Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][NH:7]1)=[O:5])[CH3:2].[O:16]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][N:7]1[C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:24]=1)=[O:5])[CH3:2]
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)C1Cc2ccccc2CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1Cc2ccccc2CN1C(=O)c1cccc(Oc2ccccc2)c1
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a stirred solution of (±)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester (6.26 g, 30.5 mmol) and 3-phenoxybenzoic acid (7.19 g, 33.6 mmol) in chloroform (150 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.43 g, 33.5 mmol). The reaction was allowed to proceed overnight and then washed with aqueous sodium bicarbonate solution, dried (sodium sulfate) and concentrated. The crude product was purified by flash chromatography over silica (hexanes/ethyl acetate) to afford 12.07 g (99%) of product as a colorless gum. In chloroform-d solvent, the proton NMR spectra of this compound appears as a 55:45 mixture of rotamers: 1H NMR (CDCl3) δ 7.46-6.90 (m, 13H), 5.46 (t, J=5.6 Hz, 0.55H), 5.18 (d, J=17.6 Hz, 0.45H), 4.80-4.73 (m, 0.45H), 4.68-4.50 (m, 1.55H), 4.22-4.07 (m, 1.10H), 4.05-3.92 (m, 0.90H), 3.34-3.19 (m, 1.55H), 3.16-3.06 (m, 0.45H), 1.19 (t, J=7.1 Hz, 1.65H), 1.04 (t, J=7.1 Hz, 1.35H) ppm.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1.[CH2:16]1OCCOCCOCCOCCOCCO[CH2:17]1.[OH-].[K+].BrCCBr>C(Cl)Cl>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:6]2([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[CH2:17][CH2:16]2)=[O:8])=[CH:10][CH:11]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: BrCCBr
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)C1(n2cncn2)CC1
Reaction time: 18 h
Yield: 25 %

Procedure:
To a solution of 2-(1H-1,2,4-triazol-1-yl)-4'-fluoroacetophenone (10.24 g, 50 mMole) in methylene chloride (70 ml) was added 18-Crown-6 ether (1 g) (trade mark for 1,4,7,10,13,16-hexaoxacyclooctadecane) and potassium hydroxide (6.1 g, 109 mMole) with stirring. Ten minutes later 1,2-dibromoethane was added (10.3 g, 55 mMole in one batch. Stirring was continued for 18 hours. The mixture was poured into saturated saline solution (100 ml) and the organic phase was separated, washed with water (3×30 ml) and dried over anhydrous magnesium sulphate. Evaporation gave an oil, weight 13.7 g. Purification was carried out by flash column chromatography under slight pressure (2 p.s.i.) on a Merck "Kieselgel 60" (trade mark) 230-400 mesh fractions after collection and evaporation gave a solid, the pure title compound, 2.9 g, m.p. 73°-75° (25% yield).
Reaction SMILES: [BH4-].[Na+].O.C(=O)(O)[O-].[Na+].[F:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][N:14]=[C:15]2[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1>C(OCC)(=O)C>[F:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][NH:14][CH:15]2[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=1
Reactant: Fc1cccc2c1CCN=C2c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1cccc2c1CCNC2c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-fluoro-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline (1.9 g, 6.6 mmol) in methanol (40 mL) from step 2 was cooled to 0° C. and sodium borohydride (0.6 g, 17 mmol) was added in small portions over 5 min and the reaction mixture was stirred at RT for 16 h. The reaction was quenched with ethyl acetate (20 mL) and concentrated to yield a reddish-yellow residue which was taken up in ethyl acetate (100 mL), water (30 mL), and saturated sodium bicarbonate (30 mL). After stirring for 15 min, it was transferred to a separatory funnel, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by silica gel chromatography (20-30% EtOAc in hexanes) to give 5-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline as a pale-yellow solid. MS (ESI pos. ion) m/z: 296 (M+H).
Reaction SMILES: [BrH:1].C1(O)C=CC=CC=1.C[O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[O:20]C)[CH2:16][N:15](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:14]2>C(O)(=O)CC>[BrH:1].[OH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[OH:20])[CH2:16][NH:15][CH2:14]2
Reactant: COc1cc2c(cc1OC)CN(S(=O)(=O)c1ccc(C)cc1)C2
Agent: Br
Solvent: CCC(=O)O
Solvent: Oc1ccccc1
Product: Oc1cc2c(cc1O)CNC2
Yield: 61.4 %

Procedure:
360 ml of 47% hydrobromic acid, 45 m1 of phenol and 60 ml of propionic acid were added to 60 g (0.18 mol) of 5,6-dimethoxy-2-p-tolylsulfonylisoindoline, and the mixture was refluxed for 4 hours under vigorous stirring under a nitrogen atmosphere. The reaction solution was evaporated under reduced pressure to dryness, and 120 ml of 47% hydrobromic acid was added to the residue. The mixture was again refluxed under a nitrogen atmosphere for 3 hours. The reaction solution was cooled, and then 300 ml of water and 300 ml of chloroform were added thereto. The water layer was separated, and subjected to active carbon treatment. The water layer was evaporated under reduced pressure to dryness, and the crystalline residue was washed with ether/ethanol (1/1) to obtain 25.62 g (yield: 61.4%) of the above identified compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:18])=[CH:14][C:15]=2[CH3:17])[C:10]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[S:36](Cl)(=[O:38])=[O:37]>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:18][S:36]([C:30]3[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:29]=3[F:28])(=[O:38])=[O:37])=[CH:14][C:15]=2[CH3:17])[C:10]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: Cc1cc(O)cc2c(C3CCN(C)CC3)cn(Cc3ccccc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(OS(=O)(=O)c2c(F)cccc2F)cc2c(C3CCN(C)CC3)cn(Cc3ccccc3)c12
Yield: 44.5 %

Procedure:
By a method similar to Example 56, using 1-benzyl-7-methyl-3-(1-methylpiperdin-4-yl)-5-hydroxy-1H-indole (1.81 mmol, 0.604 g) in THF (4.5 mL), sodium hydride (2.17 mmol, 0.087 g, 60% dispersion in mineral oil), and 2,6-diflurobenzenesulfonyl chloride (1.99 mmol, 0.422 g) afforded 0.411 g (45%) of the title compound: mp=158° C.; mass spectrum (ion spray): m/z=511 (M+1); 1H NMR (DMSOd6): 7.96-7.86 (m, 1H), 7.41 (dd, J=5.73, 3.48 Hz, 2H), 7.31-7.19 (m, 4H), 6.94 (d, J=2.20 Hz, 1H), 6.82 (d, J=6.59 Hz, 2H), 6.62 (d, J=1.87 Hz, 1H), 5.55 (s, 2H), 2.81-2.77 (m, 2H), 2.56-2.42 (m, 1H), 2.36 (s, 3H), 2.20 (s, 3H), 1.96 (m, 2H), 1.72-1.67 (m, 2H), 1.53 (m, 2H); Calculated for C28H28F2N2O3S-0.3H2O: C, 65.17; H, 5.59; N, 5.43. Found: C, 65.27; H, 5.47; N, 5.49.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[C:8]([CH3:25])[CH:7]=1)=[O:5])[CH3:2].[ClH:26]>O1CCOCC1.C(OCC)C>[ClH:26].[CH2:1]([NH:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[C:8]([CH3:25])[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCNC(=O)c1ccc(N2CCNCC2)c(C)c1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Tert-butyl 4-(4-(ethylcarbamoyl)-2-methylphenyl)piperazine-1-carboxylate (0.9323 g, 2.68 mmol) was diluted with 4.0M HCl in dioxane (8 mL) and stirred for 30 min. The thick white precipitate that formed was diluted with ethyl ether (10 mL) and stirred until a fine suspension resulted. The precipitate was filtered under nitrogen, washed with ether (5 mL) and dried in vacuum to afford N-ethyl-3-methyl-4-(piperazin-1-yl)benzamide hydrochloride (0.7528 g, 2.65 mmol, 99% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.20 Hz, 3H) 2.29 (s, 3H) 3.00-3.14 (m, 4H) 3.16-3.32 (m, 6H) 7.07 (d, J=8.34 Hz, 1H) 7.62-7.71 (m, 2H) 8.34 (t, J=5.43 Hz, 1H) 9.17 (br. s., 2H). ESI-MS: m/z 248.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]3[CH:18]=[C:19]([NH:23]C(=O)OC(C)(C)C)[CH:20]=[N:21][CH:22]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:31])=[CH:4][N:3]=1.CO.[ClH:34]>O1CCOCC1>[ClH:1].[ClH:34].[NH2:23][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][C:11]2[CH:10]=[C:9]([NH:8][C:6]3[C:5]([Cl:31])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:14]=[CH:13][CH:12]=2)[CH:22]=[N:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cncc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
Into the reaction vessel were added tert-butyl [5-(2-{3-[(2,5-dichloropyrmidin-4-yl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (0.20 g, 0.43 mmol) and methanol (2.0 mL) and 4.0 M hydrogen chloride in 1,4-dioxane (2.0 mL). The reaction mixture was stirred at rt for 2 h and then concentrated under vacuum to give the desired product as an off-white powder (140 mg, 96%). LCMS for C17H16Cl2N5 (M+H)+: m/z=360.0, 362.0.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39]1.C(N(CC)C(C)C)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:38]5[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O[C@H]1CCNC1
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CC[C@H](O)C1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
A stirred solution of (1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea from Example 27B (102 mg, 0.194 mmol), (S)-3-pyrrolidinol (51 mg, 0.582 mmol), N,N-diisopropylethylamine (75 mg, 0.582 mmol) and tetrabutylammonium iodide (71 mg, 0.194 mmol) in dry N,N-dimethylformamide (5 mL) was heated at 60° C. for 20 h. After cooling to room temperature, the reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL) and the organic layer was separated, washed with brine (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC (using a phenyl-hexyl reverse phase column, eluted with gradient of solvent B=0.05% HOAC/CH3CN and solvent A=0.05% HOAc/H2O). The combined fractions were washed with saturated aqueous NaHCO3 and the aqueous layer extracted with a mixture of 20% methanol in dichloromethane (2×50 mL). Concentration under reduced pressure afforded (S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea as a colorless solid (16 mg, 14%). 1H NMR (300 MHz, CDCl3) δ 8.59 (brs, 1H), 7.68 (brs, 1H), 7.52-7.55 (m, 2H), 7.26-7.35 (m, 4H), 6.95 (m, 1H), 6.11 (s, 1H), 4.34-4.40 (m, 3H), 4.04 (s, 3H), 3.00-3.20 (m, 2H), 2.84 (m, 1H), 2.67-2.68 (m, 2H), 2.50 (m, 1H), 2.10-2.30 (m, 3H), 1.80 (m, 1H), 1.51 (m, 1H), 1.26 (s, 9H); LC-MS (ESI) m/z 577 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][NH:4][C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([SH:12])[S:11][C:7]=2[CH:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>CC(C)=O>[SH:12][C:10]1[S:11][C:7]2[CH:6]=[C:5]([N:4]([CH2:3][CH:2]([CH3:15])[CH3:1])[C:26](=[O:27])[O:28][CH:29]([CH3:31])[CH3:30])[CH:14]=[CH:13][C:8]=2[N:9]=1
Reactant: CC(C)CNc1ccc2nc(S)sc2c1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: CC(C)CN(C(=O)OC(C)C)c1ccc2nc(S)sc2c1
Reaction time: 10 h
Yield: 22 %

Procedure:
Into a 50 ml round bottomed flask were added 6-[(2-methylpropyl)amino]-1,3-benzothiazole-2-thiol (100 mg, 0.42 mmol), acetone (10 ml), N,N-diisopropylethylamine (54.2 mg, 0.42 mmol) and isopropyl chloroformate (51.5 mg, 0.42 mmol). The reaction mixture was stirred for 10 h, filtered, and the solid that was obtained was triturated with diethyl ether to afford 30 mg (59%) of the title compound. 1H NMR (DMSO-d6) δ=0.80 (d, 6H), 1.11 (d, 6H), 1.60 (m, 1H), 3.43 (d, 2H), 4.76 (m, 1H), 7.24 (br s, 2H), 7.60 (s, 1H); ESIMS: m/z 323 (M−H).
Reaction SMILES: [C:1]1([C:12]2[C:13]([NH2:22])=[CH:14][CH:15]=[C:16]3[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]3)[C:2]([NH2:11])=[CH:3][CH:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([NH:22][C:13]2[C:12]([C:1]3[C:2]([NH:11][S:29]([C:26]4[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=4)(=[O:31])=[O:30])=[CH:3][CH:4]=[C:5]4[C:10]=3[CH:9]=[CH:8][CH:7]=[CH:6]4)=[C:21]3[C:16](=[CH:15][CH:14]=2)[CH:17]=[CH:18][CH:19]=[CH:20]3)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc2ccccc2c1-c1c(N)ccc2ccccc12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Nc2ccc3ccccc3c2-c2c(NS(=O)(=O)c3ccc(C)cc3)ccc3ccccc23)cc1
Yield: 95 %

Procedure:
Under nitrogen atmosphere, to a solution in which 1,1′-binaphthyl-2,2′-diamine (0.5 mmol) was dissolved in pyridine (1 mL) was added p-toluenesulfonyl chloride (1.1 mmol) at room temperature, and the mixture was reacted for 5 to 12 hours with stirring. After completion of the reaction, the resulting red suspension was diluted with ethyl acetate, and back-extracted with 1N hydrochloric acid to remove pyridine. The resulting organic layer was dried with sodium sulfate to remove the solvent, and the residue was purified by column chromatography to obtain an objective substance as a pale yellow to white solid in more than 95% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[C@@H:23]([NH2:25])[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][N:31]2[CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1.CCN(C(C)C)C(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[C@@H:23]([NH:25][C:27]2[N:35]=[CH:34][N:33]=[C:32]3[C:28]=2[N:29]=[CH:30][N:31]3[CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](N)c1nc2ccccc2n1[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccccc2n1[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 90 °C
Reaction time: 48 h
Yield: 86.7 %

Procedure:
A mixture of (R)-3-[2-((S)-1-aminoethyl)benzoimidazol-1-yl]piperidine-1-carboxylic acid tertbutyl ester (1.65 g, 4.79 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (1.14 g, 4.79 mmol), and DIPEA (2.5 mL, 14.4 mmol) in IMS (10 mL) was stirred in a sealed vial for 48 h at 90° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc). The product containing fractions were concentrated in vacuo affording (R)-3-(2-{(S)-1-[9-(Tetrahydropyran-2-yl)-9H-purin-6-ylamino]ethyl}benzoimidazol-1-yl)piperidine-1-carboxylic acid tertbutyl ester as a white foam (2.27 g, 87%). LCMS: RT 2.88 min [M+H]+ 547.1.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([O:24][CH3:25])=[O:23])=[CH:12][CH:11]=2)=[C:4]([CH2:26][CH2:27][CH2:28][CH3:29])[N:3]=1.[Cl:30][CH2:31][C:32](O)=[O:33].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:26]([C:4]1[N:3]=[C:2]([NH:1][C:32](=[O:33])[CH2:31][Cl:30])[NH:7][C:6](=[O:8])[C:5]=1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([O:24][CH3:25])=[O:23])=[CH:14][CH:15]=1)[CH2:27][CH2:28][CH3:29]
Reactant: O=C(O)CCl
Reactant: CCCCc1nc(N)[nH]c(=O)c1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCc1nc(NC(=O)CCl)[nH]c(=O)c1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reaction time: 8 h

Procedure:
A solution of 0.4 g of 2-amino-6-butyl-5-[(2'-methoxycarbonylbiphenyl-4-yl)methyl]pyrimidin-4-one in, 10 ml of anhydrous DMF is added in succession with 0.1 g of chloroacetic acid, 0.21 g of DCC and 0.17 g of HOBT. After 8 h under magnetic stirring, the resulting solid is filtered off and the solvent is evaporated under reduced pressure. The residue is taken up with H2O and extracted with AcOEt. The organic phase is dried over Na2 SO4 and evaporated under reduced pressure to obtain 0.47 g of a yellowish spongy solid which can be reacted without further purification.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[NH:35][C:34]([SH:36])=[N:33][N:32]=4)[CH:26]=3)[O:18]C3CCCCO3)=[CH:13][CH:12]=2)[CH:5]=[CH:4][C:3]=1[C:37](=[O:39])[CH3:38].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[OH:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([OH:18])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[NH:35][C:34]([SH:36])=[N:33][N:32]=4)[CH:26]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:4][C:3]=1[C:37](=[O:39])[CH3:38]
Reactant: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(-c4nnc(S)[nH]4)c3)cc2)c(C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(OCc2ccc(C(O)c3cccc(-c4nnc(S)[nH]4)c3)cc2)c(C)c1O

Procedure:
Stir a solution of 1-(2-hydroxy-4-{4-[[3-(5-mercapto-4H-[1,2,4]triazol-3-yl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzyloxy}-3-methyl-phenyl)-ethanone (1.12 g, 2.04 mmol) and p-toluenesulfonic acid (50 mg) in methanol (0.2M). Dilute with ethyl acetate and wash with water. Dry the organic layer and concentrate to afford the title compound (0.250 g, 0.551 mmol, 27% overall from acid chloride). 1H NMR (400 MHz, DMSO-d6) δ 2.02 (s, 3H), 2.50 (s, 3H), 5.21 (s, 2H), 5.76 (s, 1H), 6.05 (s, 1H), 6.71 (d, J=9.4 Hz, 1H), 7.39 (m, 6H), 7.53 (m, 1H), 7.73 (m, 1H), 7.78 (d, J=9.0 Hz, 1H), 7.98 (s, 1H), 12.83 (s, 1H). MS (m/z): 460 (M−H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH2:9][C:8](=O)[N:7](C)[C:6]=2[CH:18]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])[C:25]([Cl:39])=[CH:24][N:23]=1>>[Cl:39][C:25]1[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])=[N:27][C:22]([NH:1][C:2]2[C:3]([O:19][CH3:20])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH:13]4[CH2:14][CH2:15]4)[CH2:9][CH2:8][NH:7][C:6]=3[CH:18]=2)=[N:23][CH:24]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc2c(cc1N)N(C)C(=O)CN(CC1CC1)C2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)NCCN(CC1CC1)C2

Procedure:
The title compound was prepared from 8-Amino-4-cyclopropylmethyl-7-methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to example 730 (0.058 g, 42%). Mp 149-151° C.; LCMS (m/e) 538 (M); 1H-NMR (DMSO, 400 MHz) δ 8.25 (s, 1H), 8.00 (s, 1H), 7.83 (d, 1H, J=7.58 Hz), 7.78 (s, 1H), 7.75 (s, 1H), 7.25 (s, 1H), 7.05 (s, 1H), 6.30 (t, 1H), 6.07 (t, 1H), 5.75 (s, 1H), 4.16-4.12 (t, 1H, J=8.08 Hz), 3.90 (s, 3H), 3.60-3.50 (q, 2H, J=11.87 Hz), 3.19 (s, 3H), 3.11 (s, 2H), 2.86 (s, 1H), 2.72 (s, 1H), 2.41-2.40 (d, 2H, J=6.57 Hz), 2.11-2.09 (d, 1H, J=8.84 Hz), 1.40-1.35 (d, 1H, J=8.84 Hz), 0.92-0.80 (m, 1H), 0.50-0.48 (d, 2H, J=7.83 Hz), 0.20-0.12 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1.Cl.[CH3:18][C:19]1[CH:24]=[C:23]([CH:25]=[CH:26][C:27]#[N:28])[CH:22]=[C:21]([CH3:29])[C:20]=1[NH2:30].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:18][C:19]1[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]#[N:28])[CH:22]=[C:21]([CH3:29])[C:20]=1[NH:30][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1
Reactant: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Reactant: Cc1cc(C=CC#N)cc(C)c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(/C=C/C#N)cc(C)c1Nc1ccnc(Nc2ccc(C#N)cc2)n1
Temperature: 87.5 °C
Yield: 69.2 %

Procedure:
4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (100 gms) and 2,6-dimethyl-4-(2-cyanoethenyl) phenylamine hydrochloride (90.65 gms) were mixed with acetonitrile (800 ml) in an inert atmosphere and heated at 85-90° C. till completion of the reaction, as monitored by HPLC. The reaction mixture was cooled to 40° C. and pH of the reaction mass was adjusted to ≈ pH 10 with 20% sodium carbonate solution. The reaction mass was filtered at 5 to 10° C. and dried to yield Rilpivirine (110 gms). Rilpivirine thus obtained was dissolved in acetone (3600 ml) and after optional charcoal treatment was concentrated to 500 ml and was filtered at 5-10° C., dried to give Rilpivirine (80 gms), which was then added to dimethyl sulfoxide (338 ml) and heated to 70-75° C. The mixture was cooled to 50 to 55° C. and mixed with hydrochloric acid (25 ml) with constant stirring. Water (1350 ml) was added to the mixture at 40 to 45° C., which was stirred and cooled further. The reaction mass was filtered at 25 to 30° C. and the wet cake was dried to give 90 gms of Rilpivirine hydrochloride (I) having Z isomer less than 0.1%.