Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:25][C@@:23]3([CH3:24])[C@@H:19]([CH2:20][C@@H:21]([CH3:31])[C@@H:22]3[C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C@H:18]3[C:9]2=[C:10]2[C:15]([CH2:16][CH2:17]3)=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1)CCC>>[CH:28]1([C:26]([C@H:22]2[C@H:21]([CH3:31])[CH2:20][C@H:19]3[C@H:18]4[C:9]([C@@H:8]([C:5]5[CH:4]=[CH:3][C:2]([C:38]6[N:43]=[CH:42][CH:41]=[CH:40][N:39]=6)=[CH:7][CH:6]=5)[CH2:25][C@:23]23[CH3:24])=[C:10]2[C:15](=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)[CH2:16][CH2:17]4)=[O:27])[CH2:29][CH2:30]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(Br)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(-c4ncccn4)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Temperature: 110 °C
Yield: 17 %

Procedure:
According to the procedure described in example 8, (11β,16α,17β)-11-(4-bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one and 2-tributylstannylpyrimidine were heated for four hours at 110° C. to give the title compound (17% yield). 1H NMR (400 MHz, CDCl3): δ 0.32 (s, 3H), 0.83-2.87 (m, 24H), 4.47 (d, J=7.0 Hz, 1H), 5.80 (s, 1H), 7.18 (t, J=4.7 Hz, 1H), 7.28-7.31 (m, 2H), 8.32-8.35 (m, 2H), 8.79 (d, J=4.7 Hz, 2H).
Reaction SMILES: [O-]Cl.[Na+].[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[CH:8]=[N:9][OH:10].[CH3:15][O:16][C:17]([C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([C:29]([NH:31][CH:32]([CH2:40][C:41]#[CH:42])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:30])([CH2:22]3)[CH2:20]1)[CH2:26]2)=[O:18]>C(Cl)(Cl)Cl.CCN(CC)CC>[CH3:15][O:16][C:17]([C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([C:29]([NH:31][CH:32]([CH2:40][C:41]4[O:10][N:9]=[C:8]([C:7]5[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=5[O:5][CH3:4])[CH:42]=4)[C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[O:30])([CH2:22]3)[CH2:20]1)[CH2:26]2)=[O:18]
Reactant: C#CCC(NC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2)C(=O)OC(C)(C)C
Reactant: COc1ccccc1C=NO
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C12CC3CC(CC(C(=O)NC(Cc4cc(-c5ccccc5OC)no4)C(=O)OC(C)(C)C)(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5.25% aqueous NaOCl (1.33 g, 0.77 mmol) in CHCl3 at 0° C. was added a solution of 2-methoxybenzaldehyde oxime (0.77 mmol, 0.116 g) dropwise and tert-butyl 2-(3-methoxycarbonyladamant-1-ylcarbonylamino)pent4-ynoate (300 mg, 0.77 mmol) and one drop of Et3N. After addition, the reaction mixture was allowed to warm up to room temperature and stirred overnight. The solvent was evaporated under reduced pressure and the crude product was purified on a prep plate (silica gel; EtOAc/hexanes, 2:3) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([O-])=O.[Na+].Cl.[NH2:15]O.C(O)=O>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:15])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: N#Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
4-chlorobenzaldehyde (50 g; 0.36 mol), sodium formate (48.4 g; 0.71 mol), and hydroxylamine hydrochloride (24.7 g; 0.36 mol) were added to 400 ml formic acid (98 wt.%). The reaction mixture was refluxed for 1 hour at l30.C, cooled to room temperature and poured into 1 liter cold water to produce a white precipitate, which was filtered and air-dried to yield 43 g 4-chlorobenzonitrile (m.p.=91°-92° C). The yield for this step in the reaction sequence was about 88%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CO>O1CCCC1.[C].[Pd]>[NH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([OH:1])[CH:9]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(N)cc1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.1 %

Procedure:
To a solution of 2-hydroxy-4-nitrobenzonitrile (3.98 g, 24.25 mmol) in tetrahydrofuran (17 mL) were added methanol (70 mL) and 10% palladium-carbon (460 mg), and the mixture was stirred at room temperature for 14 hr under a hydrogen atmosphere (2.5 atm). The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (3.16 g, 97%) as a brown oil. This was used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]2([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[O:29][C@@H:28]([CH2:37][C:38]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[O:39])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]4([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]4)[O:29][C@@H:28]([CH2:37][C:38]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[O:39])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: NCC[C@@H]1C[C@H](CC(=O)N2CCOCC2)OC2(CCCCC2)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)N2CCOCC2)OC2(CCCCC2)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and 2-((2R,4R)-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecan-2-yl)-1-morpholinoethanone.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3O[C:36]([CH3:42])=[C:37]([CH:39]([CH3:41])[CH3:40])[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH2:43]([NH:45]C=O)[CH3:44].C(N)C>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:45]([CH2:43][CH3:44])[C:36]([CH3:42])=[C:37]([CH:39]([CH3:41])[CH3:40])[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCNC=O
Reactant: CCCc1nc2c(C)cc(-c3nc(C(C)C)c(C)o3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: CCN
Product: CCCc1nc2c(C)cc(-c3nc(C(C)C)c(C)n3CC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 146 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4-isopropyl-5-methyl-oxazol-2-yl)-l H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and N-ethyl-formamide/ethylamine.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:29])[CH3:28])[CH:22]=3)=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14].C(N(CC)CC)C>ClCCl>[C:27]([C:23]1[CH:22]=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:11]3[O:12][C:13]([CH3:14])=[C:9]([CH2:8][CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])[N:10]=3)=[CH:20][CH:19]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:29])[CH3:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1cccc(-c2ccc(-c3nc(CCO)c(C)o3)cc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cccc(-c2ccc(-c3nc(CCOS(C)(=O)=O)c(C)o3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.7 %

Procedure:
Add methanesulfonyl chloride (0.110 g, 0.760 mmol) to a cool (0° C.) solution of 1-{4′-[4-(2-hydroxy-ethyl)-5-methyl-oxazol-2-yl]-biphenyl-3-yl}-ethanone (0.188 g, 0.584 mmol) and triethylamine (0.089 g, 0.88 mmol) in dichloromethane (5 mL). Warm the reaction mixture to room temperature and stir for 1 hour. Add dichloromethane and wash the crude organic layer with saturated sodium chloride solution. Dry the organic extracts over Na2SO4, filter, and concentrate to give crude methanesulfonic acid 2-[2-(3′-acetyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl ester (0.256 g, >100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Cl:9]Cl>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:9])=[CH:4][N:3]=1
Reactant: ClCl
Reactant: Cc1ccc(Cl)nc1
Solvent: CC#N
Product: ClCc1ccc(Cl)nc1
Yield: 69 %

Procedure:
1 Mol of 2-chloro-5-methylpyridine and 128 g of acetonitrile are heated to reflux. The mixture is irradiated with UV light and chlorine gas is introduced in a slight excess. The reaction is terminated as soon as 0.37 mol of product has been formed. 0.46 Mol of starting material is simultaneously recovered. Based on the reacted starting material, a yield of 69% results.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[Br:31]N1C(=O)CCC1=O>>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([Br:31])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[CH:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Product: COC(=O)c1nc(Br)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A mixture of 1,3-dibenzyl-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (470 mg, 1.18 mmol) and N-bromosuccinimide (220 mg, 1.23 mmol) was refluxed for 3 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was chromatographed (0-30% EtOAc/hexanes+2% AcOH) to give 451 mg of the title compound. MS: (+) m/z 479.06, 480.88 (M+1, 79/81Br)
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@@H:7]([O:20][C@@H:21]2[C@H:27]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@@H:26]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@H:25]([CH3:44])[O:24][C@H:22]2[OH:23])[C@@H:6]1[NH:45][C:46](=[O:51])[C:47]([Cl:50])([Cl:49])[Cl:48])(=[O:3])[CH3:2].[Cl:52][C:53]([Cl:57])([Cl:56])[C:54]#[N:55].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[Cl:52][C:53]([Cl:57])([Cl:56])[C:54]([O:23][C@@H:22]1[O:24][C@@H:25]([CH3:44])[C@H:26]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:21]1[O:20][C@@H:7]1[O:8][C@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:6]1[NH:45][C:46](=[O:51])[C:47]([Cl:50])([Cl:49])[Cl:48])=[NH:55]
Reactant: CC(=O)OC[C@H]1O[C@@H](O[C@@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](C)O[C@H]2O)[C@H](NC(=O)C(Cl)(Cl)Cl)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#CC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)O[C@@H](C)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](NC(=O)C(Cl)(Cl)Cl)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
The hemiacetal 318 (539 mg, 0.68 mmol) was dissolved in CH2Cl2 (50 mL), placed under argon and cooled to 0° C. Trichloroacetonitrile (0.6 mL, 6.8 mmol), then DBU (10 μL, 70 μmol) were added. The mixture was stirred at 0° C. for 30 min. The mixture was concentrated and toluene was co-evaporated from the residue. The residue was eluted from a column of silica gel with 7:3 cyclohexane-EtOAc and 0.2% of Et3N to give 306 (498 mg, 78%) as a colourless foam; [α]D−18° (c 1, CHCl3). 1H NMR: δ 8.48 (s, 1H, NH), 7.40-7.15 (m, 10H, Ph), 6.75 (d, 1H, J2,NH=8.5 Hz, NHD), 6.18 (d, 1H, J1,2=1.1 Hz, H-1A), 5.15 (pt, 1H, J2,3=J3,4=9.5 Hz, H-3D), 5.07 (pt, 1H, J4,5=9.5 Hz, H-4D), 4.82-4.50 (m, 4H, CH2Ph), 4.62 (d, 1H, J1,2=8.5 Hz, H-1D), 4.20-4.03 (m, 2H, J5,6=4.5, J6a,6b=12.3 Hz, H-6aD, 6bD), 3.98 (m, 1H, H-2D), 3.85 (dq, 1H, J3,4=9.5, J5,6=6.2 Hz, H-5A), 3.84 (dd, 1H, J2,3=3.3 Hz, H-2A), 3.83 (dd, 1H, J3,4=9.5 Hz, H-3A), 3.55 (m, 1H, H-5D), 3.45 (pt, 1H, H-4A), 1.98, 1.96, 1.93 (3s, 9H, OAc), 1.23 (d, 3H, H-6A); 13C NMR: δ 171.1, 170.0, 169.6, 162.1 (C═O), 138.4-127.2 (Ph), 101.7 (C-1D), 97.2 (C-1A), 92.6 (CCl3), 80.5 (C-4A), 79.1 (C-3A), 76.2 (C-2A), 76.2, 74.1 (2C, CH2Ph), 74.4 (C-3D), 74.1 (C-5D), 71.3 (C-5A), 68.6 (C-4D), 62.3 (C-6D), 56.3 (C-2D), 21.1, 21.0, 20.9 (3C, OAc), 18.2 (C-6A). Anal. Calcd for C36H40Cl6N2O13: C, 46.93; H, 4.38; N, 3.04%. Found: C, 46.93; H, 4.52; N, 2.85%.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:28]=2[C:29]([NH:31][CH2:32][C:33]#[CH:34])=[O:30])[C:23]([Cl:40])=[CH:22][N:21]=1>>[CH:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([NH:18][C:20]3[N:25]=[C:24]([NH:26][C:27]4[C:28]([C:29](=[O:30])[NH:31][CH2:32][C:33]#[CH:34])=[CH:35][CH:36]=[CH:37][C:38]=4[F:39])[C:23]([Cl:40])=[CH:22][N:21]=3)=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC(C)OC(=O)N1CCCOc2cc(N)ccc21
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OC(C)C)ncc1Cl

Procedure:
3-[5-Chloro-4-(2-fluoro-6-prop-2-ynylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid isopropyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid isopropyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 1410. Product isolated as a pale yellow solid (99 mg, 53%). m.p.=242-244° C.; LCMS (m/e) 553 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.47-9.35 (m, 1H), 9.25-9.15 (m, 1H), 9.04-8.95 (m, 1H), 8.19 (s, 1H), 7.57-7.40 (m, 3H), 7.26 (s, 1H), 7.13-7.04 (m, 1H), 6.98-6.87 (m, 1H), 4.87-4.71 (m, 1H), 4.06-3.82 (m, 4H), 3.68-3.41 (m, 2H), 3.11 (s, 1H), 1.97-1.79 (m, 2H), 1.33-0.98 (m, 6H).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:13][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)=[O:4].[H-].[Na+].Br[CH2:17][C:18]1[CH:22]=[C:21]([C:23]2[S:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[O:20][N:19]=1.[OH-].[Na+]>CN(C=O)C>[Cl:28][C:25]1[S:24][C:23]([C:21]2[O:20][N:19]=[C:18]([CH2:17][N:13]3[C:8]4=[N:9][CH:10]=[CH:11][CH:12]=[C:7]4[CH:6]=[C:5]3[C:3]([OH:2])=[O:4])[CH:22]=2)=[CH:27][CH:26]=1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: COC(=O)c1cc2cccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)c1cc2cccnc2n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.195 g (1.1 mmol) of 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester was dissolved in 4 mL of DMF and 48.7 mg (1.2 mmol) of sodium hydride (60% in mineral oil) was added. The reaction was stirred at RT for 20 min, cooled to −78° C. then 324 mg (1.2 mmol) of 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001) 460 pp. WO 0107436 A2] was added. The reaction was allowed to warm to RT overnight. 0.3 mL of 2N aqueous sodium hydroxide was added and the reaction was stirred at RT for 24 h. The product was purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:19]O>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([O:10][CH3:19])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Product: COC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
In a 500 cc 1-necked, round bottom flask, fitted with a condenser and stirring bar, were placed under nitrogen: 37.55 g. (0.15 mole) 3,5-di-tert.-butyl-4-hydroxybenzoic acid, 7.5 g. Amberlyst 15 catalyst, and 300 cc (7.43 moles) methanol. The solution was refluxed 15 hours, after which time the hot solution was filtered, concentrated, and cooled to afford 31.9 g. (81%) white crystals which were washed with hexane and dried. The melting point was 165.0° -166.5° C. The infrared and NMR spectra of the product were consistent with those expected from methyl 3,5-di-tert. butyl-4-hydroxybenzoate.
Reaction SMILES: [CH2:1]([C:3]1[C:4](N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[CH:32]([NH2:34])[CH2:31][CH2:30][CH2:29]2>>[CH2:1]([C:3]1[C:4]([NH:34][CH:32]2[C:33]3[C:28](=[CH:27][CH:26]=[CH:25][C:24]=3[O:23][CH3:22])[CH2:29][CH2:30][CH2:31]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: COc1cccc2c1C(N)CCC2
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(NC2CCCc3cccc(OC)c32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 8-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.63, 7.22, 6.78, 5.40, 4.31, 3.71, 2.86-2.65, 2.53-2.38, 1.88-1.67, 1.32, 1.21; HRMS (FAB) calcd for C19H25N3O+H 312.2076, found 312.2077.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[NH:10][C:9](=O)[N:8]([CH3:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1.N.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:9]1[N:8]([CH3:13])[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=2[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc2c1[nH]c(=O)n2C
Agent: N
Product: COc1cccc2c1nc(Cl)n2C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3.7 g 4-methoxy-1-methyl-1,3-dihydrobenzimidazol-2-one are suspended in 15 ml phosphorus oxychloride. The reaction mixture is stirred for 3 hours at reflux temperature, slowly combined with ice water and made alkaline with conc. Ammonia. The precipitated product is suction filtered. 3.6 g product are obtained as a solid. M.p=118-119° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][CH:8]=[N:7][C:6]=1[N:10]1[C:14](=[O:15])[NH:13][C:12]([CH:16]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[C:33]([CH2:39][NH:40]C(OC(C)(C)C)=O)[CH:32]=2)[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH2:26][CH2:27][OH:28])[C:18]=2[F:29])=[N:11]1)=[O:4].CO.[OH-].[Na+]>C(O)(=O)C>[F:29][C:18]1[C:19]([O:25][CH2:26][CH2:27][OH:28])=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:17]=1[CH:16]([NH:30][C:31]1[CH:32]=[C:33]2[C:34](=[CH:35][CH:36]=1)[C:37](=[NH:38])[NH:40][CH2:39]2)[C:12]1[NH:13][C:14](=[O:15])[N:10]([C:6]2[N:7]=[CH:8][O:9][C:5]=2[C:3]([OH:2])=[O:4])[N:11]=1
Reactant: COC(=O)c1ocnc1-n1nc(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2cc(OC)cc(OCCO)c2F)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc3c(c2)CNC3=N)c2nn(-c3ncoc3C(=O)O)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.4 %

Procedure:
To a mixture of 4-(3-{[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylamino]-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)oxazole-5-carboxylic acid methyl ester (39 mg) and methanol (2.0 mL) there was added a 5 M sodium hydroxide aqueous solution (28 μL), and the mixture was stirred overnight at room temperature. After neutralizing the mixture with acetic acid, the solvent in the mixture was distilled off under reduced pressure. Dichloromethane (2.0 mL) was added to the residue, and then a 4M hydrogen chloride-ethyl acetate solution (500 μL) was added to the solution prior to stirring at room temperature for 15 minutes. Toluene (10 mL) was added to the mixture, and the solvent in the mixture was distilled off. The residue was purified by reverse-phase high performance liquid chromatography (acetonitrile/water mixed solvent, 0.1% acetic acid) to obtain the target compound (8.5 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:37])[C:5]([C:34](O)=[O:35])=[N:6][N:7]2[CH2:32][CH3:33].C(N(CC)CC)C.ClC(OCC(C)C)=O.[N:53]1([CH2:58][CH2:59][NH2:60])[CH2:57][CH2:56][CH2:55][CH2:54]1>O1CCCC1>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:37])[C:5]([C:34]([NH:60][CH2:59][CH2:58][N:53]1[CH2:57][CH2:56][CH2:55][CH2:54]1)=[O:35])=[N:6][N:7]2[CH2:32][CH3:33]
Reactant: NCCN1CCCC1
Reactant: CCn1nc(C(=O)O)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCn1nc(C(=O)NCCN2CCCC2)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
To a suspension of 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carboxylic acid (3 g, 5.71 mmol) in tetrahydrofuran (THF) (25 mL) was added triethylamine (0.876 mL, 6.29 mmol), followed by isobutyl chloroformate (0.826 mL, 6.29 mmol). The reaction mixture was stirred at 0° C. for 30 min. 2-(Pyrrolidin-1-yl)ethanamine (0.979 g, 8.57 mmol) was added and the mixture was stirred at 0° C. for 30 min and warmed up to room temperature for 2 h. Solvent was removed and the residue was chromatographed to afford 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydrocinnoline-3-carboxamide (1.2 g, 1.932 mmol, 33.8% yield). LCMS: (M+H)+: 621.2
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:18]2[CH:23]=[CH:22][N+:21]([O-])=[CH:20][CH:19]=2)[CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15]>>[Cl:3][C:22]1[CH:23]=[C:18]([C:10]2[CH:9]=[C:8]([O:7][CH3:6])[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:19]=[CH:20][N:21]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(-c2cc[n+]([O-])cc2)cc(OC)c1OC
Product: COc1cc(-c2ccnc(Cl)c2)cc(OC)c1OC
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Phosphorus oxychloride (2 mL) was added to 4-(3,4,5-Trimethoxyphenyl)pyridine-N-oxide (27 mg) at 0° C., and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and neutralized with a saturated aqueous solution of sodium hydrogencarbonate at 0° C. The neutralized product was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by column chromatography on silica gel (ethyl acetate) to obtain the title compound.