Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl-].[Ca+2].[Cl-].O.[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:30]=[CH:31][CH:32]=[C:6]([C:3]4([C:1]#[N:2])[CH2:5][CH2:4]4)[CH:7]=3)[CH:17]=[CH:16][C:15]=2[O:18][CH3:19])=[CH:26][CH:25]=1
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc([N+](=O)[O-])cc1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc(N)cc1
Yield: 89.1 %

Procedure:
A solution of 3-(1-cyanocyclopropyl)-N-[4-methoxy-3-(4-nitrophenoxy)phenyl]benzamide (2.10 g, 4.89 mmol), reduced iron (0.56 g, 10.0 mmol) and calcium chloride (1.11 g, 10.0 mmol) in ethanol (40 mL)/water (10 mL) was stirred at 80° C. for 18 hr. The reaction mixture was poured into 0.5N aqueous sodium hydroxide solution (400 mL), ethyl acetate (300 mL) was added and the mixture was stirred. The insoluble material was filtered off through celite, and the organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (1.74 g, 82%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3[CH:18]=[C:17](I)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[CH2:23]>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.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3[CH:18]=[C:17](/[CH:23]=[CH:22]/[C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(I)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: C=Cc1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CCN1c2ncc(/C=C/c3ccncc3)cc2C(=O)N(C)c2ccc(Cl)nc21

Procedure:
2-Chloro-5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (prepared by procedures analogous to those described in Example 1a-g) (0.5 g, 1.2 mmol) was coupled with 4-vinylpyridine in the presence of bis(triphenylphosphine)palladium(II) chloride and triethylamine as described in example 1h to give 0.28 g of the title compound as brown crystals, m.p. 150°-152° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C@@:9]([OH:19])([C:14]#[C:15][CH:16]1[CH2:18][CH2:17]1)[C:10]([F:13])([F:12])[F:11].Cl[C:21]([O-])=[O:22]>>[CH:6]1[C:5]([Cl:8])=[CH:4][C:3]2[C@:9]([C:10]([F:13])([F:11])[F:12])([C:14]#[C:15][CH:16]3[CH2:18][CH2:17]3)[O:19][C:21]([NH:1][C:2]=2[CH:7]=1)=[O:22]
Reactant: Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F
Reactant: O=C([O-])Cl
Product: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O1

Procedure:
This intermediate, (2S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol, as a free base, is reacted with a chloroformate derivative in basic conditions to give, after 1 to 6 hours reaction, an alkyl carbamate intermediate (reaction of the amine moiety of intermediate (II) with the chloroformate derivative) that is then cyclized to yield Efavirenz.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[O:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[O:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: OB(O)c1cccnc1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cccnc4)nc(N4CCOCC4)c3o2)CC1

Procedure:
2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[3,2-d]pyrimidine (Example 153) was reacted with pyridine-3-boronic acid via General Procedure E to give, after purification by reverse HPLC, 14 mg of 224. MS (Q1) 459 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[N:7]([CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([N+:38]([O-])=O)[CH:36]=2)[NH:31][C:30]=1[C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[C:43]([CH3:48])[CH:42]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[C:13]=1[S:23]([CH3:26])(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:49])[N:7]([CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([NH2:38])[CH:36]=2)[NH:31][C:30]=1[C:41]1[CH:42]=[C:43]([CH3:48])[CH:44]=[C:45]([CH3:47])[CH:46]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([S:19]([CH3:22])(=[O:20])=[O:21])[C:13]=1[S:23]([CH3:26])(=[O:25])=[O:24])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCN(CCCCc2ccc(N)c(S(C)(=O)=O)c2S(C)(=O)=O)C(=O)OC(C)(C)C)c1
Agent: [Pd]
Product: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(CCCCc2ccc(N)c(S(C)(=O)=O)c2S(C)(=O)=O)C(=O)OC(C)(C)C)c1
Yield: 90.5 %

Procedure:
The title compound was prepared essentially as described in EXAMPLE 2.1 StepE starting from {2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]-ethyl}-[4-(4-amino(dimethanesulfonyl)phenyl)butyl]-carbamic acid tert-butyl ester (330 mg) and using 10% palladium on carbon as catalyst to give the title compound (286 mg).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH:25]([O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][C:30]=1[O:37][CH3:38])([CH3:27])[CH3:26]>C(Cl)Cl.[Zn]>[Br:2][C:1]([Br:5])=[CH:33][C:32]1[CH:35]=[CH:36][C:29]([O:28][CH:25]([CH3:27])[CH3:26])=[C:30]([O:37][CH3:38])[CH:31]=1
Reactant: COc1cc(C=O)ccc1OC(C)C
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(C=C(Br)Br)ccc1OC(C)C
Temperature: 0 °C
Reaction time: 22 h
Yield: 100.5 %

Procedure:
Carbon tetrabromide (51.3 g, 154.7 mmol) was added portion-wise to a magnetically stirred mixture of zinc dust (10.1 g, 154.5 mmol) and PPh3 (40.5 g, 159.4 mmol) in CH2Cl2 (350 ml) maintained at 0° C. on an ice-salt bath. This suspension was allowed to warm to room temperature and then stirred at for a further 22 h. After this time the reaction mixture was re-cooled to 0° C. and vanillin isopropyl ether (15.0 g, 77.3 mmol) was added dropwise over 2 min. and allowed to stir at room temperature for 1 h. After dilution with hexane (200 ml) the resulting mixture was filtered through a sintered glass funnel and the filtrate concentrated on to silica gel (30 g). The resulting solid was added to the top of a flash chromatography column (silica gel: 20 cm long×10 cm wide) which was subjected to gradient elution (2:1, 1:1 and then 1:2 hexane/CH2Cl2). Concentration of the appropriate fractions (Rf 0.5 in 1:1 hexane/CH2Cl2) then afforded the title compound (27.2 g, 99.8%) as white crystalline masses, m.p. 36-38° C. IR (KBr disc, cm−1) 2976, 2973, 1599, 1510, 1464, 1418, 1383, 1373, 1267, 1235, 1141, 1110, 1036. 1H NMR (300 MHz, CDCl3) δ 7.41 (s, 1H), 7.21 (d, J=2.1 Hz, 1H), 7.07 (dd, J=2.1, 8.4 Hz, 1H), 6.87 (d, J=8.4 Hz), 4.58 (septet, J=6.0 Hz, 1H), 3.87 (s, 3H), 1.39 (d, J=6.0 Hz, 6H). 13C NMR+APT (75.5 MHz, CDCl3) δ 149.7 (C), 147.7 (C), 136.5 (CH), 127.9 (C), 121.9 (CH), 114.4 (CH), 111.8 (CH), 87.1 (CH), 71.1 (CH), 56.0 (CH3), 22.1 (CH3). MS (70 eV) m/z (%): 352 (28), 350 (49), 448 (31) (M+·), 310 (51), 308 (100), 306 (54) (M+·-CH2CHCH3), 295 (34), 293 (38), 291 (36) (M+·-CH2CHCH3—CH3). Anal. Calcd for C12H14O2Br2, 41.17; H, 4.03; Br, 45.65. Found: C, 41.21; H, 3.92; Br, 45.47.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[F:13][C:12]([F:15])([F:14])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccnc3c(C(F)(F)F)cccc23)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 99.2 %

Procedure:
4-Chloro-8-(trifluoromethyl)quinoline (500 mg, 2.16 mmol), 4-hydroxybenzaldehyde (264 mg, 2.16 mmol), and cesium carbonate (845 mg, 2.59 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the resulting mixture was stirred at 100° C. for 5 hours. Water was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 70:30 (v/v)), whereby the objective title compound was obtained as a white solid (680 mg, yield: 99%).
Reaction SMILES: OS(C(F)(F)F)(=O)=O.N1C=CN=CC=1.[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[CH3:27][C:28]1[C:29](=O)[NH:30][CH:31]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:33]=1.FC(F)(F)S(O)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.C(Cl)Cl.C(OCC)(=O)C>[CH3:27][C:28]1[C:29]([N:24]2[CH2:25][CH2:26][N:21]([C:16]3[N:17]=[CH:18][CH:19]=[CH:20][N:15]=3)[CH2:22][CH2:23]2)=[N:30][CH:31]=[C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:33]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Cc1nc(-c2ccccc2)c[nH]c1=O
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: c1cnccn1
Product: Cc1nc(-c2ccccc2)cnc1N1CCN(c2ncccn2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
This compound was prepared via the pyrazine triflate with 1-(2-pyrimidyl)piperazine as the amine following the procedure of Adams et al (Synlett 2004, 11, 2031-2033). Pyridine was used as an anhydrous reagent kept under argon in a sure-seal bottle (Aldrich). The compound 24 (100 mg, 0.52 nmol) and DMAP (65.7, 0.52 mmol) were dissolved in pyridine and methylene chloride (0.5:4 ml v/v), and cooled to 0° C. The trifluoromethane sulfonic acid (0.8 mmol, 135.5 μL) was added dropwise and stirred for 15 min at 0° C. and then 3 h at RT. The triflate was confirmed by ESI (363.7 (MH+)) and HPLC (tR=25.33 min). The reaction mixture was diluted with dichloromethane and washed one time each with 20 ml of water, sodium bicarbonate and brine. The dichloromethane was removed under reduced pressure, and the remaining residue was dissolved directly in DMSO. 1-(2-pyrimidyl)piperazine (5.3 mmol, 750 μL) was added and the reaction heated to 60° C. and stirred for 2 h. When complete, the reaction was diluted with ethyl acetate and washed with 1N HCl, after washes with brine and water to remove remaining pyridine. The organics were then dried and evaporated in vacuo to give 25 as a yellow solid (63% yield). HPLC (tr/purity): 24.74 min, >98%. ESI m/z (CH2Cl2) 333.29 (MH+). 1H NMR (500 MHz, CDCl3): δ 8.56 (s, 1H); 8.36 (d, J=4 Hz, 2H); 8.01 (d, J=7.5 Hz, 2H); 7.48-7.40 (m, 3H); 6.54 (bs, 1H); 4.03 (bs, 4H), 3.42 (bs, 4H); 2.62 (s, 6H). HRMS calculated GIVEN Apr. 21, 2006
Reaction SMILES: Cl.O1CCOCC1.[CH3:8][C:9]1[CH:10]=[C:11](/[CH:48]=[CH:49]/[CH2:50][CH2:51][N:52]2[CH2:55][C:54]3([CH2:60][CH2:59][CH2:58][N:57](C(OC(C)(C)C)=O)[CH2:56]3)[CH2:53]2)[CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[C:17]([O:24][C@@H:25]2[O:42][C@H:41]([CH2:43][O:44]C(=O)C)[C@@H:36]([O:37]C(=O)C)[C@H:31]([O:32]C(=O)C)[C@H:26]2[O:27]C(=O)C)=[N:18][NH:19][C:20]=1[CH:21]([CH3:23])[CH3:22]>ClCCl>[O:24]([C:17]1[C:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11](/[CH:48]=[CH:49]/[CH2:50][CH2:51][N:52]3[CH2:53][C:54]4([CH2:60][CH2:59][CH2:58][NH:57][CH2:56]4)[CH2:55]3)=[CH:10][C:9]=2[CH3:8])=[C:20]([CH:21]([CH3:23])[CH3:22])[NH:19][N:18]=1)[C@@H:25]1[O:42][C@H:41]([CH2:43][OH:44])[C@@H:36]([OH:37])[C@H:31]([OH:32])[C@H:26]1[OH:27]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CC4(CCCN(C(=O)OC(C)(C)C)C4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(/C=C/CCN2CC3(CCCNC3)C2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Add 4.0 M HCl/1,4-dioxane (1.5 mL, 1.5 mmol) to a solution of tert-butyl 2-{(3E)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)oxy]-1 h-pyrazol-4-yl}methyl)phenyl]but-3-en-1-yl}-2,6-diazaspiro[3.5]nonane-6-carboxylate in dichloromethane (2 mL) and stir at rt for 4.0 h. Concentrate the mixture under the reduced pressure to a foamy solid. Treat the solid with 2.0 M ammonia in MeOH (2 mL) overnight. After 18 hours at room temperature, concentrate to remove the solvent under reduced pressure. The resulting residue is purified by preparative HPLC method: high pH, 19% B for 3 min, 19-34 B % for 5 min @ 85 mL/min using a 30×75 mm, 5 um C18XBridge ODB column, solvent A—H2O w NH4HCO3 @ pH 10, solvent B-MeCN to yield the title compound as solid (47 mg, 0.08 mmol). MS (m/z): 570.8, 571.8 (M+1), 568.7, 569.8 (M−1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:19]=[C:18]([C:20]3[C:21]([C:26]([F:29])([F:28])[F:27])=[N:22][CH:23]=[CH:24][CH:25]=3)[N:17]=[CH:16][N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.B(Br)(Br)Br>ClCCl>[N+:11]([C:7]1[CH:6]=[C:5]([C:14]2[N:19]=[C:18]([C:20]3[C:21]([C:26]([F:29])([F:28])[F:27])=[N:22][CH:23]=[CH:24][CH:25]=3)[N:17]=[CH:16][N:15]=2)[CH:4]=[C:3]([OH:2])[C:8]=1[OH:9])([O-:13])=[O:12]
Reactant: COc1cc(-c2ncnc(-c3cccnc3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(-c2ncnc(-c3cccnc3C(F)(F)F)n2)cc(O)c1O
Temperature: -78 °C
Reaction time: 18 h

Procedure:
A portion of 2-(3,4-dimethoxy-5-nitrophenyl)-4-(2-(trifluoromethyl)pyridin-3-yl)-1,3,5-triazine (1.221 g, 3 mmol) was taken up in dichloromethane (25 mL). The yellowish solution was cooled to −78° C. under argon and boron tribromide (2.55 mL, 27 mmol) was added dropwise. The red reaction mixture was allowed to warm to room temperature and stirred for 18 hours. It was then carefully poured into ice-water (100 mL) and stirred for 1 hour. The yellow precipitate was filtered off, washed with water and dried over P2O5 under vacuum. Recrystallisation from a dichloromethane-ethanol mixture gave 3-nitro-5-(4-(2-(trifluoro-methyl)pyridin-3-yl)-1,3,5-triazin-2-yl)benzene-1,2-diol as a yellow solid, 0.966 g (85%).
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[NH3:20]>C(O)C>[OH:1][CH2:2][C:3]1[NH:20][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1
Reactant: N
Reactant: COc1ccc(COc2coc(CO)cc2=O)cc1
Solvent: CCO
Product: COc1ccc(COc2c[nH]c(CO)cc2=O)cc1
Reaction time: 3 h
Yield: 66 %

Procedure:
To a suspension of 2-(hydroxymethyl)-5-({[4-(methoxy)phenyl]methyl}oxy)-4(1H)-pyrone (40 g, 153 mmol) in ethanol (105 mL) was added concentrated aqueous ammonia (295 mL) and refluxed for 18 hours. The mixture was cooled, then refrigerated for 3 hours, and cooled in an ice-bath for 45 minutes. The solid was filtered off, washed with cold ethanol, followed by cold petroleum ether and dried in vacuo to afford the product as brown solid (26.21 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH2:30])[N:17]=[CH:16]2.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>ClCCl>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH:30][C:40](=[O:43])[CH:41]=[CH2:42])[N:17]=[CH:16]2
Reactant: C=CC(=O)Cl
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3c2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1CCCC[C@@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a solution of (1R,2S)—N1-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)cyclohexane-1,2-diamine (0.12 mmol) in dichloromethane (1.3 mL) at 0° C. was added DIEA (0.004 mL, 0.02 mmol) and acryloyl chloride (0.012 mL, 0.15 mmol) and the reaction was stirred for 1 h. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-((1S,2S)-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)cyclohexyl)acrylamide (35 mg, 58%). MS (ES+) C25H26Cl2N4O3 requires: 500, found: 501.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH:18]C(=O)OC(C)(C)C)[N:14]=[CH:15]2)=[CH:10][N:9]=1.FC(F)(F)C(O)=O>ClCCCl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]2)=[CH:10][N:9]=1
Reactant: Cc1ccncc1-c1cc2cnc(NC(=O)OC(C)(C)C)cc2cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Cc1ccncc1-c1cc2cnc(N)cc2cn1
Temperature: 40 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
A suspension of tert-butyl 7-(4-methylpyridin-3-yl)-2,6-naphthyridin-3-ylcarbamate (190 mg, 0.565 mmol) in DCE (3 mL) was treated with trifluoroacetic acid (0.437 mL, 5.65 mmol) and the mixture was stirred at 40° C. for 3 hours. The reaction mixture was concentrated in vacuo and then diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford the title compound as a bright yellow solid (133 mg, 99%), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH3:10])[NH2:9])[N:3]=1.[N:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C:14](=O)[CH2:13][CH2:12]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:3]=[C:4]([N:8]([CH3:10])/[N:9]=[C:14]2/[CH2:13][CH2:12][N:11]3[CH2:19][CH2:18][CH:15]/2[CH2:16][CH2:17]3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN2CCC1CC2
Reactant: CN(N)c1cccc(Br)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN(/N=C1/CCN2CCC1CC2)c1cccc(Br)n1
Yield: 36.2 %

Procedure:
A solution of 2-bromo-6-(1-methylhydrazinyl)pyridine (4.50 g, 22.2 mmol), 1-azabicyclo[3.2.2]nonan-4-one (3.00 g, 22.2 mmol) and p-toluenesulphonic acid (844 mg, 4.40 mmol) in toluene (140 mL) was heated under reflux, with water removal (azeotrope), for 4 h. The mixture was concentrated and made basic using saturated aqueous NaHCO3. The aqueous layer was extracted with methylene chloride (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, 0%-100% solvent mixture B in methylene chloride; solvent mixture B=80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to give the title compound (2.60 g, 36%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.29 (t, J=8.0 Hz, 1H), 6.83 (d, J=7.0 Hz, 1H), 6.55 (d, J=8.5 Hz, 0.7H), 6.41 (d, J=8.5 Hz, 0.3 H), 3.20 (s, 3H), 3.17-2.94 (m, 7H), 2.80 (t, J=7.0 Hz, 0.6H), 2.73 (t, J=7.0 Hz, 1.4H), 1.89-1.85 (m, 3H), 1.74-1.60 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[CH2:17]O)[C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[CH2:17][Br:20])[C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CO)c(OCc2ccccc2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CBr)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4.3 g (18 mmol) of the alcohol (a) underwent substitution in 40 ml of THF with 7.9 g (24 mmol) of CBr4 and 6.3 g (24 mmol) of PPh3, which was added in portions over the course of 30 min. The reaction mixture was stirred at RT for 20 h. The product was purified by column chromatography (mobile phase: t-butyl methyl ether/petroleum ether 2:1). 4.6 g were obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].NCCCOC1C=CN2C(C=1)=CC(C(NC[C@H](NS(C1C=CC=CC=1)(=O)=O)C(O)=O)=O)=CC2=O.C([O:46][C:47](=[O:87])[C@@H:48]([NH:77][S:78]([C:81]1[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=1)(=[O:80])=[O:79])[CH2:49][NH:50][C:51]([C:53]1[CH:54]=[C:55]2[N:60]([C:61](=[O:63])[CH:62]=1)[CH:59]=[CH:58][C:57]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][NH:69]C(OC(C)(C)C)=O)=[CH:56]2)=[O:52])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:69][CH2:68][CH2:67][CH2:66][CH2:65][O:64][C:57]1[CH:58]=[CH:59][N:60]2[C:55]([CH:56]=1)=[CH:54][C:53]([C:51]([NH:50][CH2:49][C@H:48]([NH:77][S:78]([C:81]1[CH:82]=[CH:83][CH:84]=[CH:85][CH:86]=1)(=[O:80])=[O:79])[C:47]([OH:87])=[O:46])=[O:52])=[CH:62][C:61]2=[O:63]
Reactant: CC(C)(C)OC(=O)NCCCCOc1ccn2c(=O)cc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)OC(C)(C)C)cc2c1
Agent: NCCCOc1ccn2c(=O)cc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCOc1ccn2c(=O)cc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2c1
Yield: 90 %

Procedure:
Using the procedure described for the preparation of compound XXX (step E), (S)-2-benzenesulfonylamino-3-{[8-(4-tert-butoxycarbonylamino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionic acid tert-butyl ester (38 mg, 0.058 mmol) was treated with trifluoroacetic acid in dichloromethane to afford compound XXXII (32 mg, 90%) as a yellow solid which was characterized by 1HNMR (400 MHz, CD3OD) δ: 9.06 (1H, d, J=8.0 Hz), 7.86 (2H, dd, J=1.2, 7.7 Hz), 7.46-7.54 (3H, m), 7.23 (1H, d, J=2.5 Hz), 7.07 (1H, d, J=1.2 Hz), 7.03 (1H, dd, J=2.7, 8.0 Hz), 6.59 (1H, d, J=1.6 Hz), 4.27 (2H, t, J=5.7 Hz), 4.22 (1H, dd, J=5.1, 8.6 Hz), 3.79 (1H, dd, J=5.0, 13.4 Hz), 3.51 (1H, dd, J=8.6, 13.5 Hz), 3.06 (2H, t, J=7.4 Hz), 1.88-2.01 (4H, 2 multiplets).
Reaction SMILES: [N].N1C2[C:5](=CC=CC=2)[CH:4]=[CH:3]1.[Br:11][C:12]1[CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[C:15]2[CH:16]=[CH:17][NH:18][C:19]=2[CH:20]=1.[Cl-].C(C[P+](C)(C)C)#N.CC(O)C.[H-].[Na+]>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[C:15]2[CH:16]=[CH:17][N:18]([CH:4]([CH3:5])[CH3:3])[C:19]=2[CH:20]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1cc(Br)cc2[nH]ccc12
Agent: C[P+](C)(C)CC#N
Agent: [Cl-]
Agent: [H-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Alternatively, the alkylation of the indole nitrogen could be performed as follows: To a cooled (0° C.) suspension of methyl 6-bromo-1H-indole-4-carboxylate (10 g, 39.4 mmol) and (cyanomethyl)(trimethyl)phosphonium chloride (14.91 g, 98 mmol) in THF (400 mL) was added 2-propanol (6.06 mL, 79 mmol), followed by sodium hydride (3.46 g, 87 mmol). The mixture was stirred at ambient temperature for 2 h, at which time LCMS showed no product formation. Heated at 50° C. for 18 h. LC/MS showed reaction complete. Filtered reaction mixture and concentrated in vacuo. The residue was diluted with methylene chloride and passed through a pad of silica (washed with methylene chloride). Purification by flash chromatography (Analogix SF65-200 g; 5-10% EtOAc/hexanes) gave methyl 6-bromo-1-(1-methylethyl)-1H-indole-4-carboxylate (9.7 g, 31.4 mmol, 80% yield). MS (ES) [M+H]+296.2, 298.4.