Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:58]1[CH:63]=[CH:62][CH:61]=[C:60]([CH2:64][NH2:65])[CH:59]=1>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:65][CH2:64][C:60]3[CH:59]=[N:58][CH:63]=[CH:62][CH:61]=3)=[O:13])=[CH:14][CH:15]=2)=[N:4][C:3]=1[CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)(=[O:18])=[O:19]
Reactant: NCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(C(F)(F)F)cc1
Yield: 39.2 %

Procedure:
A solution of 4-(5-methyl-4-((4-(trifluoromethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoic acid (420 mg, 0.99 mmol, 1.00 equiv), EDCI (230 mg, 1.20 mmol, 1.22 equiv), HOBt (170 mg, 1.26 mmol, 1.27 equiv), triethylamine (300 mg, 2.97 mmol, 3.01 equiv) and pyridin-3-ylmethanamine (140 mg, 1.30 mmol, 1.31 equiv) in N,N-dimethylformamide (20 mL) was stirred overnight at room temperature. The product was precipitated by the addition 60 mL of water/ice. The solid was collected by filtration, washed with 2×20 mL of water and dried in a vacuum oven to give 0.20 g (39%) of 4-(5-methyl-4-((4-(trifluoromethyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide as a white solid. LC-MS: (ES, m/z): 557 [M+CH3CN+H]+, 516 [M+H]+, 102. 1HNMR (400 MHz, CDCl3, ppm) δ 9.22 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 8.06-7.89 (m, 6H), 7.82 (d, J=8.0 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.38-7.36 (m, 1H), 4.84 (s, 2H), 4.51 (d, J=5.2 Hz, 2H), 2.24 (s, 3H).
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[N:10]=[C:9]([Cl:11])[C:8]([O:12][CH:13]([F:15])[F:14])=[C:7](F)[N:6]=1>CO>[NH2:4][C:5]1[N:10]=[C:9]([Cl:11])[C:8]([O:12][CH:13]([F:15])[F:14])=[C:7]([O:2][CH3:1])[N:6]=1
Reactant: Nc1nc(F)c(OC(F)F)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc(Cl)c1OC(F)F
Reaction time: 1 h

Procedure:
26.1 g (0.145 mol) of 30% strength sodium methylate were added to 31.0 g (0.145 mol) of 2-amino-4-chlorodifluoromethoxy-6-fluoropyrimidine in 300 ml of methanol in the course of 15 minutes at -10° to 0° C. while stirring. Stirring was continued for 30 minutes at 0° C. and for 1 hour at 25° C. The reaction mixture was evaporated down under reduced pressure and worked up as described above. 31.6 g (96.6% of theory) of the title compound were obtained as a colorless oil of nD22 =1.5039.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[SH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N+:22]=1[O-:27]>>[O-:27][N+:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[S:20][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: [O-][n+]1ccccc1S
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3cccc[n+]3[O-])cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 2-mercapto-pyridine-1-oxide.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:17][CH:16]2[OH:31])=[CH:11][CH:10]=1.Cl[CH2:38][C:39]1[CH:40]=[CH:41][C:42]2[O:47][CH2:46][C:45](=[O:48])[N:44]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[C:43]=2[CH:54]=1>>[F:1][C:2]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH2:17][CH:16]2[O:31][CH2:38][C:39]2[CH:40]=[CH:41][C:42]3[O:47][CH2:46][C:45](=[O:48])[N:44]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[C:43]=3[CH:54]=2)=[CH:11][CH:10]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(OCCOCc3cc(F)ccc3F)cc2)C(O)C1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCOCc4cc(F)ccc4F)cc3)cc21

Procedure:
Analogously to Method D, 0.430 g of benzyl 4-{4-[2-(2,5-difluorobenzyloxy)ethoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.261 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as a colourless oil. Rf=0.10 (1:1 EtOAc-heptane). Rt=5.72.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=O.Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=[N:13][OH:14]
Reactant: CC(C)=CCCC(C)CC=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)=CCCC(C)CC=NO

Procedure:
(Compound 8). 3,7-Dimethyloct-6-enal (15.4 g) in 50 ml ethyl alcohol was added to a solution of hydroxylamine hydrochloride (7 g) and sodium carbonate (5 g) in 25 ml of water. The mixture was heated on the steambath for 15 minutes and then allowed to cool. Addition of an excess of water yielded 3,7-dimethyl-oct-6-enal oxime as an oil. The oil was extracted with ether and the organic layer dried and evaporated. The residue was added dropwise to a solution of lithium aluminum hydride (3.8 g) in 380 ml anhydrous ethyl ether. After refluxing overnight an additional quantity of lithium aluminum hydride (0.78 g) was added to complete the reduction. Decomposition of the reaction mixture with excess aqueous sodium hydroxide (200 ml of 10 percent solution), separation of the ether layer, and distillation yielded 3,7-dimethyloct-6-enyl amine (10 g) bp 60°/0.5 mm). To an ice cold solution of this amine (1.5 g) and triethylamine (1.1 g) in ether (25 ml) was added dropwise a solution of ethyl chloroformate (1.1 g) in ether (10 ml). The reaction mixture was allowed to stand overnight at room temperature. The triethylamine hydrochloride was filtered off and the ether solution washed with water, dilute hydrochloric acid, and again with water. The ether solution was dried and evaporated and the residue distilled to yield 2 g carbamic acid (3,7-dimethyl-6-octenyl)-, ethyl ester (Compound 7), bp 102°-103°/0.1 mm. The ester was epoxidized as described in the previous examples to yield VII. The crude reaction product can be readily purified by chromatography using neutral activated alumina.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([S:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22])(=[O:17])=[O:16])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][S:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22])(=[O:16])=[O:17]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNS(=O)(=O)c1cccc(C(=O)O)c1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNS(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 100 °C
Yield: 71 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 3-(hydrazinosulfonyl)benzoic acid. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 131 mg of the title compound (71%) as a yellow solid in 87.8% purity by HPLC (Rt: 4.71, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@H:10]([C:26](O)=[O:27])[NH:11][C:12](=[O:25])[C:13]([CH3:24])([CH3:23])[CH2:14][S:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:30]([O:32][C:33](=[O:36])[CH2:34][NH2:35])[CH3:31].ON1C2C=CC=CC=2N=N1.Cl>CN(C)C=O.CN1CCOCC1>[CH2:30]([O:32][C:33](=[O:36])[CH2:34][NH:35][C:26](=[O:27])[C@@H:10]([CH2:9][S:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[NH:11][C:12](=[O:25])[C:13]([CH3:23])([CH3:24])[CH2:14][S:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:31]
Reactant: CC(C)(CSCc1ccccc1)C(=O)N[C@H](CSCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CNC(=O)[C@@H](CSCc1ccccc1)NC(=O)C(C)(C)CSCc1ccccc1
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a stirred solution of S-benzyl-N-(3-benzylthio-2,2-dimethyl-propionyl)-D-cysteine (0.32 g) and glycine ethyl ester hydro-chloride (0.12 g) in N,N-dimethylformamide (DMF, 3 ml), N-methylmorpholine (NMM, 0.19 ml), 1-hydroxybenzotriazole (HOBt, 0.17 g) and then a solution of N,N,-dicyclohexylcarbodiimide (DCC, 0.18 g) in DMF (2 ml) were added under ice cooling. The mixture was stirred for 2 hr. at 0° C. and for 2 hr. at room temperature, and stood overnight. 1 N hydrochloric acid (30 ml) was added into the reaction mixture and the mixture was extracted with ether. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 0.35 g (91%) of the titled compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16][CH2:15]1>C1COCC1>[OH:13][C:14]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:18][CH2:19]1
Reactant: Brc1ccccn1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2ccccn2)CC1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-bromopyridine (0.47 mL, 5 mmol) in THF (20 mL) was cooled to −60° C. and treated dropwise with nBuLi (1.6M in hexanes, 5.2 ml, 5.2 mmol). The reaction mixture was stirred for 30 minutes at −60° C. and then benzyl 4-oxo-1-piperidine carboxylate 1.14 g, 4.9 mmol) in THF (10 mL) was slowly added to the reaction mixture. The reaction mixture was stirred at −60° C. for 15 minutes and then quenched with saturated NH4Cl. The cooling bath was removed and reaction mixture was allowed to warm to room temperature. The mixture was were extracted with CH2Cl2 and the organics were dried (MgSO4), filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography using hexane:ethyl acetate (1:1) to provide the title compound, 400 mg (27%). 1H NMR (d6-DMSO, 300 MHz) δ 1.54 (m, 4H), 2.05 (m, 4 H), 3.25 (m, 4H), 3.95 (m, 4H), 5.11 (s, 2H), 5.35 (s, 1H), 7.25 (m, 2H), 7.35 (m, 5H), 7.68 (m, 1H), 8.5 (m, 1H); MS (DCI/NH3) m/z 313 (M+H)+.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:29])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:28])[CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].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>[CH2:14]([O:16][C:17]([C:19]1([NH:29][C:11]([C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:28])[CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: O=C(O)c1cccc2c1CCCC2
Reactant: CCOC(=O)C1(N)Cc2ccc(F)cc2C1
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: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (400 mg, 2.27 mmol), 2-amino-5-fluoro-indan-2-carboxylic acid ethyl ester (610 mg, 2.72 mmol), HATU (1.30 g, 3.41 mmol) in anhydrous DMF (15 mL) is added DIPEA (563 μL, 3.41 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (70 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5%-40% EtOAc in heptane) to give a pure product (86) as white solid (345 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:3]=1[C:4]#[N:5].[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[N:9]=[C:8]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:7]=[C:6]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:31])=[CH:19][CH:20]=2)[C:3]=1[C:4]#[N:5]
Reactant: Cc1ccccc1B(O)O
Reactant: N#Cc1c(-c2ccc(O)cc2)cc(C2CCCC2)nc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: Cc1ccccc1Oc1ccc(-c2cc(C3CCCC3)nc(Cl)c2C#N)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 57.6 %

Procedure:
A mixture of 2-chloro-6-cyclopentyl-4-(4-hydroxyphenyl)nicotinonitrile (20 mg, 0.067 mmol, product A from Step 4 of Example 2), o-tolylboronic acid (36.4 mg, 0.268 mmol), copper(II) acetate (14.59 mg, 0.080 mmol) and 4 A molecular sieves (100 mg) in dichloromethane (3 mL) was stirred at room temperature while opening to the air for 40 h. The mixture was filtered through a CELITE® pad and the pad rinsed with ethyl acetate (50 mL). The filtrate was washed with saturated sodium bicarbonate (5 mL), water (5 mL), brine (5 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0-15% ethyl acetate in hexanes, gave 2-chloro-6-cyclopentyl-4-(4-(o-tolyloxy)phenyl)nicotinonitrile as a colorless liquid (15 mg, 58% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.50 (2H, δ, J=8.53 Hz), 7.07-7.32 (5H, m), 6.91-7.03 (2H, m), 3.05-3.28 (1H, m), 2.20 (3H, s), 1.98-2.13 (2H, m), 1.60-1.91 (6H, m); MS (ES+) m/z: 389 (M+H); LC retention time: 4.578 min (analytical HPLC Method A).
Reaction SMILES: [C:1]([C@H:3]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][C@H:4]1[C:15]([O:17]CC)=[O:16])#[N:2].[OH-].[K+].Cl>CO.O>[C:1]([C@@H:3]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][C@@H:4]1[C:15]([OH:17])=[O:16])#[N:2]
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1C#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#C[C@@H]1CN(Cc2ccccc2)C[C@@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 182.5 %

Procedure:
Dissolve ethyl(3S,4R)-4-cyano-1-(phenylmethyl)-3-pyrrolidinecarboxylate (2.0 g, 7.72 mmol) in 4:1 methanol/water (50 mL). The solution was cooled to 0 degrees C. and potassium hydroxide (0.867 g, 15.4 m, mol) was added. The reaction was allowed to stir at 0 degrees C. for 1 hour. 1 N HCl was added with cooling and the solution brought to pH=7. The solvent was removed under reduced pressure yielding a crude solid (3.244 g) which was taken on to the next step. LCMS: m/z 231.4 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:4][N:3]=1.C(O)(=O)C>C(OCC)(=O)C.[Zn]>[F:8][C:7]1[CH:2]=[N:3][CH:4]=[C:5]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)[C:6]=1[CH3:9]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnc(Cl)c1F
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1c(F)cncc1B1OC(C)(C)C(C)(C)O1
Temperature: 60 °C

Procedure:
A mixture of 2-chloro-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (212 mg; 0.7808 mmol), zinc powder (155.3 mg; 2.37 mmol), and acetic acid (3.0 mL; 47 mmol) was heated at 60° C. for 3 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate (30 mL) filtered through celite, and evaporated under vacuum to yield the title compound in quantitative yield. LCMS (ESI): [M-pinacol]+H=156.4; 1H NMR (400 MHz, DMSO) δ 8.55-8.47 (m, 2H), 2.42 (d, J=2.0 Hz, 3H), 1.33 (s, 12H).
Reaction SMILES: C(NC(C)C)(C)C.[F:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.CN(C)[CH:19]=[O:20]>C1COCC1>[F:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[CH:19]=[O:20]
Reactant: N#Cc1ccc(F)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#Cc1ccc(F)c(C=O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a stirred, cooled solution (0° C.) of diisopropylamine (15.4 mL, 0.11 mol) in anhydrous tetrahydrofuran (200 mL) n-butyllithium (40 mL of 2.5M in hexane, 0.11 mol) was added from a dropping funnel over a period of 30 min. under argon. The mixture was stirred at that temperature for 30 min. and then cooled to −78° C. A solution of 4-fluoro-benzonitrile (12.1g, 0.1 mol) in dry THF (50 mL) was then added dropwise over 15 min. via syringe and stirred for 1 hour at −78° C. Dimethylformamide (8 mL) was added dropwise from a syringe and the stirring was continued for another 20 min. The reaction was quenched by the rapid addition of acetic acid (20 mL) followed by water (500 mL) and the product was extracted with diethyl ether (2×500 mL). The combined organic layers were washed with 1N HCl, water, saturated sodium chloride and then dried over anhydrous magnesium sulfate, and evaporated to give 2-fluoro-5-cyano-benzaldehyde (11.8 g, 79% yield) as a light yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:19])=[N:8][N:9]2[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=2)=[CH:5][CH:4]=1)#[CH:2].[Li+].CC([N-]C(C)C)C.[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[N:34]1[CH:38]=[N:37][C:36]([C:39](=[O:41])[CH3:40])=[N:35]1>C1COCC1>[NH2:18][C:14]1[N:13]=[C:12]([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[C:2][C:39]([C:36]4[N:37]=[CH:38][N:34]([CH:29]5[CH2:30][CH2:31][CH2:32][CH2:33][O:28]5)[N:35]=4)([OH:41])[CH3:40])[CH:11]=3)[C:7]([CH3:19])=[N:8]2)[CH:17]=[CH:16][N:15]=1
Reactant: CC(=O)c1ncn(C2CCCCO2)n1
Reactant: C#Cc1ccc2c(C)nn(-c3ccnc(N)n3)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3ncn(C4CCCCO4)n3)ccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-(6-ethynyl-3-methylindazol-1-yl)pyrimidin-2-amine (90 mg, 0.36 mmol) in dry THF (1.5 mL) at −78° C. under an atmosphere of nitrogen was added 2M LDA in THF (0.45 mL, 0.903 mmol). After 5 minutes, 1-[1-(oxan-2-yl)-1,2,4-triazol-3-yl]ethanone (211.45 mg in 1.5 mL dry THF, 1.08 mmol) was added. After 20 minutes the mixture was allowed to warm up to RT, then stirred for a further 30 minutes. The reaction mixture was quenched by addition of saturated aqueous NH4Cl (0.5 mL). The volatiles were removed in vacuo and the mixture was diluted with DCM (10 ml) and washed with water (2 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage, 2-11% methanol gradient in DCM) to give the title intermediate as a pale yellow oil: 1H NMR (500 MHz, DMSO) delta 1.76-1.56 (3H, m), 1.90 (3H, s), 2.18-1.94 (3H, m), 2.58 (3H, s), 3.74-3.60 (1H, m), 4.03-3.87 (1H, m), 5.60-5.43 (1H, m), 6.27 (1H, s), 6.96 (2H, s), 7.04 (1H, d, J=5.5 Hz), 7.34 (1H, d, J=8.1 Hz), 7.84 (1H, d, J=8.4 Hz), 8.26 (1H, d, J=5.5 Hz), 8.68 (1H, s), 8.84 (1H, s); LC-MS: m/z=+445.05 (M+H)+.
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[C:12]1[S:16][C:15]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:14]=2[C:13]=1[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:27][CH:26]=1)=[O:24]>C1COCC1>[CH2:1]([C:12]1[S:16][C:15]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:14]=2[C:13]=1[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:27][CH:26]=1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(Cc3ccccc3)sc2c1
Reaction time: 0.5 h

Procedure:
Add benzylmagnesium bromide (1.5 mL, 3M) to a stirred solution of (2-dimethylamino-6-methoxy-benzo[b]thiophen-3-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (1.0 g, 2.28 mmol) in THF (10 mL) at room temperature (r.t.). Stir the mixture for 30 min. and quench with sat. NaHCO3. Dilute the reaction mixture with CH2Cl2 and wash with water and brine, dry over MgSO4, filter and concentrate. Use the crude product without further purification.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH2:7][C:6](=O)[C:5]=2[CH:4]=[CH:3][N:2]=1.[NH2:12][OH:13].C(O)C>N1C=CC=CC=1>[OH:13][N:12]=[C:6]1[CH2:7][CH:8]=[CH:9][C:10]2[CH:1]=[N:2][CH:3]=[CH:4][C:5]1=2
Reactant: O=C1CC=Cc2cnccc21
Reactant: NO
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1CC=Cc2cnccc21
Yield: 61.8 %

Procedure:
Isoquinolin-5-one (21.57g, 0.147M) and hydroxylamine (15.55g, 0.22M) together with approximately 300 ml of dry ethanol and 75 ml of pyridine were stirred at reflux temperature of the mixture for 6 hours. The solvent was then removed by evaporation and the residue was dissolved in a mixture of diethyl ether and water (600 ml, ca. 1:1). The organic phase was separated and extracted with water to remove residual pyridine, washed with saturated, aqueous solution of sodium chloride and dried over magnesium sulfate crystals. The inorganic matter was removed by filtration and the solvent by evaporation leaving 14.7 grams of the desired product (61.7% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[S:19])[NH:9]2)[CH:7]=1.O=[C:23]1[C:32]2[N:31]=[CH:30][C:29]([C:33]#[N:34])=[CH:28][C:27]=2[CH2:26][CH2:25][CH2:24]1>>[F:15][C:14]1([F:16])[C:13]([CH3:17])([CH3:18])[O:12][CH2:11][C:10](=[S:19])[NH:9][C@@:8]1([C:6]1[CH:7]=[C:2]([NH:1][CH:23]2[C:32]3[N:31]=[CH:30][C:29]([C:33]#[N:34])=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)[CH:3]=[CH:4][C:5]=1[F:21])[CH3:20]
Reactant: CC1(C)OCC(=S)N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: N#Cc1cnc2c(c1)CCCC2=O
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(NC3CCCc4cc(C#N)cnc43)ccc2F)C1(F)F
Yield: 63.2 %

Procedure:
Prepared in an analogous manner as described for intermediate A22A from (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepane-3-thione (intermediate A19B) (102 mg, 320 μmol) and 8-oxo-5,6,7,8-tetrahydroquinoline-3-carbonitrile (66.2 mg, 384 μmol). The 8-(3-((R)-6,6-difluoro-5,7,7-trimethyl-3-thioxo-1,4-oxazepan-5-yl)-4-fluorophenylamino)-5,6,7,8-tetrahydroquinoline-3-carbonitrile (96 mg, 63.1%) was obtained as a white foam. MS (ISN): m/z=473.1 [(M−H)−].
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([S:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:11][CH:12]=1.[C:19](OC)(=[O:24])[C:20]([O:22][CH3:23])=[O:21].[NH4+].[Cl-]>C(OCC)C>[CH:14]1([S:13][C:10]2[N:11]=[CH:12][C:7]([C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:8][CH:9]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Brc1ccc(SC2CCCC2)nc1
Reactant: COC(=O)C(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: COC(=O)C(=O)c1ccc(SC2CCCC2)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 23.2 %

Procedure:
Under anhydrous condition n-BuLi (1.6 M solution in hexane, 5.08 mL, 8.13 mmol) was added to stirred solution of 5-bromo-2-cyclopentylsulfanyl-pyridine (2.0 g, 8.13 mmol) in 15 mL dry diethyl ether at −78° C. and stirred for 20 minutes. A solution of dimethyl oxalate (1.09 g, 9.30 mmol) in 15 mL of dry diethyl ether was added dropwise with the help of syringe and resulted reaction mixture was allowed to warm slowly to 0° C. within 1 hr. Reaction mixture was poured on aq. saturated solution of NH4Cl (25 mL), mixture was then extracted with (3×50 mL) diethyl ether; organic layer was washed with brine, dried over anhydrous sodium sulfate, sodium sulfate was filtered and washed with diethyl ether and solvent was removed under reduced pressure. The crude material was purified by silica-gel column chromatography (3 to 5% ethyl acetate in hexane) to afford pure compound (0.5 g).