Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[C:8]([N+:15]([O-:17])=[O:16])=[CH:9][C:10]([CH3:14])=[N+:11]([O-])[CH:12]=1)=[O:4].[F:18][C:19]([F:30])([F:29])[C:20]([O:22]C(=O)C(F)(F)F)=[O:21]>>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[C:8]([N+:15]([O-:17])=[O:16])=[CH:9][C:10]([CH2:14][O:22][C:20](=[O:21])[C:19]([F:30])([F:29])[F:18])=[N:11][CH:12]=1)=[O:4]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)COc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Product: COC(=O)COc1cnc(COC(=O)C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The pyridine N-oxide (d) (3.8 g) in trifluoroacetic anhydride (120 ml) was refluxed under argon for 24 hours, the solvent evaporated and the residue partitioned between chloroform and aqueous NaHCO3 (50 ml each). The aqueous fraction was re-extracted with chloroform (3×50 ml) and the combined organic solution dried and evaporated to give the product (1.8 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([O-])=O>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ncnc2cc(N)ccc12
Reaction time: 8 h
Yield: 71.6 %

Procedure:
A mixture of 600 mg of tert-butyl 7-nitroquinazolin-4-ylcarbamate and 150 mg of 10% Pd—C in 15 ml each of THF and MeOH was stirred overnight under a hydrogen balloon, filtered through a Celite® pad, concentrated and purified by chromatography eluting with 5% methanol in dichloromethane to provide 385 mg of tert-butyl 7-aminoquinazolin-4-ylcarbamate (compound 98-4). MS m/e=261.1 (MH+)
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[N:16]=[C:6]2[N:7]=[C:8]3[CH2:15][CH2:14][CH2:13][S:12][C:9]3=[C:10](Cl)[N:5]2[N:4]=1.CC(O)C.[NH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.C(N(CC)CC)C>C(N(CC)CC)C>[CH3:1][N:2]([CH3:17])[C:3]1[N:16]=[C:6]2[N:7]=[C:8]3[CH2:15][CH2:14][CH2:13][S:12][C:9]3=[C:10]([NH:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:5]2[N:4]=1
Reactant: NCCN1CCOCC1
Reactant: CN(C)c1nc2nc3c(c(Cl)n2n1)SCCC3
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CN(C)c1nc2nc3c(c(NCCN4CCOCC4)n2n1)SCCC3
Reaction time: 1 h

Procedure:
To a suspension of 5.40 g (0.02 mole) of 2-(dimethylamino)-5-chloro-7,8-dihydro-9H-thiopyrano[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine in 20 ml of 2-propanol 2,125 g (0.021 mole) of triethylamine and 2.73 g (0.021 mole) of 2-aminoethylmorpholine are successively added, and the reaction mixture is boiled for one hour. Upon cooling triethylamine hydrochloride gets separated, which is filtered and washed with 2-propanol. The filtrate is evaporated to dryness in vacuo and the residue is dissolved in chloroform. The solution thus obtained is extracted twice with water, dried over anhydrous Na2SO4 and evaporated in vacuo. The oily product is suspended in ethyl acetate, the crystalline product thus obtained is filtered off and washed with ethyl acetate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:43]=[CH:42][C:8]2[N:9]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[C:17]([C:22]3[C:27]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)=[CH:26][CH:25]=[C:24]([OH:35])[CH:23]=3)[CH:16]=[CH:15]4)=[N:11][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].Br[CH2:47][CH2:48][O:49][CH3:50]>CN(C=O)C>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:27]2[C:22]([C:17]3[CH:16]=[CH:15][C:14]4[C:19](=[CH:20][CH:21]=[C:12]([C:10]5[N:9]([CH:36]6[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]6)[C:8]6[CH:42]=[CH:43][C:5]([C:3]([OH:2])=[O:4])=[CH:6][C:7]=6[N:11]=5)[CH:13]=4)[N:18]=3)=[CH:23][C:24]([O:35][CH2:47][CH2:48][O:49][CH3:50])=[CH:25][CH:26]=2)=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(O)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reaction time: 8 h

Procedure:
Compound 475a (100 mg, 0.162 mmol) was dissolved in 2 mL of DMF and treated with 16.8 mg (0.7 mmol) of NaH for 30 min. 1-bromo-2-methoxy ethane (30.5 μL) was added and the mixture was agitated overnight. The next day the reaction mixture was evaporated to dryness, the oily residue dissolved in 3 mL methanol followed by the addition of 1 mL 1M NaOH. The mixture was refluxed for 2 h before it was evaporated to dryness. The product was purified by RP-HPLC for a yield of 19.3 mg of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][C:9]=2[NH2:11])[CH:4]=[CH:3][CH:2]=1.[C:12]1([CH3:25])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[S:20]([O:23][NH2:24])(=[O:22])=[O:21]>C(Cl)Cl>[NH:11]=[C:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH:6]=[CH:7][N:8]1[NH2:24].[CH3:19][C:14]1[CH:15]=[C:16]([CH3:18])[CH:17]=[C:12]([CH3:25])[C:13]=1[S:20]([O-:23])(=[O:22])=[O:21]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Nc1nccc2cccnc12
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: N=c1c2ncccc2ccn1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a solution of 1,7-naphthyridin-8-amine (600 mg, 4.13 mmol) in DCM (5 mL) was added a solution of O-(mesitylsulfonyl)hydroxylamine (2.7 g, 12.4 mmol) in DCM (10 mL) at 0° C. The mixture was stirred at 0° C. for 2 h. The precipitate was filtered and collected to give 8-imino-1,7-naphthyridin-7(8H)-amine-2,4,6-trimethylbenzenesulfonate as a brown solid (1.2 g, yield 67%). ESI MS: m/z 161.1 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[CH:7]1>O1CCCC1>[CH:2]12[S:1][CH:5]([CH:4]=[CH:3]1)[CH:7]1[C:6]([O:11][C:9](=[O:10])[CH:8]21)=[O:12]
Reactant: c1ccsc1
Reactant: O=C1C=CC(=O)O1
Solvent: C1CCOC1
Product: O=C1OC(=O)C2C3C=CC(S3)C12
Temperature: 700 °C
Reaction time: 24 h

Procedure:
In tetrahydrofuran solvent (500 g), thiophene (1 mole) and maleic anhydride (1 mole) are dissolved, and the solution is introduced into a 2-liter flask. After stirring at 700° C. for 24 hours, the solvent is removed by using a rotary evaporator. The residue is distilled in vacuo to obtain pure 7-thiabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride of the following Chemical Formula 201 (yield: 90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:7]1=[O:20].C([Li])CCC.[C:29]([SiH:33]([CH3:35])[CH3:34])([CH3:32])([CH3:31])[CH3:30].C1C[O:39][CH2:38][CH2:37]1>>[Si:33]([O:39][CH2:38][CH2:37][CH:5]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:7]1=[O:20])[C:4]1[CH:21]=[CH:22][CH:23]=[C:2]([F:1])[CH:3]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:35])[CH3:34]
Reactant: O=C1N(Cc2cccc(F)c2)c2ccccc2C12CCCCC2
Reactant: C[SiH](C)C(C)(C)C
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: CC(C)(C)[Si](C)(C)OCCC(c1cccc(F)c1)N1C(=O)C2(CCCCC2)c2ccccc21
Temperature: 0 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
1′-(3-fluorobenzyl)spiro[cyclohexane-1,3′-indol]-2′(1′H)-one (0.61 g, 1.97 mmol) was dissolved in THF and cooled to −78° C. n-Butyl lithium (2.5 M in hexane, 0.87 mL, 2.2 mmol) was added dropwise and the mixture was warmed to 0° C. 2-Bromoethoxy)-tert-butyldimethylsilane (0.65 mL, 3 mmol) was added and the mixture was allowed to warm to 25° C. The mixture was stirred for 16 hours then quenched with saturated aqueous ammonium chloride, diluted with ether, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0-10% ethyl acetate in hexane) to afford 0.86 g (92%) 1′-[3-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-fluorophenyl)propyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[N:13]([O-])=O.[Na+].O.O.[Sn](Cl)[Cl:20]>Cl.O>[ClH:20].[C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][NH2:13])=[CH:12][CH:11]=1)([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(NN)cc1
Temperature: -13 °C
Yield: 20142.8 %

Procedure:
To a cooled (-13° C.) and stirred suspension of ethyl 4-aminobenzoate (100 g, 605.3 mmol) in concentrated hydrochloric acid (780 ml) was added dropwise a solution of sodium nitrite (43.9 g, 635.9 mmol) in water (312 ml) at such a rate as to keep the temperature below -4° C. (ca 50 minutes). After being stirred for further 10 minutes at -5° C., the mixture was quickly filtered to remove solids and the clear yellow filtrate was added portionwise to a cooled (-20° C.) and stirred solution of tin (II) chloride dihydrate (682.9 g, 3.02 mmol) in concentrated hydrochloric acid (470 ml) at such a rate as to maintain the temperature below -10° C. (ca 25 minutes). The resulting mixture was allowed to warm to -5° C. over 25 min and the solid was collected by filtration, washed with diethyl ether (2×300 ml) and dried over phosphorous pentoxide-potassium hydroxide at 60° C. in vacuum oven to give 131.8 g (100%) of the title compound as a white solid. A sample recrystallized from absolute ethanol showed: mp 208°-212° C. (needles); δH (360 MHz, DMSO-d6) 10.42 (3H, br s, --N+H3), 8.92 (1H, br s, --NH--), 7.86 (2H, d, J=8.8 Hz, Ar-H), 7.01 (2H, d, J=8.8 Hz, Ar-H), 4.26 (2H, q, J=7.1 Hz, --OCH2 --), 1.30 (3H, t, J=7.1 Hz, --CH3); m/z (CI) 181 (M+ +1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:6]([NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[OH:16])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1Cl.ClCCl>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[O:16][C:6]([C:5]3[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:8][C:9]=2[CH:14]=1
Reactant: COc1ccc(C(=O)Nc2cc(Cl)ccc2O)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: COc1ccc(-c2nc3cc(Cl)ccc3o2)cc1OC
Yield: 31.1 %

Procedure:
A solution of N-(3,4-dimethoxybenzoyl)-2-hydroxy-5-chloroaniline (5.0 g, 0.015 mol) was heated under reflux for 11 hours in 30 ml o-dichlorobenzene and p-toluenesulfonic acid monohydrate (0.3 g, 15 mmol). The reaction mixture was diluted with dichloromethane and filtered through a pad of alumina (25 g). The solvent was evaporated under reduced pressure and the residue was triturated with petroleum ether and filtered to give 2.7 g of crudeproduct. The material was crystallized from methyl t-butyl ether with charcoal to give 1.35 g of material which was crystallized again from methyl t-butyl ether and sublimed at 130° C. (0.05 mm) to give pure title compound as tan crystals, mp 142-145° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.Cl.[NH2:26][O:27][CH2:28][CH2:29][OH:30]>CO>[OH:30][CH2:29][CH2:28][O:27][N:26]=[C:22]([C:19]1[N:20]=[C:21]2[N:13]([CH2:12][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][C:2]=3[F:1])[N:9]=[CH:8][CH:7]=[CH:6]4)[N:14]=[N:15][C:16]2=[N:17][CH:18]=1)[CH3:23]
Reactant: NOCCO
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Agent: Cl
Solvent: CO
Product: CC(=NOCCO)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Temperature: 45 °C
Yield: 74.7 %

Procedure:
To a solution of 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (190.0 mg, 0.59 mmol) in MeOH (40 mL) was added 2-(aminooxy)ethanol hydrochloride (134.0 mg, 1.18 mol). The mixture was heated at 45° C. overnight. The solvent was removed under reduced pressure. The residue was purified by column chromatography with gradient (DCM:MeOH=10:1) to give the title compound as a white solid (168.0 mg, 71%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.30 (s, 1H), 8.93 (d, 1H), 8.41 (d, 1H), 8.19 (d, 1H), 7.83 (d, 1H), 7.54 (dd, 1H), 6.24 (s, 2H), 4.78 (t, 1H), 4.31 (t, 2H), 3.72 (m, 2H), 2.29 (s, 3H). LCMS (method A): [MH]+=382, tR=4.99 min.
Reaction SMILES: [NH2:1][C:2](=[N:4][N:5]=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[NH:9][CH:8]=1)[NH2:3].[CH:17]1(N=C=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C[N:27]([CH:29]=[O:30])C>>[NH2:3][C:2](=[N:4][N:5]=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[NH:9][CH:8]=1)[N:1]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:29]([NH2:27])=[O:30]
Reactant: NC(N)=NN=Cc1c[nH]c2ccc(O)cc12
Reactant: O=C=NC1CCCCC1
Reactant: CN(C)C=O
Product: NC(=O)N(C(N)=NN=Cc1c[nH]c2ccc(O)cc12)C1CCCCC1
Reaction time: 4 h

Procedure:
To a solution of 0.8 g 5-hydroxy-indole-3-carboxaldehyde diaminomethylenehydrazone (3.7 mmol) in 20 ml DMF is added over 5 min. at 0° a solution of 0.5 ml cyclohexyl isocyanate (4.0 mmol) in 5 ml DMF. The solution is stirred for 4 hours. The solvent is then evaporated and the residue chromatographied (eluant: Toluene/EtOH/NH3 85:15:0.5) to yield the title compound as crystals. M.p.=135° (foaming).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[N:10][N:11]([CH:13]([CH2:15][CH3:16])[CH3:14])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[BrH:23].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Br:23][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[N:10][N:11]([CH:13]([CH2:15][CH3:16])[CH3:14])[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCC(C)n1cc(-c2ccnc(Cl)c2)c(-c2ccc(Cl)s2)n1
Reactant: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCC(C)n1cc(-c2ccnc(Br)c2)c(-c2ccc(Cl)s2)n1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
To 2-Chloro-4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (0.57 mmol) was added slowly 0.5 mL of a 33% solution hydrobromic acid in acetic acid. The resulting mixture was stirred in the microwave at 140° C. for 20 min. After cooling to room temperature, potassium carbonate (2 molar solution) was added and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4 and evaporated. The residue was purified by chromatography on silica gel (hepthane:ethyl acetate 5:1 to 2:1) to afford 178 mg of 2-bromo-4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (79% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11](I)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:15]([C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1)#[CH:16].C(N(CC)CC)C>C1COCC1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11]([C:16]#[C:15][C:17]3[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:29][CH:30]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(OCCN2CCCC2)cc1
Reactant: Clc1ccc(-c2cnc(I)cn2)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Clc1ccc(-c2cnc(C#Cc3ccc(OCCN4CCCC4)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an N2 atmosphere 19 mg (0.1 mmol) CuI, 82 mg (0.1 mmol) [1,1′-bis-(diphenylphosphine)-ferrocene]-palladium(II)-chloride are added to a solution of 316 mg (1.0 mmol) 2-(4-chloro-phenyl)-5-iodo-pyrazine and 215 mg (1.0 mmol) 1-[2-(4-ethynyl-phenoxy)-ethyl]-pyrrolidine in 50 mL THF and 0.4 mL (3 mmol) triethylamine and the reaction mixture is stirred overnight at RT. To complete the reaction another 100 mg (0.32 mmol) 2-(4-chloro-phenyl)-5-iodo-pyrazine are added and the mixture is again stirred overnight. It is evaporated down i. vac., the residue is combined with 10% Na2CO3 solution, extracted exhaustively with DCM, the combined organic phases are washed three times with water and dried over MgSO4. This is filtered through activated charcoal, evaporated down i.vac. and the residue is purified by chromatography (silica gel, gradient: EtOAc to EtOAc/MeOH/NH3 9:9:1).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[C:2]1([O:1][C:8]2[CH:9]=[C:10]([CH2:14][CH2:15][NH2:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1cccc(Oc2ccccc2)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NCCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.38 g (6.59 mmol) of 3-phenoxyphenylacetonitrile and 1.57 g (6.59 mmol) of cobalt(II) chloride hexahydrate are dissolved in 25 ml of methanol. The solution is cooled with an iced water bath and 1.74 g (46 mmol) of sodium borohydride are added in portions. The reaction mixture is stirred overnight at ambient temperature. It is filtered on paper and rinsed with twice 25 ml of methanol. The filtrate is concentrated under reduced pressure and the residue is taken up in 50 ml of aqueous hydrochloric acid (1N) and 25 ml of ether. After distinct phases have separated out they are separated. The aqueous phase is washed with three times 25 ml of ether. The aqueous phase is rendered alkaline with 10 ml of aqueous 36% sodium hydroxide and extracted with three times 50 ml of dichloromethane. The extracts are washed with saturated aqueous sodium chloride solution and dried over sodium sulphate and the filtrate is concentrated under reduced pressure. This gives 0.67 g of product in the form of a brown-orange oil, which is used as it is in the following step.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])=[C:4]2[N:9]([C:10]=1[C:11]#[N:12])[CH:8]=[CH:7][CH:6]=[CH:5]2.[C:22](OC(=O)C)(=O)[CH3:23].C(O)(=[O:31])C>>[OH:31][C:11]1[C:10]2[N:9]3[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]3)=[C:3]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:2]=2[N:1]=[C:22]([CH3:23])[N:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Reactant: Cc1cc(C)c(-c2c(N)c(C#N)n3ccccc23)c(C)c1
Product: Cc1cc(C)c(-c2c3nc(C)nc(O)c3n3ccccc23)c(C)c1
Temperature: 25 °C

Procedure:
A solution of 2-amino-3-cyano-1-(2,4,6-trimethylphenyl)indolizine (220 mg) in an acetic anhydride (0.5 mL)—acetic acid (2 mL) mixture is heated at 100° C. for 1 hour. The mixture is cooled to room temperature and concentrated in vacuo. The residue is then heated in 85% phosphoric acid (5 mL) at 100° C. for 1.5 hours, allowed to cool to room temperature, diluted with water, and neutralized to pH 7 by adding aqueous ammonium hydroxide. The resulting yellow suspension is extracted twice with dichloromethane and the combined extracts are dried (Na2SO4), filtered, concentrated, and chromatographed (50% ethyl acetate in hexane to 10% methanol in ethyl acetate) to give 120 mg of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:32]([F:38])=[CH:31][C:30]=1[O:39][CH3:40]>>[F:38][C:32]1[C:33]([CH:35]([CH3:37])[CH3:36])=[CH:34][C:29]([C:20]2[CH:21]=[CH:22][C:23]([C:25]([F:27])([F:28])[F:26])=[CH:24][C:19]=2[CH2:18][N:8]2[C@@H:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:14][CH:13]=3)[CH2:11][O:10][C:9]2=[O:12])=[C:30]([O:39][CH3:40])[CH:31]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Reactant: Cc1ccc(C[C@H]2COC(=O)N2)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)OC[C@@H]1Cc1ccc(C)cc1

Procedure:
(4S)-4-(4-methylbenzyl)-1,3-oxazolidin-2-one (Step B, 14 mg, 0.074 mmol) was treated with sodium hydride (60% in oil, 6.2 mg, 0.154 mmol) and 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl (Intermediate 10, 25 mg, 0.062 mmol) as described in Example 305 to afford (4S)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-(4-methylbenzyl)-1,3-oxazolidin-2-one as clear gum. LCMS=516.4 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.65-7.60 (m, 1 H), 7.53 (s, 1 H), 7.35-7.32 (m, 1 H), 7.06-7.20 (m, 2 H), 6.82-6.75 (m, 2 H), 6.69 (d, J=11.7 Hz, 1 H), 4.67 (d, J=15.8 Hz, 1 H), 4.06 (d, J=15.8 Hz, 1 H), 4.04-4.00 (m, 1 H), 3.96-3.93 (m, 1 H), 3.73 (s, 3 H), 3.55-3.48 (m, 1 H), 3.23-3.15 (m, 1 H), 2.63 (dd, J=13.5, 3.6 Hz, 1 H), 2.35 (d, J=13.5 Hz, 1 H), 2.29 (s, 3 H), 1.25-1.13 (m, 6 H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6]1.[C-:16]#[N:17].[Na+]>CS(C)=O.O>[C:16]([CH2:2][CH2:3][CH2:4][CH:5]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6]1)#[N:17]
Reactant: [C-]#N
Reactant: O=C1Nc2ccccc2SC1CCCBr
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCC1Sc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
To a solution of 2.86 g of 2-(3-bromopropyl)-2H-1,4-benzothiazin-3(4H)-one in 10 ml of dimethyl sulfoxide was added 0.54 g of sodium cyanide. The mixture was stirred at room temperature for 3 hours and diluted with water. The resulting crystals were collected by filtration and washed with water. Recrystallization from methanol gave 1.55 g (66.7%) of 2-(3-cyanopropyl)-2H-1,4-benzothiazin-3(4H)-one as prisms, m.p. 107°-108° C.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[N:6]3[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]3=[N:4][C:3]=2[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: CON(C)C(=O)c1nc2cccc(C)n2c1Br
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CON(C)C(=O)c1nc2cccc(C)n2c1-c1cc(F)cc(F)c1
Temperature: 95 °C
Yield: 81.1 %

Procedure:
A solution of 3-bromo-N-methoxy-N,5-dimethylimidazo[1,2-a]pyridine-2-carboxamide (0.48 g, 1.6 mmol), (3,5-difluorophenyl)boronic acid (0.33 g, 2.1 mmol), and sodium carbonate (0.26 g, 2.4 mmol) in 1,4-dioxane (10 mL) and water (1.9 mL) was degassed with nitrogen and treated with tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol). The reaction mixture was degassed with nitrogen and heated at 95° C. for 19 h. The reaction mixture was concentrated, diluted with ethyl acetate (100 mL), washed with water and brine, dried with sodium sulfate, filtered, and concentrated to a crude solid. Purification by flash column chromatography gave the desired product (0.43 g, 80%). LCMS for C17H16F2N3O2 (m+H)+: m/z=332.1.
Reaction SMILES: I[C:2]1[C:3]([CH3:12])=[N:4][N:5]([CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])[CH:6]=1.C1COCC1.C([Mg]Cl)(C)C.CO[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1.[NH4+].[Cl-]>>[CH3:9][C:8]([OH:10])([CH3:11])[CH2:7][N:5]1[CH:6]=[C:2]([B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[C:3]([CH3:12])=[N:4]1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: Cc1nn(CC(C)(C)O)cc1I
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nn(CC(C)(C)O)cc1B1OC(C)(C)C(C)(C)O1
Reaction time: 1 h

Procedure:
A solution of 1-(4-iodo-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (250.0 mg, 0.8925 mmol) in THF (10 mL, 200 mmol) was added 2 M of isopropylmagnesium chloride in THF (1.339 mL, 2.678 mmol) at rt, and the reaction was allowed to stir for 1 h. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.5850 mL, 3.570 mmol) was then added, and the mixture was stirred at rt for 2 h. Sat. NH4Cl was added to quench, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as a white solid. The material was used in the next step without further purification.