Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@:3]1([CH3:27])[S:9][C@H:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[C@H:4]1[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=O.[Cl-].[O:29]1[CH:33]=[N:32][C:31]([CH2:34][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:30]1>C1OC1CC>[CH3:27][C@@:3]1(/[CH:1]=[CH:34]/[C:31]2[N:32]=[CH:33][O:29][N:30]=2)[S:9][C@H:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[C@H:4]1[C:11]([O:13][CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:12]
Reactant: c1ccc([P+](Cc2ncon2)(c2ccccc2)c2ccccc2)cc1
Reactant: C[C@@]1(C=O)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Agent: CCC1CO1
Agent: [Cl-]
Product: C[C@@]1(/C=C/c2ncon2)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
1.14 g (3.0 mmol) of benzhydryl (2S,3R,5R)-3-formyl-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate were dissolved in 15 ml of 1,2-butylene oxide, treated with 1.38 g (3.6 mmol) of (1,2,4-oxadiazol-3-yl)methyl-triphenylphosphonium chloride and refluxed for 10 hours. Subsequently, the mixture was filtered, the filtrate is evaporated and the residual brown oil was chromatographed over silica gel (0.040-0.063 mm particle size) with methylene chloride as the eluent. Yield: 280 mg (21%) of colorless crystals MS: (M+NH4)+ 465.3 IR (KBr): 1792, 1753, 1658, 1492, 1200, 991 cm-1
Reaction SMILES: C(OC([NH:11][C@H:12]([C@@H:33]([NH:41][C:42](=[O:63])[C@@H:43]([NH:48][C:49](=[O:62])[C@@H:50]([NH:55][C:56](=[O:61])[CH2:57][CH:58]([CH3:60])[CH3:59])[CH2:51][CH:52]([CH3:54])[CH3:53])[C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:13][C:14]([NH:16][C@@H:17]([C@@H:29]([CH3:32])[CH2:30][CH3:31])[C:18]([NH:20][C@@H:21]([CH:26]([CH3:28])[CH3:27])[C:22]([O:24][CH3:25])=[O:23])=[O:19])=[O:15])=O)C1C=CC=CC=1>C1COCC1.[Pd]>[NH2:11][C@H:12]([C@@H:33]([NH:41][C:42](=[O:63])[C@@H:43]([NH:48][C:49](=[O:62])[C@@H:50]([NH:55][C:56](=[O:61])[CH2:57][CH:58]([CH3:60])[CH3:59])[CH2:51][CH:52]([CH3:53])[CH3:54])[C:44]([CH3:45])([CH3:47])[CH3:46])[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:13][C:14]([NH:16][C@@H:17]([C@@H:29]([CH3:32])[CH2:30][CH3:31])[C:18]([NH:20][C@@H:21]([CH:26]([CH3:28])[CH3:27])[C:22]([O:24][CH3:25])=[O:23])=[O:19])=[O:15]
Reactant: CC[C@H](C)[C@H](NC(=O)C[C@H](NC(=O)OCc1ccccc1)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)CC(C)C)C(C)(C)C)C(=O)N[C@H](C(=O)OC)C(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)C[C@H](N)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)CC(C)C)C(C)(C)C)C(=O)N[C@H](C(=O)OC)C(C)C
Yield: 35 %

Procedure:
300 mg of methyl (S)-2-[(2S,3S)-2-((3S,4S)-3-benzyloxycarbonylamino-4-{(S)-3,3-dimethyl-2-[(S)-4-methyl-2-(3-methylbutyrylamino)pentanoylamino]-butyrylamino}-5-phenylpentanoylamino)-3-methylpentanoylamino]-3-methylbutyrate were hydrogenated in a suitable vessel in the presence of 300 mg of Pd/C (5% of Pd) in 30 ml of THF at RT at atmospheric pressure until the starting material had reacted completely (overnight). The solvent was removed in vacuo, and the residue was triturated with MTBE and filtered off with suction. Purification by preparative HPLC (Chromolith®prep, RP18e, 100-25; gradient water:acetonitrile 1-60% in 12 min) and subsequent lyophilisation gave 89 mg of methyl (S)-2-[(2S,3S)-2-((3S,4S)-3-amino-4-{(S)-3,3-dimethyl-2-[(S)-4-methyl-2-(3-methylbutyrylamino)pentanoylamino]butyrylamino}-5-phenylpentanoylamino)-3-methylpentanoylamino]-3-methylbutyrate as a white powder (yield 31%). MS-FAB (M+H+)=746.1 Rf (polar method): 2.02 min.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:32])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][C:5]2=O.Cl.[CH3:34][O:35][NH2:36].CO.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[OH:1][C:2]1[C:3]([CH3:32])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=1)([CH3:14])[CH2:6]/[C:5]/2=[N:36]\[O:35][CH3:34]
Reactant: CON
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CO/N=C1\CC(C)(COc2ccc(CC3SC(=O)NC3=O)cc2)Oc2c(C)c(C)c(O)c(C)c21
Reaction time: 240 h

Procedure:
A mixture of 1 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Example 22 of copending U.S. Ser. No. 644,996), 0.6 g of methoxyamine hydrochloride and 5 g of methanol was allowed to stand for 10 days at room temperature. At the end of this time, ethyl acetate and an aqueous solution of potassium carbonate were added. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography eluted with a 3:1 by volume mixture of hexane and ethyl acetate, to give the title compound softening at 72°-76° C.
Reaction SMILES: F[C:2]1[C:20]2[C:19](=[O:21])[C:18]([C:22]([OH:24])=[O:23])=[CH:17][N:7]3[C@H:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:25][CH2:26][CH2:27][NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[C:3]=1[F:35].[CH3:36][O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=1>CS(C)=O>[F:35][C:3]1[C:4]([NH:25][CH2:26][CH2:27][NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[C:5]2[O:10][CH2:9][C@@H:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:7]3[CH:17]=[C:18]([C:22]([OH:24])=[O:23])[C:19](=[O:21])[C:20]([C:2]=1[NH:43][CH2:42][C:41]1[CH:44]=[CH:45][C:38]([O:37][CH3:36])=[CH:39][CH:40]=1)=[C:6]23
Reactant: O=C(O)c1cn2c3c(c(NCCNc4ccccn4)c(F)c(F)c3c1=O)OC[C@H]2c1ccccc1
Reactant: COc1ccc(CN)cc1
Solvent: CS(C)=O
Product: COc1ccc(CNc2c(F)c(NCCNc3ccccn3)c3c4c2c(=O)c(C(=O)O)cn4[C@H](c2ccccc2)CO3)cc1
Temperature: 0 °C
Yield: 76.4 %

Procedure:
A solution of (R)-8,9-difluoro-2,3-dihydro-7-oxo-3-phenyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (432 mg, 0.903 mmol) and 4-methoxybenzylamine (400 μL, 4.51 mmol) in DMSO (4 mL) was stirred at 150° C. for 2 h. The reaction mixture was added portionwise at 0° C. with ice-water and the resulting precipitate was combined by filtration, washed with water. The cake washed with EtOH and collected by filtration and then dried to give (R)-9-fluoro-2,3-dihydro-8-(4-methoxybenzylamino)-7-oxo-3-phenyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (411 mg, 78%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:20])([C:16]([F:19])([F:18])[F:17])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([CH2:21][CH3:22])[C:3]=1[NH:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([N+:33]([O-])=O)[CH:26]=1.[OH-].[Na+].S([O-])(O)=O.[Na+]>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[NH2:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[C:31]#[N:32])[C:24]([NH:23][C:3]1[C:4]([CH2:21][CH3:22])=[CH:5][C:6]([C:8]([F:20])([C:16]([F:17])([F:18])[F:19])[C:9]([F:14])([F:15])[C:10]([F:12])([F:13])[F:11])=[CH:7][C:2]=1[Br:1])=[O:36]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(Br)c1NC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])O
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(Br)c1NC(=O)c1ccc(C#N)c(N)c1
Temperature: 65 °C
Reaction time: 1.33 h
Yield: 109.4 %

Procedure:
N-[2-Bromo-6-ethyl-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethyl-propyl)-phenyl]-4-cyano-3-nitro-benzamide (63.9 g, 102.6 mmol) was dissolved in tetrahydrofuran (1200 ml). Aqueous sodium hydroxide (0.1 M, 550 ml), sodium hydrogen sulfite (65.3 g, 307.7 mmol) and tetrabutylammonium bromide (“TBAB”) (3.4 g, 10.3 mmol) were added. The mixture was vigorously stirred at 65° C. Further portions of sodium hydrogen sulfite were added after 20 minutes (65.3 g, 307.7 mmol) and after 80 minutes (32.7 g, 153.8 mmol). The reaction mixture was stirred at 65° C. for 30 minutes. Then the reaction mixture was cooled to 25° C. and diluted with ethyl acetate (1300 ml). The phases were separated and the organic phase was extracted with ethyl acetate (300 ml). The combined organic phases were washed with water, aqueous sodium hydrogen carbonate (10% w/v) (400 ml) and brine, dried over sodium sulfate and concentrated to yield 3-amino-N-[2-bromo-6-ethyl-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethyl-propyl)-phenyl]-4-cyano-benzamide as a yellow solid (63.1 g) which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([CH3:16])[N:13](S(C3C=CC=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1)=[O:5].C([O-])([O-])=O.[K+].[K+]>CO.O>[F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:32])=[O:33])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([CH3:16])[NH:13][C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(C)n3S(=O)(=O)c2ccccc2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(C)cc3c2)c1F

Procedure:
2,6-Difluoro-N-(2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.379 g, 0.691 mmol) was dissolved in MeOH (6 mL) and water (2 mL). K2CO3 (1.91 g, 13.8 mmol) was added, and the reaction mixture was stirred at reflux overnight. The solution was partitioned between water and EtOAc. The organic layer was washed with water (3×), brine, dried over Na2SO4 and concentrated to a solid. The solid was triturated with DCM to provide 2,6-difluoro-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide as a solid (150 mg, 53% for three steps). 1H NMR (400 MHz, DMSO-d6) δ 11.48 (br s, 1H), 10.80 (s, 1H), 9.80 (br s, 1H), 8.26 (br s, 1H), 8.20 (br s, 1H), 7.53-7.59 (m, 1H), 7.25-7.30 (m, 1H), 6.17 (br s, 1H), 3.10-3.14 (m, 2H), 2.40 (br s, 3H), 1.74-1.82 (m, 2H), 0.98-1.03 (m, 3H); m/z (APCI-neg) M−1=407.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][C:12]2=O)=[CH:7][CH:6]=1)=[O:4].C[Si]([C:20]#[N:21])(C)C.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(C1C=CC(C(CC)C(O)=O)=CC=1)(O)=O.[I-].[Zn+2].[I-]>[C:20]([C:12]1[C:13]2[CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7][C:8]=2[CH2:9][CH2:10][CH:11]=1)#[N:21]
Reactant: COC(=O)c1ccc2c(c1)C(=O)CCC2
Reactant: C[Si](C)(C)C#N
Agent: CCC(C(=O)O)c1ccc(C(=O)O)cc1
Agent: [I-]
Agent: [Zn+2]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)C(C#N)=CCC2
Yield: 47.1 %

Procedure:
Part B--A solution of 1-tetralon-7-carboxylic acid methyl ester (3.50 g, 0.017 mol), trimethylsilylcyanide (1.98 g, 0.02 mol) and zinc iodide (0.10 g) in benzene 5 (20 mL) was stirred at ambient temperature over 15 hours. Then added, sequentially and dropwise, was pyridine (20 mL) and phosphorous oxychloride (4.0 mL, 6.55 g, 0.0425 mol). The reaction mixture was stirred at reflux over 1 hour then evaporated to dryness under reduced pressure. The residue was taken up in chloroform, backwashed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give methyl 8-cyano-5,6-dihydro-2-naphthoate (1.70 g, 0.008 mol, 47%) as a yellow solid. mp=73°-75° C.; 1H NMR (CDCl3) d 8.0-7,9 (m, 1H), 7.3-7.2 (m, 1H), 6.95 (t, 1H, J=4.8 Hz), 3.95 (s, 3H), 2.9 (t, 2H, J=8.3 Hz), 2.6-2.4 (m, 3H)
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=O.[C:11]([CH2:13][C:14]([NH2:16])=[S:15])#[N:12]>>[CH:5]1([C:3]2[N:16]=[C:14]([CH2:13][C:11]#[N:12])[S:15][CH:2]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(CBr)C1CCCCC1
Reactant: N#CCC(N)=S
Product: N#CCc1nc(C2CCCCC2)cs1
Yield: 80 %

Procedure:
This compound was synthesized from 2-bromo-1-cyclohexylethanone and 2-cyanothioacetamide as described in example 1 step 1 (0.4 g, yield 80%). 1H NMR (300 MHz, CDCl3) δ 6.88 (s, 1H), 4.11 (s, 2H), 2.74 (m, 1H), 2.06-2.04 (m, 2H), 1.84-1.72 (m, 4H), 1.44-1.31 (m, 4H). MS (ESI) m/z: Calculated for C11H14N2S: 206.09. found: 207.2 (M+H)+.
Reaction SMILES: [OH-].[Na+].C(OC([NH:10][C:11]1[S:12][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([O:25][CH3:26])=[O:24])[CH:18]=2)=[CH:14][N:15]=1)=O)(C)(C)C>CO.C1COCC1>[CH3:26][O:25][C:23](=[O:24])[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([S:16][C:13]2[S:12][C:11]([NH2:10])=[N:15][CH:14]=2)[CH:18]=1
Reactant: COC(=O)c1cccc(Sc2cnc(NC(=O)OC(C)(C)C)s2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cccc(Sc2cnc(N)s2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 1 N aqueous sodium hydroxide solution (50 mL, 50 mmol) was added dropwise to a stirred solution of 2-tert-butoxycarbonylamino-5-[(3-carbomethoxyphenyl)thio]thiazole (1.8 g, (contaminated with bis(tert-butoxycarbonyl)amino adduct)) in a methanol-THF mixture (160 mL, 3:1). The solution was stirred at rt. for 24 h and concentrated. The residue was acidified with 2 N aqueous HCl (30 mL) and the suspension was extracted with dichloromethane-methanol mixture (120 mL, 3:1, 2×). The combined organic extract was dried (MgSO4), filtered and concentrated in vacuo to obtain the titled compound (1.32 g, 75% overall yield from Example 1, part A) as an off-white solid. D. 5-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]phenyl]thio]thiazol-2-ylcarbamic acid 1,1-(dimethylethyl) ester
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)=[CH:20]2.C(N(CC)CC)C>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[NH:22][C:21]([CH:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]4)=[CH:20]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(N)ccc3[nH]2)CC1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(NC(=O)C4(c5ccc6c(c5)OCO6)CC4)ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (43 mg, 0.19 mmol) and tert-butyl 4-(5-amino-1H-indol-2-yl)piperidine-1-carboxylate (60 mg, 0.19 mmol) were dissolved in dichloromethane (1 mL) containing a magnetic stir bar and triethylamine (0.056 mL, 0.40 mmol). The resulting solution was allowed to stir for two days at room temperature. The crude product was then evaporated to dryness, dissolved in a minimum of N,N-dimethylformamide, and then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield tert-butyl 4-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-yl)piperidine-1-carboxylate. ESI-MS m/z calc. 503.2, found 504.5. (M+1)+. Retention time of 1.99 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]2=[O:22])[CH:7]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]2=[O:22])[CH:7]=1
Reactant: CCCCCN1C(=O)C(O)(c2cc(F)ccc2O)c2ccccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN1C(=O)C(c2cc(F)ccc2O)c2ccccc21
Temperature: 40 °C
Reaction time: 15 h
Yield: 91.2 %

Procedure:
To a solution of 3-(5-fluoro-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one (2.42 g, 7.35 mmol) in dichloromethane (10.0 mL) were added trifluoroacetic acid (1.00 mL) and triethylsilane (1.00 mL) at ambient temperature. The reaction mixture was stirred at 40° C. for 15 hrs and concentrated in vacuo to dryness. The residue was triturated with ether to give the title compound (2.10 g, 91%) as a solid: MS (ES+) m/z 314 (M+1).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:29][CH:30]=2)O1.C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:25]3[CH:30]=[N:29][C:28]([N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)=[CH:27][CH:26]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccc(N4CCOCC4)nc3)nc12
Temperature: 110 °C
Reaction time: 0.42 h
Yield: 56.4 %

Procedure:
A mixture of 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (0.1 g, 0.354 mmol), commercially available 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]morpholine (0.206 g, 0.709 mmol), K2CO3 (0.147 g, 1.063 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.041 g, 35 micomol) in 3 mL of MeOH and 1 mL of DCM was degassed by bubbling argon through the mixture. It was then stirred at 110° C. for 25 minutes under microwave irradiation before being cooled to RT. And evaporated. The residue was adsorbed onto SiO2 and purified twice by SiO2 chromatography (hexanes/EtOAc 0-50% EtOAc, followed by DCM/MeOH 0-4% MeOH) to give 0.073 g of 2,2-Dimethyl-1-[2-(6-morpholin-4-yl-pyridin-3-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one (56% yield).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.O=[CH:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1>C(OC(=O)C)(=O)C>[OH:20][C:19]1[CH:21]=[CH:22][C:14]([CH:13]=[CH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1cc(C=O)ccc1O
Reactant: Cc1ccnc2ccccc12
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C=Cc2ccnc3ccccc23)ccc1O
Yield: 56 %

Procedure:
In 62.9 g of acetic anhydride, 26.73 g of 4-methylquinoline and 31.25 g of vanillin were refluxed overnight. The resultant reaction mixture was treated with an alkali. The product thus obtained was recrystallized via butyl cellosolve, to afford 29 g of 4-[2-(4-hydroxy-3-methoxyphenyl)-ethenyl]-quinoline having a melting point of 217°-219° C. From 0.55 g of this product, 1.75 g of triethylamine, 1.66 g of methacrylic acid chloride, and 16 cm3 of N,N-dimethylacetamide, there was obtained 4.70 g (80.3% in yield) of 4[2-(4-methacroyloxy-3-methoxyphenyl)-ethenyl]-quinoline having a melting point of 134°-135° C. This product was recrystallized via ethyl acetate and assayed by infrared absorption spectrometry and elementary analysis for its chemical structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:29]/[O:30][C:31]2([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[CH2:33][CH2:32]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23]OS(C)(=O)=O)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].[I-].[N-:52]=[N+:53]=[N-:54].[Na+]>CN(C=O)C>[N:52]([CH2:23][C@@H:19]1[C@H:18]([NH:17][C:15](=[O:16])/[C:14](=[N:29]\[O:30][C:31]2([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[CH2:32][CH2:33]2)/[C:12]2[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[S:10][CH:11]=2)[C:21](=[O:22])[NH:20]1)=[N+:53]=[N-:54]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2COS(C)(=O)=O)cs1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CN=[N+]=[N-])cs1
Temperature: 60 °C
Reaction time: 6 h
Yield: 57.3 %

Procedure:
To a solution of benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2S,3S)-2-(((methylsulfonyl)oxy)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (1.3 g, 1.82 mmol) in DMF (20 ml) was added NaI (0.82 g, 5.5 mmol) and sodium azide (0.83 g, 12.8 mmol). After stirring at 60° C. for 6 h, the reaction mixture was quenched with ice cold water and extracted with EtOAc. Combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-heptane) to afford the title compound (689 mg, 57%). LCMS: R=1.02 min, m/z=661.1 (M+1), Method 2m_acidic.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][NH2:23].CCCCCC>CS(C)=O>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:23][CH2:22][CH:21]([O:24][CH3:25])[O:20][CH3:19])[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(CN)OC
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Solvent: CS(C)=O
Solvent: CCCCCC
Product: COC(CNc1nc(-c2ccccc2)c2cc(Cl)ccc2n1)OC
Temperature: 0 °C
Yield: 100.4 %

Procedure:
The starting material may be prepared as follows: To a suspension of 5.5 g of 2,6-dichloro-4-phenylquinazoline in 70 ml of dimethylsulfoxide was added 4.2 g of 2,2-dimethoxyethylamine. The mixture was heated at 90°-100° C. for 1.5 hours with stirring. After cooling, the mixture was poured into 400 ml of ice-water. The resulting mixture was stirred with a small quantity of n-hexane, and the precipitate that formed was collected by filtration, washed with water and dried to give 6.9 g of 6-chloro-2-(2,2-dimethoxyethylamino)-4-phenylquinazoline. Recrystallization from ethanol gave yellow needles, m.p. 122.5°-123° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[CH2:11][O:12][CH3:13].[F:14][C:15]1[N:20]=[CH:19][C:18]([CH:21]([OH:23])[CH3:22])=[CH:17][CH:16]=1>C(Cl)Cl.C(Cl)(Cl)Cl.C(O)(C)C>[F:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]([O:23][CH2:11][O:12][CH3:13])[CH3:22])=[CH:19][N:20]=1
Reactant: COCCl
Reactant: CC(O)c1ccc(F)nc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC(C)c1ccc(F)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Add diisopropylethylamine and chloromethoxymethane to a solution of 1-(6-fluoro-pyridin-3-yl)-ethanol (3.0 g, 21.3 mmol) in DCM at 0° C. Continue to stir the mixture for 30 min at 0° C., then overnight at RT. Dilute the mixture with chloroform/IPA (3/1). Wash the solution with saturated aqueous sodium chloride. Dry it over sodium sulfate. Concentrate the solution in vacuo to a dark residue. Purify by column chromatography (hexane→20% ethyl acetate in hexane) to afford the title compound as a colorless solid (3 g, 66%). MS (ES) m/z 186 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[CH:21]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[N:28][CH:29]=1)[CH2:22][NH2:23])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:23][CH2:22][CH:21]([N:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[CH:12]([CH3:14])[CH3:13])[C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[N:28][CH:29]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C(CN)N2CCCCC2C(C)C)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCCCC2C(C)C)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-isopropylpiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.