the title compound (8.5 g, 79%. C38H74N4O11S requires 794. Found DCl: M++1, 795.6. δH (CDCl3) 3.45 (2H, t, CH2O), 2.9-3.3 (12H, m, CH2N), 2.99 (3H, s, MeS), 1.95 (1H, brm, CH2CH(CH2)2), 1.2-1.8 (50H, m, CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#N)=[CH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.S(=O)(=O)(O)[OH:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:23])=[CH:4][N:3]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(Cl)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled 5° C., stirred solution of 2-chloro-5-cyanopyridine (25.0 grams) in anhydrous toluene (540 mL) was added a 1M solution of diisobutylaluminum hydride (189 mL) over a 30 minute period. The resulting red-colored solution was treated with methanol (50 mL) and 2M sulfuric acid (150 mL), sequentially. The resulting biphasic solution was allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was extracted with ethyl acetate, the combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous brine. The organic phase was stirred over activated charcoal for 20 minutes, dried over anhydrous sulfate and concentrated in vacuo to afford the title compound as a light-yellow colored solid, 23.5 grams 1H NMR (400 MHz, CDCl3) δ=10.08 (s, 1H); 8.85 (s, 1H); 8.12(d, 1H); 7.50 (d, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH2:8][N:9]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:5]=[C:4]([CH2:26][N:27]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:3]=1.[NH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]#[CH:52])=[CH:47][CH:46]=1>C(N(CC)CC)C.C(Cl)(Cl)Cl.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.[Cu]I>[NH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]#[C:52][C:2]2[CH:3]=[C:4]([CH2:26][N:27]([CH2:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:28][C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[N:5]=[C:6]([CH2:8][N:9]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH:7]=2)=[CH:47][CH:46]=1
Reactant: C#Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)Cc1cc(I)cc(CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)Cc1cc(C#Cc2ccc(N)cc2)cc(CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)n1
Reaction time: 1.5 h

Procedure:
A mixture of compound 1 (1.08 g, 1.5 mmol), bis(triphenylphosphine)palladium(II) chloride (21 mg, 0.03 mmol), copper(I) iodide (11 mg, 0.06 mmol) and p-aminophenylacetylene (176 mg, 1.5 mmol) in 10 mL of triethylamine was deaerated with nitrogen and kept at 40° C. for 1.5 h. The mixture was diluted with 40 mL of chloroform, washed with water and dried with sodium sulfate. The solution was evaporated in vacuo and the product was obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[C:27](B3OCC(C)(C)CO3)[CH:26]=[CH:25][C:24]=2[F:37])[C:18]=1[C:38]#[N:39]>>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[C:27]([C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]4=[N:4][CH:3]=3)[CH:26]=[CH:25][C:24]=2[F:37])[C:18]=1[C:38]#[N:39]
Reactant: CC1(C)COB(c2ccc(F)c(-c3cccc(F)c3C#N)c2)OC1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc(F)c4C#N)c3)cnc2c1F
Yield: 75 %

Procedure:
3-Bromo-8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridine (0.10 g, 0.36 mmol) and 3,2′-difluoro-5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)biphenyl-2-carbonitrile (0.16 g, 0.47 mmol) were coupled following the procedure in Example 1 to afford 3,2′-difluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-2-carbonitrile as a white amorphous solid (110 mg, 74%): δH (360 MHz, CDCl3) 1.73 (6H, s), 2.10 (1H, s), 7.21 (1H, dd, J 7 and 7), 7.30 (1H, dd, J 8 and 8), 7.38-7.44 (2H, m), 7.61-7.72 (4H, m), 8.23 (1H, d, J 7); m/z (ES+) 408 (M++H).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:15][CH:14]2[N:16]([CH2:17][C@H:18]3[CH2:23][N:22]([S:24]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)(=[O:26])=[O:25])[CH2:21][CH2:20][NH:19]3)[CH:10]1[CH2:11][O:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:33]1[N:38]=[CH:37][C:36]([C:39]([OH:45])([CH3:44])[C:40]([F:43])([F:42])[F:41])=[CH:35][N:34]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH2:1]([O:8][CH:9]1[CH2:15][CH:14]2[N:16]([CH2:17][C@H:18]3[CH2:23][N:22]([S:24]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)(=[O:26])=[O:25])[CH2:21][CH2:20][N:19]3[C:33]3[N:34]=[CH:35][C:36]([C:39]([OH:45])([CH3:44])[C:40]([F:41])([F:42])[F:43])=[CH:37][N:38]=3)[CH:10]1[CH2:11][O:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)(c1cnc(Cl)nc1)C(F)(F)F
Reactant: O=S(=O)(c1cccs1)N1CCN[C@@H](CN2C3COCC2C(OCc2ccccc2)C3)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(O)(c1cnc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3COCC2C(OCc2ccccc2)C3)nc1)C(F)(F)F
Temperature: 120 °C
Yield: 48.2 %

Procedure:
A 20-mL vial was charged with 6-(benzyloxy)-8-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octane (endo) (250 mg, 0.54 mmol), 2-(2-chloropyrimidin-5-yl)-1,1,1-trifluoropropan-2-ol (244 mg, 1.078 mmol, Intermediate E), Hünig's base (0.29 mL, 1.62 mmol) and dioxane (5 mL). The reaction was heated to 120° C. for 12 h. The mixture was then concentrated onto silica gel and purified via column chromatography (120 g silica gel, 0 to 100% EtOAc in hexanes) to give 2-(2-((2S)-2-((6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (endo) (170 mg) as a mixture of four isomers.