Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]([OH:14])=O)=[N:9][NH:10][CH:11]=1)=[O:5].[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:30]([O:29][C:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:12]([C:8]2[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:2]=3[Cl:1])=[CH:11][NH:10][N:9]=2)=[O:14])[CH2:22][CH2:23]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2n[nH]cc2NC(=O)c2c(Cl)cccc2Cl)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.6 %

Procedure:
A mixture of 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid (6.5 g, 21.6 mmol), 4-amino-1-BOC-piperidine (4.76 g, 23.8 mmol), EDC (5.0 g, 25.9 mmol) and HOBt (3.5 g, 25.9 mmol) in DMF (75 ml) was stirred at room temperature for 20 hours. The reaction mixture was reduced in vacuo and the residue partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate solution (100 ml). The organic layer was washed with brine, dried (MgSO4) and reduced in vacuo. The residue was taken up in 5% MeOH-DCM (˜30 ml). The insoluble material was collected by filtration and, washed with DCM and dried in vacuo to give 4-{[4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (5.38 g) as a white solid. The filtrate was reduced in vacuo and the residue purified by column chromatography using gradient elution 1:2 EtOAc/hexane to EtOAc to give further 4-{[4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (2.54 g) as a white solid.
Reaction SMILES: O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27](=[O:28])[C:26](I)=[C:25]([O:30][CH3:31])[C:24](=[O:32])[NH:23][C:22]=2[CH:33]=1.C([Sn](CCCC)(CCCC)[C:39]1[S:40][CH:41]=[CH:42][CH:43]=1)CCC>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27](=[O:28])[C:26]([C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)=[C:25]([O:30][CH3:31])[C:24](=[O:32])[NH:23][C:22]=2[CH:33]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: Cc1ccccc1
Product: COc1c(-c2cccs2)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reaction time: 0.17 h

Procedure:
A solution of tri(2-furyl)phosphine (0.036 g) and tris(dibenzylideneacetonedipalladium (O) (0.26 g) in toluene (50 mL) was allowed to stir for 10 minutes. To this solution was added 8-chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H- benz[b]azepine (1.0 g), followed by 2-tributylstannylthiophene (1.24 g). The reaction was heated to reflux for 1.5 hours, was allowed to cool, and the toluene was evaporated. The residue was triturated with hot hexanes (75 mL). The title compound was afforded upon filtration (0.76 g); mp >240; NMR: 11.47 (bs, 1), 7.73 (dd, 1, J=5.1, 0.8), 7.60 (d, 1, J=7.9), 7.51 (dd, 1, J=4.0), 7.33 (d, 1, J=7.8), 7.31 (s, 1), 7.14 (dd, 1, J=5.1, 4.1), 3.88 (s, 3). Analysis for C15H10O3SClN: Calculated: C, 56.34; H, 3.15; N, 4.38; Found C, 55.96; H, 3.34; N, 4.33.
Reaction SMILES: [CH2:1]([C:4]1[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]=[CH2:3].[OH:23]O>C1COCC1.C([O-])(O)=O.[Na+]>[OH:23][CH2:3][CH2:2][CH2:1][C:4]1[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: OO
Reactant: C=CCc1c(OCc2ccccc2)cccc1C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(OCc2ccccc2)c1CCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A solution of ethyl 2-allyl-3-benzyloxybenzoate (29.6 g, 100 mmol) in THF (300 ml) was cooled to -10° C. under nitrogen. A solution of borane THF complex (110 ml of 1M, 110 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature and stirred for 1 hr. A solution of hydrogen peroxide (12 ml) in saturated NaHCO3 (200 ml) was then slowly added, and the mixture was stirred for 30 min. The mixture was extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water, dried over brine, and then concentrated in vacuo to give a clear oil (27.6 g, 88%).
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:20]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][N:22]=4)[CH:18]=3)[N:13]([CH3:34])[C:12](=[O:35])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[CH2:36](Cl)[Cl:37].[K]>COCCOC.O.CC(O)C>[Cl:37][CH2:36][C:20]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:34])[C:12](=[O:35])[CH:11]=[C:10]2[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=1)([C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:21]1[N:25]([CH3:26])[CH:24]=[N:23][N:22]=1
Reactant: ClCCl
Reactant: Cn1cnnc1C(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Agent: N#N
Agent: [K]
Solvent: COCCOC
Solvent: O
Solvent: CC(C)O
Product: Cn1cnnc1C(CCl)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reaction time: 1 h
Yield: 51 %

Procedure:
N2 was bubbled at room temperature to a solution of 4-(3-chlorophenyl)-6-[(4-chlorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone (0.00105 mol), obtained in Example B7, in DME (8.5 ml) for 30 minutes. DCM (2 ml) was added. Then 2-methyl, 2-propanol, potassium salt (0.0021 mol) was added portionwise. The mixture was stirred for 1 hour, poured out into water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated till dryness. The residue (0.55 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 100 to 95/5; 10 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.35 g, 64%) was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.28 g (51%) of 6-[2-chloro-1-(4-chlorophenyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)ethyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone, mp. 260° C.
Reaction SMILES: Cl[Si](C)(C)C.[C:6]([C:9]1[CH:10]=[C:11]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:12]([O:19]COC)=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[CH:14]=1)(=[O:8])[CH3:7].[I-].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[C:6]([C:9]1[CH:10]=[C:11]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:12]([OH:19])=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[CH:14]=1)(=[O:8])[CH3:7]
Reactant: COCOc1c(NC(C)=O)cc(C(C)=O)cc1C(C)(C)C
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(C(C)=O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
Chlorotrimethylsilane (36.5 ml, 288 mmol) was added dropwise to a solution of the N1-[5-acetyl-3-(tert-butyl)-2-(methoxymethoxy)phenyl]acetamide (56.2 g, 192 mmol) and sodium iodide (43.1 g, 288 mmol) in tetrahydrofuran (300 ml) under a nitrogen atmosphere while cooling on ice, and then the mixture was stirred at the same temperature for 10 minutes and at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate (400 ml)-ice (300 ml) mixed solvent while stirring. Following extraction twice with ethyl acetate, the organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine in that order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to yield the title compound (first crystallization=30.5 g, second crystallization=3.55 g, 71.3% yield) as white needle-like crystals.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]4[CH2:23][CH2:22]4)=[CH:15][N:14]3[CH:24]=2)=[CH:7][CH:6]=1)(=O)C.[F:25]C(F)(F)S([O-])(=O)=O.ClC1C=CC=C(Cl)[N+]=1F.C(=O)([O-])O.[Na+]>C(#N)C>[CH:21]1([CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]3[N:14]([C:24]([F:25])=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=4)[N:12]=3)[CH:15]=2)[CH2:23][CH2:22]1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CC(=O)Oc1ccc(-c2cn3cc(OCC4CC4)ccc3n2)cc1
Agent: F[n+]1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Oc1ccc(-c2nc3ccc(OCC4CC4)cn3c2F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.7 %

Procedure:
A mixture of 4-[6-(cyclopropylmethoxy)imidazo[1,2-a]pyridin-2-yl]phenyl acetate (425 mg), 2,6-dichloro-1-fluoropyridinium trifluoromethanesulfonate (1.25 g) and acetonitrile (6 mL) was stirred at room temperature for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and the obtained compound was dissolved in methanol (6 mL). 1M Aqueous sodium hydroxide solution (0.66 mL) was added at room temperature, and the mixture was stirred for 1 hr, and concentrated under reduced pressure. The residue was diluted with ethyl acetate and water, and the mixture was neutralized with 1M hydrochloric acid, and the aqueous layer was separated from the organic layer. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a pale-brown powder (54 mg).
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(O)CO>[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[N:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])=[CH:17][CH:16]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: C#CCNC(=O)c1cccnc1Cl
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1ccc(Cl)cc1
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-chloroaniline (9c, 127 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-chlorophenylamino)-N-(prop-2-ynyl)nicotinamide 10c as pure product. To a solution of 2-(4-chlorophenylamino)-N-(prop-2-ynyl)nicotinamide (10c 150 mg, 0.52 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12c, 130 mg, 0.57 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1c (204 mg 76%); mp: 127-129° C.; 1H NMR (300 MHz, CDCl3) δ 10.51 (s, 1H), 8.25 (dd, J=2.2, 1.5 Hz, 1H), 7.84 (dd, J=2.2, 1.5 Hz, 1H), 7.80 (brs, 1H), 7.61-7.58 (m, 3H), 7.35-7.23 (m, 4H), 7.08 (t, J=7.5 Hz, 1H), 6.98-6.91 (m, 7H), 6.67-6.63 (m, 1H), 5.45 (s, 2H), 4.62 (d, J=5.2 Hz, 2H); MS (ESI m/z): 511 [M+H]+. Yield: 76%
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([OH:15])[CH:12]=3)[C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]([O:24][C:25](=[O:28])[CH2:26]Br)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].O=C1C2C(=CC(OCC(OC(C)(C)C)=O)=C(Cl)C=2Cl)CC1C1CCCC1>O.CN(C)C=O>[O:18]=[C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:15][CH2:26][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:28])=[C:10]([Cl:16])[C:9]=2[Cl:17])[CH2:14][C:6]1([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH3:19]
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)OC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Reaction time: 1 h

Procedure:
A mixture of 2-cyclopentyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (2.98 g., 0.01 mole), tert.-butylbromoacetate (2.15 g., 0.011 mole), potassium carbonate (2.76 g., 0.02 mole) and dimethylformamide (15 ml.) is stirred at 25° for 1 hour then poured into water (50 ml.) the tert.-butyl (1-oxo-2-cyclopentyl-6,7-dichloro-5-indanyloxy)acetate which separates is filtered, rinsed with water and dried.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@H:4]([CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=1[NH2:27])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[OH-].[Na+]>CC(OC)(C)C.[Cl-].[Na+]>[C:9]([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:28])=[O:2])[CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=1[NH2:27])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: C=CCOC(=O)c1ccc(SC[C@H](NC(=O)OC(C)(C)C)C(=O)OC)c(N)c1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: C=CCOC(=O)c1ccc(SC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c(N)c1
Yield: 91.9 %

Procedure:
0.769 mg (1.658 mmol) of N-tert-butoxycarbonyl-3-(4-alloxycarbonyl-2-aminophenyl-thio)-L-alanine methyl ester was dissolved in 40 ml TBME and emulsified in 220 ml 0.1M sodium chloride solution; 3 mM sodium phosphate buffer pH 7.5 under vigorous stirring. 1.0 ml Alcalase 2.4 L [a subtilisin Carlsberg from Novo Nordisk] was added and the pH maintained at 7.5 under vigorous stirring by the controlled addition (pH-static) of 1.0N sodium hydroxide solution. After 45.4 h 23.6 ml of 1.0N sodium hydroxide solution was consumed and the conversion degree was >97% (HPLC analysis). The reaction mixture was extracted with 100 ml TBME. After phase separation, the aqueous phase was acidified to pH 2.3 with 32% hydrochloric acid and extracted with 3×250 ml ethyl acetate. In case a stabile emulsion was formed the phase separation was achieved by filtration on Dicalite. The combined ethyl acetate extracts were dried on anhydrous sodium sulfate and evaporated. The residue was dissolved in dichloromethane, evaporated and dried at HV to give 604 mg N-tert-butoxycarbonyl-3-(4-alloxycarbonyl-2-aminophenylthio)-L-alanine as a pale yellow solid (yield: 93.9%, purity: 95%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH:14]1[CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[O:11][CH2:13][CH:14]1[CH2:16][CH2:15]1
Reactant: COc1cc(O)c(Br)cc1F
Reactant: BrCC1CC1
Product: COc1cc(OCC2CC2)c(Br)cc1F

Procedure:
Starting from 2-bromo-4-fluoro-5-methoxy-phenol (example B.a2) and commercially available bromomethyl-cyclopropane the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH:27]1[C:32]#[N:33])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:28][CH:27]1[C:32]#[N:33])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#CC1CNCCN1C(=O)OCc1ccccc1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: N#CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CCN1C(=O)OCc1ccccc1

Procedure:
Intermediate 1 was coupled with 2-cyano-piperazine-1-carboxylic acid benzyl ester (generated according to literature procedure (ref 4)) following procedure B. LC-MS showed the product had the expected M+H+ of 448.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.ClC1N=CC=CC=1C(Cl)=O.[Cl:25][C:26]1[C:31]([NH2:32])=[C:30]([CH3:33])[CH:29]=[CH:28][N:27]=1>>[Cl:1][C:2]1[C:3]([C:4]([NH:32][C:31]2[C:26]([Cl:25])=[N:27][CH:28]=[CH:29][C:30]=2[CH3:33])=[O:6])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: Cc1ccnc(Cl)c1N
Agent: O=C(Cl)c1cccnc1Cl
Solvent: O=S(Cl)Cl
Product: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl

Procedure:
In the method of Hargrave et al., 2-chloronicotinoyl chloride is formed by reacting 2-chloronicotinic acid with thionyl chloride. Next, as shown in Scheme 1, the reaction of 2-chloronicotinoyl chloride with 2-chloro-4-methyl-3-pyridinamine produces 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide. This is reacted with cyclopropylamine to give N-(2-chloro-4-methyl-3-pyridinyl)-2-(cyclopropylamino)-3-pyridinecarboxamide. The final step is the cyclization to produce nevirapine, which occurs on treatment of the final intermediate with sodium hydride.
Reaction SMILES: C(OC(=O)NC(C1SC(SC)=C(S(C2C=C(C3C(C)=CC=CC=3N)C=CC=2)(=O)=O)C=1)=N)(C)(C)C.BrCC(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].N1C(C)=CC=CC=1C.CCN(CC)CC.C([O:69][C:70](=[O:106])[CH2:71][NH:72][C:73]1[CH:78]=[CH:77][CH:76]=[C:75]([CH3:79])[C:74]=1[C:80]1[CH:85]=[CH:84][CH:83]=[C:82]([S:86]([C:89]2[CH:93]=[C:92]([C:94]([NH:96]C(OC(C)(C)C)=O)=[NH:95])[S:91][C:90]=2[S:104][CH3:105])(=[O:88])=[O:87])[CH:81]=1)(C)(C)C>CCOC(C)=O.C1(C)C=CC=CC=1>[C:94]([C:92]1[S:91][C:90]([S:104][CH3:105])=[C:89]([S:86]([C:82]2[CH:81]=[C:80]([C:74]3[C:75]([CH3:79])=[CH:76][CH:77]=[CH:78][C:73]=3[NH:72][CH2:71][C:70]([OH:106])=[O:69])[CH:85]=[CH:84][CH:83]=2)(=[O:88])=[O:87])[CH:93]=1)(=[NH:95])[NH2:96]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NCC(=O)OC(C)(C)C)c1
Agent: CC(C)(C)OC(=O)CBr
Agent: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NCC(=O)O)c1
Temperature: 80 °C

Procedure:
{[4-(2′-Amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (75 mg, 0.15 mmol, Example 25: step c), tert-butyl bromoacetate (43 μL, 0.29 mmol), potassium carbonate (29 mg, 0.21 mmol) and 2,6-lutidine (33 μL, 0.29 mmol) were dissolved into toluene (2 mL). The reaction was stirred and heated to 80° C. for 12 hours. Et3N (41 μL, 0.3 mmol) was added to reaction and heated to 80° C. for another 12 hours. The reaction mixture was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4), the solvents were removed in vacuo followed purified by preparative SiO2 TLC purification (20% MeOH in DCM) resulting in {3′-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylamino}-acetic acid tert-butyl ester. ESI-MS (m/z): Calcd. for C30H37N3O6S3: 632.2 (M+1) found: 631.9. {3′-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylamino}-acetic acid tert-butyl ester was deprotected and purified as Example 1: step d, yielding the title compound as brown solid (1.7 mg). 1H-NMR (CD3OD): δ 8.35 (s, 1H), 8.08–8.06 (d, 1H, J=8.83 Hz), 7.77 (t, 1H, J=7.44 Hz, J=7.67 Hz), 7.63–7.61 (d, 1H, J=7.67 Hz), 7.16 (t, 1H, J=7.91 Hz, J=7.91 Hz), 7.05–6.68 (d, 2H, J=7.67 Hz), 6.52–6.50 (d, 1H, J=8.14 Hz), 3.81 (s, 1H), 2.72 (s, 3H), 2.17 (s, 3H). ESI-MS (m/z): Calcd. for C21H21N3O4S3: 476.1 (M+1); found: 476.1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:10]N1C(=O)CCC1=O.CC(O)=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccnc1C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: N#Cc1ncccc1CBr
Temperature: 25 °C
Yield: 21.4 %

Procedure:
To a solution of 3-methylpicolinonitrile (700 mg, 5.93 mmol) in CCl4 (15 mL) was added recrystallized N-bromosuccinimide (1.21 g, 6.82 mmol), followed by glacial HOAc (0.34 mL, 1.0 eq), and AIBN (97 mg, 0.60 mmol). The resultant mixture was heated to 65° C. for 3 hours, 80° C. for 2 hours, and then cooled to room temperature. The mixture was filtered through filter paper, and the filtrate was concentrated. Purification of the crude material by flash chromatography (Hexanes/EtOAc, 90:10 followed by 80:20) provided 3-bromomethyl-pyridine-2-carbonitrile (250 mg, 21%) as a white solid. 1H NMR(CDCl3) δ 4.63 (s, 2H), 7.55 (dd, 1H, J=8.0, 4.6 Hz), 7.93 (dd, 1H, J=7.9, 1.2 Hz), 8.64 (dd, 1H, J=4.8, 1.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][CH:5]=1.II.IC(C)(C)C.FC(F)(F)C(O)=[O:22].[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:22])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(C)nc1
Reactant: O=C(O)C(F)(F)F
Agent: CC(C)(C)I
Agent: II
Agent: O=C([O-])O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(C=O)nc1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
A solution of 6-methyl nicotinic acid methyl ester (1.00 g, 6.62 mmol), iodine (1.68 g, 6.62 mmol), 2-iodo-2-methylpropane (0.478.g, 2.60 mmol) and trifluoroacetic acid (2.26 g, 19.8 mmol) in anhydrous DMSO was heated for 3 h at 160° C. The reaction mixture was cooled to room temperature (rt) and treated with 1 N aq. Na2S2O3 (50 mL). The reaction mixture was adjusted to pH 10 with 1 N aq. NaHCO3. The reaction mixture was extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. Chromatography of the residue (SiO2; 0-3% EtOH:DCM) gave the title compound as a solid (0.506 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:46])([F:45])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43]Br)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26]>>[F:21][C:22]([F:45])([F:46])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43][N:16]2[CH2:15][CH2:14][N:13]([C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([O:6][C:5]4[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:12]=3)[CH2:18][CH2:17]2)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Clc1ccc(Oc2cccc(N3CCNCC3)n2)cc1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cccc(Oc4ccc(Cl)cc4)n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-[6-(4-chloro-phenoxy)-pyridin-2-yl]-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[CH2:5][C:4](=[O:16])[CH:3]=1.[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[CH3:15][C:9]1[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[CH:6]1[CH2:7][C:2]2[N:1]=[CH:7][CH:2]=[C:3]([CH3:4])[C:3]=2[C:4](=[O:16])[CH2:5]1
Reactant: Cc1ccc(C)c(C2CC(=O)C=C(N)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(C)c(C2CC(=O)c3c(C)ccnc3C2)c1
Temperature: 115 °C
Yield: 130.8 %

Procedure:
In a mixture of ethanol (35 ml) and toluene (90 ml) was dissolved 1-amino-5-(2,5-dimethylphenyl)cyclohexen-3-one (1.7 g), and to the solution were added 3-oxobutylaldehydedimethylacetal (2.66 g) and granulated potassium hydroxide (440 mg). The mixture was stirred at 115° C. (bath temperature), and to the mixture was added granulated potassium hydroxide (90 mg), 30 minutes later; 1 hour later; and 1.5 hours, respectively. The reaction solution was stirred at the same temperature for 1 hour and cooled. Under reduced pressure, the solvent was evaporated, and to the residue were added ethyl acetate (40 ml) and water (20 ml). The mixture was shaken and separated ethyl acetate layer was washed with brine. Under reduced pressure, ethyl acetate was evaporated, and the residue was purified with silica gel column chromatography (EtOAc/hexane) and eluted with ethyl acetate/hexane to give 7-(2,5-dimethylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.37 g) as colorless crystals.