Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:11]=[C:12]([CH:26]=[CH:27][CH:28]=2)[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)=[CH:2]1.S(O)(O)(=O)=O.[NH2:34][CH2:35][C:36]#[N:37].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:11]=[C:12]([CH:26]=[CH:27][CH:28]=2)[CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([NH:37][CH2:36][C:35]#[N:34])=[O:25])=[CH:19][CH:20]=2)=[CH:2]1
Reactant: N#CCN
Reactant: O=C(O)CCc1ccc(OCc2cccc(-c3csc4ccccc34)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCNC(=O)CCc1ccc(OCc2cccc(-c3csc4ccccc34)c2)cc1
Yield: 65.3 %

Procedure:
A solution of 3-(4-{[3-(1-benzothiophen-3-yl)benzyl]oxy}phenyl)propanoic acid (0.20 g, 0.51 mmol), aminoacetonitrile sulfate (65 mg, 0.62 mmol), triethylamine (0.17 mL, 1.22 mmol), 1-hydroxybenzotriazole (91 mg, 0.67 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.13 g, 0.68 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, and the mixture was washed successively with aqueous citric acid solution, aqueous sodium bicarbonate and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained pale-yellow oil was crystallized from diethyl ether to give the title compound (142 mg, yield 33%) as colorless needle crystals. MS: m/z 427 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1>CO>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:7]1
Reactant: CN1CCC(N2CCc3ccc([N+](=O)[O-])cc32)CC1
Solvent: CO
Product: CN1CCC(N2CCc3ccc(N)cc32)CC1
Reaction time: 8 h

Procedure:
1-(1-Methyl(4-piperidyl))-6-nitroindoline (3 g, Step A) was dissolved in 100 mL MeOH and the mixture was bubbled with H2 for 10 min. 10% Pd/C (200 mg) was added and the mixture was stirred under H2 overnight. The mixture was filtered through Celite® and concentrated in vacuo to afford light yellow oil. MS: 232 (M+1). Calc'd. for C14H21N3−231.3.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]([OH:25])=O)=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([CH:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[O:34])[N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>N1C=CC=CC=1.CC#N.C(Cl)(Cl)Cl>[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([CH:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[O:34])[N:28]=2)=[O:25])=[CH:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1cn(Cc2ccccc2)c2ccccc12
Reactant: CN1CCC(C(=O)c2cccc(N)n2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cn(Cc4ccccc4)c4ccccc34)n2)CC1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 51.2 %

Procedure:
Add oxalyl chloride (0.18 mL, 2.1 mmol) dropwise to a solution of 1-benzylindol-3-carboxylic acid (0.48 g, 1.9 mmol) in pyridine and CH3CN (5 mL each) cooled in an ice bath. Stir the reaction mixture for 2.25 hr. and then add a suspension of 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.56 g, 1.9 mmol) in CH3CN (5 mL) and pyridine (12 mL). Warm the reaction mixture to room temperature overnight. Quench the reaction with cold H2O (20 mL) and dilute with CHCl3. Adjust the pH to 11 with Na2CO3 and separate the layers. Extract the aqueous layer with CHCl3 (2×30 mL). Combine the organic fractions and dry with anhydrous MgSO4, filter and concentrate the mixture in vacuo. Purify the product by chromatography on a silica gel column, eluting with methanol/CH2Cl2 (5:95) followed by methanol/CH2Cl2 (10:90) to afford the sub-title compound (0.44 g, 51%). 1H NMR (CD3OD) 8.45 (d, J=8 Hz, 1H), 8.32 (s, 1H), 8.26 (m, 1H), 7.95 (t, J=8 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.45 (m, 1H), 7.22-7.37 (m, 7H), 5.51 (s, 2H), 3.90 (m, 1H), 2.93-3.01 (m, 2H), 2.33 (s, 3H), 2.21-2.31 (m, 2H), 1.92-1.99 (m, 2H), 1.71-1.84 (m, 2H); CIMS (Methane) m/z 453 [C28H28N4O2+H]+.
Reaction SMILES: [C:1]([C:5]1[N-:6][C:7]([C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17])=[C:8]([C:10]([CH3:14])([CH3:13])[CH2:11][CH3:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[K+].[Cl-].CC1[C-](C)C(C)=C(C)C=1C.[Ru+2:32]>C1COCC1>[C:1]([C:5]1[N-:9][C:8]([C:10]([CH3:13])([CH3:14])[CH2:11][CH3:12])=[C:7]([C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Ru+3:32].[C:1]([C:5]1[N-:9][C:8]([C:10]([CH3:13])([CH3:14])[CH2:11][CH3:12])=[C:7]([C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:1]([C:5]1[N-:9][C:8]([C:10]([CH3:13])([CH3:14])[CH2:11][CH3:12])=[C:7]([C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [Ru+2]
Agent: CCC(C)(C)c1nc(C(C)(C)C)[n-]c1C(C)(C)CC
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: [Cl-]
Solvent: C1CCOC1
Product: [Ru+3]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.1 g (37 mmoles) of potassium(2-tert-butyl-4,5-di(1,1-dimethylpropyl)imidazolate) dissolved in 25 ml of THF were added to 1 g (0.0037 moles) of ruthenium (pentamethylcyclopentadienide) chloride dissolved in 75 ml of dry THF and the resulting mixture stirred overnight at room temperature. The solvent was then removed by vacuum, 100 ml of dry hexane then added and the resulting mixture thoroughly stirred then filtered. The hexane was then removed by vacuum to yield 1.13 g of crude ruthenium (2-tert-butyl-di(1,1-dimethylpropyl)imidazolate). (pentamethylcyclopentadienide). Structure confirmed by GCMS, parent ion detected at 499 mu. The structure was also confirmed by X-ray structural analysis of a sample of crude material which was sublimed then recrystallized from hexane. This shows the imidazolate and cyclopentadienide anions to both be coordinated eta-5 to ruthenium, see FIG. 21.
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:11].[Li+].[CH3:13][CH:14]([N-]C(C)C)[CH3:15].C(Br)C=C>C1COCC1>[O:11]=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]1[CH2:15][CH:14]=[CH2:13]
Reactant: O=C1CCc2ccccc2C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC1C(=O)CCc2ccccc21
Temperature: 0 °C
Reaction time: 24 h
Yield: 33.3 %

Procedure:
To a solution of 7.3 g (50 mmol) 2-tetralone in 75 mL THF in a 3-neck round-bottomed flask, equipped with a gas inlet and septum, was added 36.7 mL LDA (55 mmol, 1.5M in cyclohexane) at -30° C. under a nitrogen atmosphere. The solution was allowed to warm to 0° C. over a 30-minute period and 5.6 mL (65 mmol) allyl bromide was added. TLC analysis was used to monitor the reaction. After stirring for 24 hours at room temperature, the reaction mixture was quenched with 10% sodium bisulfate to pH 2-3. After removal of THF under reduced pressure, the mixture was extracted with ethyl acetate (2×1 L) and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by liquid chromatography on 800 g of silica gel 60 (230-400 m), eluting with 1 L of hexane, followed by 5 L of 5% ethyl acetate/hexane, and collecting 40 mL fractions. Fractions 65-82 gave 3.1 g (33%) of pure 1,2,3,4-Tetrahydro-2-oxo-1-(2-propenyl)naphthalene as a light yellow oil.
Reaction SMILES: CS(O[CH:6]([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1)[CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])(=O)=O.C(Cl)Cl.[OH-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][CH:6]2[CH2:7][N:8]2[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:22][CH:23]=1)#[N:28]
Reactant: CS(=O)(=O)OC(CNC(=O)OCc1ccccc1)COc1ccc(C#N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: N#Cc1ccc(OCC2CN2C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 89.5 %

Procedure:
2-{[(Benzyloxy)carbonyl]amino}-1-[(4-cyanophenoxy)methyl]ethyl methanesulfonate (47.7 mg; 0.12 mol; from step (ii) above), tetrabutylammonium hydrogensulfate (4.81 g; 0.014 mol) and 290 mL of DCM were mixed and cooled to 0° C. 97 mL of 50% NaOH was added and the mixture was stirred vigorously for 50 minutes. 500 mL of water and 500 mL of ether were added. The organic phase was separated, washed with water, dried (Na2SO4) and evaporated. Purification by chromatography on silica (DCM) gave 33.13 g (89%) of the sub-title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:10]([S:17][CH:8](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Br)cc1
Reactant: SCc1ccccc1
Agent: [Na]
Product: Brc1ccc(/C=C\C(SC(/C=C\c2ccc(Br)cc2)c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 4-bromophenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to Procedure 2 to form (Z)-4-bromostyryl benzylsulfide. The title compound was obtained in 80% yield following oxidation. 1HNMR (CDC13) δ4.52 (2H, s), 6.80 (1H, d, JH,H=11.98), 7.18-7.59 (9H aromatic+1H ethylenic).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][C:10]([F:9])([F:20])[F:21])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S)cc1
Reactant: FC(F)(F)Oc1ccc(CCl)cc1
Product: Cc1ccc(SCc2ccc(OC(F)(F)F)cc2)cc1
Yield: 80.1 %

Procedure:
The procedure of Example 87 is repeated using 11.8 g of p-thiocresol and 9.6 g of 4-(trifluoromethoxy)benzyl chloride. This affords 10.9 g of the desired product as white crystals. mp 74°-76° C. MS(CI): m/z 299(MH+). Calcd for C15H13F3OS: C=60.39, H=4.39, F=19.11, S=10.75 Found C=60.33, H=4.26, F=19.34, S=11.01
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][NH2:14]>C1COCC1>[CH3:13][NH:14][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
4-Fluoro-3-nitrobenzonitrile (0.25 g, 1.5 mmol) was cautiously added to a solution of methylamine (2.0 M, 5.0 mL) in THF. The mixture was stirred at room temperature for 8 h, concentrated under reduced pressure, and chromatographed (silica gel, DCM) to give the title product (0.18 g, 68%) as a yellow solid. 1H-NMR (CDCl3): δ 8.52 (1H, d), 8.41 (1H, br s), 7.64 (1H, dd), 6.92 (1H, d), 3.10 (3H, d).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]2[NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:13][C:3]=12.Cl.[CH3:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH2:29].C(N(CC)C(C)C)(C)C.CN1CCN(C)C1=O>CCOC(C)=O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[NH:11][C:4]3=[N:5][CH:6]=[C:7]([C:8]([NH2:10])=[O:9])[C:2]([NH:29][C@H:24]4[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]4[CH3:22])=[C:3]3[CH:13]=2)=[CH:15][CH:16]=1
Reactant: NC(=O)c1cnc2[nH]c(-c3ccc(F)cc3)cc2c1Cl
Reactant: C[C@@H]1CCCC[C@@H]1N
Agent: Cl
Solvent: CN1CCN(C)C1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCCC[C@@H]1Nc1c(C(N)=O)cnc2[nH]c(-c3ccc(F)cc3)cc12
Temperature: 25 °C
Yield: 15.5 %

Procedure:
4-Chloro-2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (70 mg),(1S,2R)-2-methylcyclohexanamine hydrochloride (108.5 mg),N,N-diisopropylethylamine (0.126 ml) and 1,3-dimethyl-2-imidazolidinone (0.35 ml) were combined and irradiated microwave at 16° C. for 1 hour. After cooled to ambient temperature, the mixture was diluted in EtOAc. The organic solution was washed with saturated aqueous sodium hydrogencarbonate, dried over MgSO4 and evaporated in vacuo. The residue was purified by preparative NH2 silica gel column chromatography with 5% methanol in chloroform to give 2-(4-fluorophenyl)-4-{[(1S,2R)-2-methylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (13.7 mg) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[C:24](=[O:25])[N:23]([O:26][CH3:27])[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[CH:18][C:13]=2[CH:12]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32].Cl>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[C:24](=[O:25])[N:23]([O:26][CH3:27])[C:14]2[N:15]=[C:16]([NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])[N:17]=[CH:18][C:13]=2[CH:12]=1
Reactant: COn1c(=O)c(-c2cc([N+](=O)[O-])ccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: CN(C)CCN
Agent: Cl
Solvent: CC(C)O
Product: COn1c(=O)c(-c2cc([N+](=O)[O-])ccc2Cl)cc2cnc(NCCN(C)C)nc21
Temperature: 100 °C

Procedure:
6-(2-Chloro-5-nitrophenyl)-8-methoxy-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (4.87 mmol), N,N-dimethylethane-1,2-diamine (11.3 mmol), and conc. aq. hydrochloric acid (2.0 mL) were placed in a microwave vessel and dissolved in 2-propanol (18 mL). The mixture was heated with microwave irradiation in a sealed vessel at 100° C. for 15 min. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc. The organic layer was washed with water and aqueous buffer (aq. KH2PO4 and NaOH. pH 7.0). The aqueous layer was backextracted with EtOAc (4×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give solid 6-(2-chloro-5-nitrophenyl)-2-(2-(dimethylamino)ethylamino)-8-methoxypyrido[2,3-d]pyrimidin-7(8H)-one that was used without furoom temperatureher purification (53%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[C:6](=[O:26])[N:7]=[C:8]([C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)[CH:13]=[CH:12][N:11]=3)[S:9][C:4]=2[CH:3]=1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[NH2:18][CH2:17][CH2:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([C:8]2[S:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:28]=[CH:27][C:5]=3[C:6](=[O:26])[N:7]=2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccnc(-c2nc(=O)c3ccc(Cl)cc3s2)c1
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccnc(-c2nc(=O)c3ccc(Cl)cc3s2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
tert-Butyl 2-[2-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]ethylcarbamate (0.36 g, 0.86 mmol) was dissolved in trifluoroacetic acid (10 ml), and the mixture was stirred at room temperature for 3 hrs. The solvent was evaporated, and the residue was recrystallized from methanol-diisopropyl ether to give the titled compound (0.33 g, 89%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[C:4](=[O:17])[C:3]=1[CH:18]=[N:19]O.S(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[C:4](=[O:17])[C:3]=1[C:18]#[N:19]
Reactant: N#Cc1cccc(F)c1-n1ccc(Cl)c(C=NO)c1=O
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: N#Cc1cccc(F)c1-n1ccc(Cl)c(C#N)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a solution of 2-(4-chloro-3-((hydroxyimino)methyl)-2-oxopyridin-1(2H)-yl)-3-fluorobenzonitrile obtained in Step D (8.0 g) in acetonitrile (180 mL) was added thionyl chloride (3.98 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was crystallized from diisopropyl ether/methanol. The obtained solid was collected by filtration to give the title compound (7.05 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])([CH3:10])[CH3:9])[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[N:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.COCCOC.O.C(O)C.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>[CH2:14]([S:11]([C:8]([C:6]1[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[N:3]=[C:2]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[N:7]=1)([CH3:10])[CH3:9])(=[O:13])=[O:12])[CH3:15]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CCS(=O)(=O)C(C)(C)c1cc(N2CCOC[C@@H]2C)nc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CCS(=O)(=O)C(C)(C)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(N)cc2)n1
Temperature: 85 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
Dichlorobis(triphenylphosphine)palladium(II) (0.360 g, 0.51 mmol) was added to a degassed solution of 2-chloro-4-(2-ethylsulfonylpropan-2-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (1.784 g, 5.13 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.404 g, 6.41 mmol) and sodium carbonate (12.82 mL, 25.64 mmol) in a mixture of 18% DMF in DME:water:ethanol (7:3:2) (25 mL). The resulting solution was stirred at 85° C. for 2 hours. The reaction mixture was concentrated and partitioned between DCM (150 mL), and water (100 mL) and the organics washed with brine (100 mL), dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 2.5% methanol in DCM, to give the desired material as a brown solid (1.20 g).
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:55][O:56][C:57]1[CH:65]=[C:64]2[C:60]([CH2:61][CH2:62][C:63]2=[O:66])=[CH:59][CH:58]=1>CO.ClCCl>[Br:1][CH:62]1[CH2:61][C:60]2[C:64](=[CH:65][C:57]([O:56][CH3:55])=[CH:58][CH:59]=2)[C:63]1=[O:66]
Reactant: [Br-]
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(c1)C(=O)C(Br)C2

Procedure:
49.2 g (102 mmol) of tetra-n-butylammonium tribromide are added in fractions over the course of 15 minutes, at room temperature, to 16.2 g (100 mmol) of 6-methoxy-indan-1-one dissolved in 400 ml of methanol and 1 litre of dichloromethane, and the mixture is then stirred overnight at room temperature. After evaporation, the residue is taken up in 500 ml of dichloromethane and washed twice with 250 ml of N hydrochloric acid. Drying over magnesium sulphate and concentration, and then rapid filtration over 500 g of silica (eluant:dichloromethane) yield 23.4 g of the desired product.
Reaction SMILES: Cl.[Cl:2][C@H:3]1[CH2:20][C@@:19]2([CH3:21])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][C@H:12]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:13]2=[O:22])[CH2:5][C@@H:4]1[OH:29].[OH-].[Na+].[BH4-].[Na+]>C(Cl)Cl.CO>[Cl:2][C@H:3]1[CH2:20][C@@:19]2([CH3:21])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][C@H:12]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C@@H:13]2[OH:22])[CH2:5][C@@H:4]1[OH:29]
Reactant: C[C@]12C[C@H](Cl)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@@H](N3CCCCC3)C[C@@H]12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C[C@]12C[C@H](Cl)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCCC3)C[C@@H]12
Reaction time: 5 h

Procedure:
25 g (0.056 mole) of 2β-chloro-3α-hydroxy-17-oxo-16β-piperidino-5α-androstane-hydrochloride (Example 14) are dissolved in the mixture of 52 ml of methylene chloride and 125 ml of methanol. Under vigorous stirring 2.75 g (0.069 mole) of pulverized sodium hydroxide are added at a temperature of 15°-20° C. 12.5 g (0.33 mole) of sodium borohydride are also added to the solution. The product precipitated immediately. The crystalline solution is stirred for 5 hours, whereafter the product is filtered and washed with water. The mother liquor is evaporated at reduced pressure at a temperature of below 30° C, the residue is triturated with water, the mixture is filtered and the second crop above the filter is washed with water. The two fractions are combined, dried in vacuo at 50° C, followed by recrystallization from acetone. Yield: 20.2 g (88%) of 2β-chloro-3α,17β-dihydroxy-16β-piperidine-5α-androstane; m.p. 232°-234° C.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[C:8]([CH3:15])=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[Cl:6][C:7]1[C:8]([CH3:15])=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[CH2:1]
Reactant: Cc1c(Cl)cccc1C=O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cc1cccc(Cl)c1C
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Methyltriphenylphosphonium bromide (6.9 g, 0.019M) was suspended in dry tetrahydrofuran (100 ml) at -40° C. under an atmosphere of dry nitrogen. n-Butyllithium (13.5 ml. of a 1.55M solution in hexane, 0.021M) was added dropwise during 10 minutes and the mixture was stirred at -40° C. for 30 minutes. 3-Chloro-2-methylbenzaldehyde (3.0 g, 0.019M) in dry tetrahydrofuran (10 mls) was then added. The mixture was maintained at -40° C. for 30 minutes and then allowed to warm to room temperature. Hexane (150 ml) was added and the mixture was filtered. The hexane was evaporated to give crude 3-chloro-2-methylstyrene which was used directly without further purification.