Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:15][C:14](=[O:16])[N:13]([C:17]2[CH:18]=[CH:19][C:20]3[O:21][CH2:22][C:23](=[O:27])[NH:24][C:25]=3[N:26]=2)[CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[NH2:10][CH:11]1[CH2:12][N:13]([C:17]2[CH:18]=[CH:19][C:20]3[O:21][CH2:22][C:23](=[O:27])[NH:24][C:25]=3[N:26]=2)[C:14](=[O:16])[CH2:15]1
Reactant: O=C1COc2ccc(N3CC(NC(=O)OCc4ccccc4)CC3=O)nc2N1
Agent: [Pd]
Solvent: CO
Product: NC1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reaction time: 0.75 h
Yield: 92.3 %

Procedure:
[5-oxo-1-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)pyrrolidin-3-yl]carbamic acid benzyl ester (66.8 mg, 0.175 mmol) was dissolved in methanol (4 ml), 10% palladium on carbon (50% wet, 50 mg) was added thereto and catalytic hydrogenation was carried out at room temperature for 1 hour and at 50° C. for 45 minutes. The catalyst was removed by filtration and washed with methanol, and the filtrate and washings were concentrated under reduced pressure to yield 40.1 mg (92%) of the title compound in the form of a colorless solid.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18]CCC2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](CCO)=[CH:38][CH:37]=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:18][CH2:17][N:16]([C@H:27]2[CH2:28][CH2:29][C@H:30]([CH3:33])[CH2:31][CH2:32]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:6])([CH3:1])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(CCO)cc1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: COc1ccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(4-phenyl-butyl) -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 2-(4-methoxy-phenyl)-ethanol and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1.[CH3:41][C:42]1(C2C=CC=CC=2)CC(=O)O[C:43]1=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]([CH3:30])([C:33]2[CH:32]=[CH:31][CH:43]=[CH:42][CH:41]=2)[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:39][CH:40]=1
Reactant: CC1(c2ccccc2)CC(=O)OC1=O
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Product: CCOC(=O)C(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Br)cc1)c1ccccc1

Procedure:
The title compound was prepared using analogous conditions to those described for ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate using racemic 3-methyl-3-phenyldihydrofuran-2,5-dione. MS (ESI): mass calcd. for C36H32BrN3O3, 633.16; m/z found, 634.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4]Cl)[CH3:2].[OH:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([O:3][CH2:4][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)[CH3:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of chloromethyl ethyl ether (5.65 g, 0.06 mol) in 20 ml of THF at 0° C. is added to a mixture of 4-hydroxybenzaldehyde (5 g, 0.041 mol) and 12 ml of triethylamine in 30 ml of THF and the mixture is stirred at ambient temperature for 2 hrs. The triethylamine hydrochloride is filtered off and the solvent is evaporated under reduced pressure to give the 4-ethoxymethoxybenzaldehyde in the form of an oil (6.63 g, 90%).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Br.Cl[C:10]1[C:11]([CH3:21])=[C:12]([CH3:20])[C:13]2[N:14]([C:16]([NH2:19])=[N:17][N:18]=2)[N:15]=1>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:10]2[C:11]([CH3:21])=[C:12]([CH3:20])[C:13]3[N:14]([C:16]([NH2:19])=[N:17][N:18]=3)[N:15]=2)[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: Cc1c(Cl)nn2c(N)nnc2c1C
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(OCC2CC2)nn2c(N)nnc2c1C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Cyclopropylmethanol (2.84 ml) was initially charged in DMF (20 ml), admixed under argon with sodium hydride (862 mg) and stirred at 50° C. for 1 h. Subsequently, 6-chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.006, 2 g), dissolved in DMF (20 ml), and one equivalent of the alkoxide solution were added. After stirring at 50° C. for one hour, two further equivalents of alkoxide solution were added and the mixture was stirred further at 50° C. Then the reaction mixture was dried and purified using silica gel (40 g cartridge, dichloromethane/methanol gradient of 0-10% in 40 min). 625 mg of the title compound were obtained. LC-MS rt: 0.62 min [M+H]+: 234.1 (met. b)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]4[CH2:27][CH2:26]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[O:28]=[C:29]1[NH:33][C@H:32]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:31][O:30]1>>[C:36]([O:35][CH2:34][C@@H:32]1[CH2:31][O:30][C:29](=[O:28])[N:33]1[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]4[CH2:27][CH2:26]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([C:7]#[N:8])[CH:9]=1)(=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2C#N)CC1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3COC(=O)c3ccccc3)cc2C#N)CC1
Yield: 74.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using 5-bromo-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (1.58 g) described in Preparation Example 194 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (906 mg), the title compound (1.56 g) was obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[CH2:16][NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C@@H:39]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[CH2:40][CH2:41][N:42]([CH:46]([CH3:48])[CH3:47])[CH:43]([CH3:45])[CH3:44])[CH:33]=3)=[CH:22][CH:21]=2)=[CH:11][C:10]=1[NH:63][S:64]([CH3:67])(=[O:66])=[O:65])C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[OH-].[Pd+2]>[Si:56]([O:55][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:63][S:64]([CH3:67])(=[O:65])=[O:66])[CH:11]=1)[CH2:16][NH:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C@@H:39]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH2:40][CH2:41][N:42]([CH:46]([CH3:48])[CH3:47])[CH:43]([CH3:45])[CH3:44])[CH:33]=2)=[CH:24][CH:25]=1)([C:59]([CH3:62])([CH3:60])[CH3:61])([CH3:58])[CH3:57]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)cc2)ccc1O)C(C)C
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(NS(C)(=O)=O)c3)cc2)ccc1O)C(C)C
Temperature: 90 °C

Procedure:
N-[2-(benzyloxy)-5-{(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-[(2-{4-[(5-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}pentyl)oxy]phenyl}ethyl)amino]ethyl}phenyl]methanesulfonamide (Preparation 60, 350 mg, 0.37 mmol) was dissolved in ethanol (10 ml) and ammonium formate (1.0 g, 16 mmol) and 20% palladium hydroxide on carbon (250 mg) were added and heated to 90° C. for 1 hour. Reaction mixture was then cooled and filtered through Arbocel and the solvent removed in vacuo to furnish the title compound as a colourless oil, 250 mg.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)([O-:7])=[O:6].[CH3:19]O>>[CH3:19][O:17][C:16](=[O:18])[CH:15]=[CH:14][C:11]1[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][CH:12]=1
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (28.8 ml, 0.4 mol) was added dropwise to methanol (450 ml) at −10° C. temperature. To the obtained solution was added 3-(4-nitrophenyl)-acrylic acid (71) (38.63 g, 0.2 mol) and the reaction mixture was stirred at 0° C. for 3 hours, at ambient temperature for 24 hours and at 40° C. for 1 hour. The resulting-precipitate was filtered, washed with methanol (2×10 ml) and dried affording the title compound in a form of yellow crystals (39.55 g, 96%). 1H NMR (DMSO-d6, HMDSO), δ: 3.69 (2H, br s); 3.77 (3H, s); 6.87 (1H, d, J=16.0 Hz); 7.67-8.39 (5H, m).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:8]=2[F:13])[C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CCOCC>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:8]=2[F:13])[C:3]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:26][CH:27]=1
Reactant: CCCCCCCCc1ccc2c(-c3ccc(O)cc3)c(F)c(F)cc2c1F
Reactant: CCCCCCCCBr
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2c(F)c(F)cc3c(F)c(CCCCCCCC)ccc23)cc1

Procedure:
From 4-(2,3,5-trifluoro-6-octylnaphthalen-1-yl)phenol and 1-octyl bromide by means of the Williamson ether synthesis.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:32])(=[N:26]C(OCC)=O)=[O:25])[CH:19]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:33][C:34]1[S:35][CH:36]=[CH:37][N:38]=1)=[O:5])[CH3:2].[O-]CC.[Na+]>>[CH3:32][S:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][O:16][C:15]1[CH:14]=[C:13]2[C:8]([C:9]([NH:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[NH:26])=[O:25]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(Nc4nccs4)c3cc2C(=O)OCC)c1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)c1cc2c(Nc3nccs3)ncnc2cc1OCc1cccc(S(C)(=N)=O)c1
Yield: 42 %

Procedure:
According to GWP 6, ethyl-7-({(RS)-3-[N-(ethoxycarbonyl)-S-methyl-sulphonimidoyl]-benzyl}oxy)-4-(thiazol-2-ylamino)quinazoline-6-carboxylate (175 mg, 0.182 mmol) is reacted at 80° C. for 2 hours with sodium ethoxide (55 mg, 0.8 mmol). After cooling, the reaction mixture is concentrated to dryness. The residue is taken up in ethyl acetate and water. The organic phase is separated off, dried over sodium sulphate and subsequently concentrated. The desired product is obtained after chromatographic purification (silica gel, dichloromethane/methanol: 9/1) in 42% yield (39 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43]OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:49]#[N:50].[Na+]>CS(C)=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][C:49]#[N:50])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCOS(C)(=O)=O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCC#N)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 50 °C

Procedure:
To a stirred solution of 0.90 g of (2S,4R,5R)-2-(2-methanesulfonyloxy-ethyl)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (from example 18b) in 10 ml of dimethylsulfoxide are added 0.25 g of sodium cyanide and the mixture is heated to 50° C. for 4 hours. The reaction mixture is diluted with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a colourless oil. Rf=0.30 (EtOAc-heptane 1:1); Rt=5.20.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[CH2:36][CH2:35][C:14]2[N:15]=[C:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)[N:17]=[CH:18][C:13]=2[C:12]1=[O:37].C1COCC1>[Pd].CO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N:11]2[CH2:36][CH2:35][C:14]3[N:15]=[C:16]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([C:26]([N:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[O:27])=[CH:24][CH:25]=4)[N:17]=[CH:18][C:13]=3[C:12]2=[O:37])[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCc2nc(Nc3ccc(C(=O)N4CCN(C)CC4)cc3)ncc2C1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N)cc1N1CCc2nc(Nc3ccc(C(=O)N4CCN(C)CC4)cc3)ncc2C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 6-(2-Methyl-5-nitro-phenyl)-2-[4-(4-methyl-piperazine-1-carbonyl)phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one (100 mg, 0.199 mmol) in the mixed solvent of THF (3 ml) and methanol (3 ml) was added 10% Pd/C, and the reaction mixture was stirred for 12 hours at room temperature under a hydrogen balloon. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give 6-(5-Amino-2-methyl-phenyl)-2-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one [23] as a off white solid [Yield: 83.0 mg, 88.3%]
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:15]Br>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][Br:15])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: BrBr
Reactant: Cc1ccc(-c2ccccc2)c(F)c1
Product: Fc1cc(CBr)ccc1-c1ccccc1

Procedure:
In this instance the 2-fluoro-4-methylbiphenyl was heated to 140° to 170° C. with a heating mantle and under irradiation with light without a solvent while one equivalent of Br2 was added dropwise. Subsequent NMR analysis showed the starting material:monobromide:dibromide ratio to be 25:58:18.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.C([O-])(=O)C.[Na+].[CH3:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][OH:16]>>[C:4]([O:16][CH2:15][CH2:14][N:13]([CH3:12])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: C=C1CC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)CC(=O)OCCN(C)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To 84 g. (1.0 mole) of diketene contained in a three-necked round-bottom flask fitted with a mechanical stirrer addition funnel and reflux condenser and heated to 50° C. is added 500 mg. of sodium acetate followed by 175.2 g. (1.0 mole) of N-methyl-N-t-butyloxycarbonylethanolamine over a period of 20-30 minutes. The reaction mixture is allowed to stir at room temperature for 1 hour, after which it is distilled under reduced pressure to provide the desired product, 2-(N-methyl-N-t-butyloxycarbonylamino)ethyl acetoacetate.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[Na].Cl[CH2:11][C:12]1[CH:20]=[C:18]([CH3:19])[CH:17]=[C:15]([CH3:16])[C:13]=1[CH3:14]>C(O)C>[CH3:11][C:12]1[CH:20]=[C:18]([CH3:19])[CH:17]=[C:15]([CH3:16])[C:13]=1[CH2:14][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8]
Reactant: [O-][n+]1ccccc1S
Reactant: Cc1cc(C)c(C)c(CCl)c1
Agent: [Na]
Solvent: CCO
Product: Cc1cc(C)c(CSc2cccc[n+]2[O-])c(C)c1

Procedure:
A mixture of 17 gms (0.05 mole) 2-mercaptopyridine N-oxide, sodium salt (40% aqueous solution) and 8.5 gms (0.05 mole) α 2 chloroisodurene in 50 ml of ethanol is brought to reflux for 15 minutes. The volatiles are removed and the residue extracted with 150 ml of boiling chloroform, filtered and dried over sodium sulfate. Evaporation and trituration of the residue with a few drops of acetone induced crystallization. A yield of 11.5 gms of 2-(2,4,6-trimethylphenylmethylthio)pyridine N-oxide is obtained. Melting point 137° - 138°C. Structure confirmed by IR and NMR.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:33])([CH3:32])[O:6][C@H:7]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[CH2:8]1)([CH3:4])[CH3:3].[H][H].N#N>CCO.[Pd]>[CH3:4][C:2]([Si:5]([CH3:33])([CH3:32])[O:6][C@H:7]1[CH2:8][NH:9][CH2:10][C@@H:11]([CH2:13][NH:14][C:15](=[O:16])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12]1)([CH3:1])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)(C)OC(=O)NC[C@@H]1CNC[C@H](O[Si](C)(C)C(C)(C)C)C1
Reaction time: 1.5 h
Yield: 102.9 %

Procedure:
To cis-phenylmethyl (3RS,5RS)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-1-piperidinecarboxylate (550 mg; 1.1 mmol) in EtOH (50 ml) was added Pd/C (150 mg; 10%). The reaction was hydrogenated on a Parr apparatus at 40 psi of H2 for 1.5 hours. The hydrogen was displaced with N2 and the solution was filtered through a pad of Celite® to remove the catalyst which was washed with additional EtOH (50 ml). The filtrate was then concentrated under reduced pressure to give the desired compound (390 mg; 100%) as a pale yellow oil which was used without further purification.
Reaction SMILES: C[Mg]I.C(OCC)C.I[C:10]1[N:11]=[CH:12][N:13]2[CH:17]=[CH:16][S:15][C:14]=12.[CH2:18]([O:21][C:22]([N:24]1[C@H:28]([CH:29]=[O:30])[CH2:27][C@@H:26]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:25]1)=[O:23])[CH:19]=[CH2:20].[Cl-].[NH4+]>C1COCC1>[CH2:18]([O:21][C:22]([N:24]1[C@H:28]([CH:29]([OH:30])[C:10]2[N:11]=[CH:12][N:13]3[CH:17]=[CH:16][S:15][C:14]=23)[CH2:27][C@@H:26]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34])[CH2:25]1)=[O:23])[CH:19]=[CH2:20]
Reactant: Ic1ncn2ccsc12
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1ncn2ccsc12
Temperature: -50 °C
Reaction time: 0.17 h

Procedure:
A 2 M methylmagnesium iodide/diethyl ether solution (4.6 ml) is diluted with 50 ml of anhydrous THF, and a solution of 2.0 g of 7-iodoimidazo[5,1-b]thiazole in 50 ml of THF is added dropwise to the diluted solution under ice cooling in an argon atmosphere. The mixture is stirred at that temperature for 10 min and then at room temperature for 1.5 hr and cooled to −50° C., and a solution of 1.735 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-formylpyrrolidine in 50 ml of THF is added dropwise thereto. A reaction is allowed to proceed while raising the temperature to 10° C. over a period of 3 hr, 200 ml of a semi-saturated aqueous ammonium chloride solution is added thereto, and the mixture is extracted twice with 250 ml of ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and filtered, and the solvent is removed by evaporation. The residue is purified by column chromatography on silica gel (ethyl acetate alone→ethyl acetate:methanol=20:1→10:1). Thus, 450 mg of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-7-yl)methyl]pyrrolidine (stereoisomer A: a high polar component) and 395 mg of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[l-hydroxy-1-(imidazo[5,1-b]thiazol-7-yl)methyl]pyrrolidine (stereoisomer B: a low polar component) are prepared.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]=2[C:8]([NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>C1COCC1>[NH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:19]1[C:17]([NH:16][C:8]1[C:9]2[O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]=2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1)=[O:18]
Reactant: COC(=O)c1ccc(NC(=O)c2cc3ccccc3[nH]2)c2c1OCCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(=O)O)c2c1OCCCO2)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 96 h
Yield: 47.8 %

Procedure:
9-[(1H-indole-2-carbonyl)amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methyl ester (E-2; R=H; 50 mg) was combined with 1 mL of THF and 1 mL of 1M NaOH and the reaction stirred for 4 days at room temperature. The solid was collected on a filter to yield 23 mg of a solid. LCMS: AP+ 353.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:8][C:9]([C:13]([NH2:15])=[O:14])=[N:10]2)=[CH:5][CH:4]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:7]2[C:6]3[C:11](=[CH:12][C:3]([CH2:2][C:27]4[CH:28]=[N:23][CH:24]=[N:25][CH:26]=4)=[CH:4][CH:5]=3)[N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[CH:17][CH:18]=1
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2n1
Reactant: OB(O)c1cncnc1
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: [Na+]
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(Cc3cncnc3)cc2n1
Temperature: 100 °C
Yield: 8.2 %

Procedure:
Degassed DME (1237 μl)/Water (619 μl) was added to 7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carboxamide (3-1, 100 mg, 0.278 mmol), pyrimidin-5-ylboronic acid (41.4 mg, 0.334 mmol), Pd(PPh3)4 (16.09 mg, 0.014 mmol), and Na2CO3 (62.0 mg, 0.585 mmol). The reaction was heated at 100° C. in the microwave for 10 minutes. The reaction was quenched with water and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The crude material was purified by flash column chromatography (12 g SiO2, 0-100% EtOAc/hexanes) to afford impure product. The material was purified further by reverse phase HPLC (20×150 mm, Waters Sunfire, Solvent A=0.1% TFA/H2O, Solvent B=0.1% TFA/MeCN, 20 ml/min) to afford, after basic workup, 4-(4-fluorophenyl)-7-(pyrimidin-5-ylmethyl)quinoline-2-carboxamide (6-3, 8.16 mg, 8.18% yield) as a white solid. 1H NMR (500 MHz, CDCl3): δ 9.14 (s, 1H); 8.68 (s, 2H); 8.23 (s, 1H); 8.05 (s, 1H); 7.97 (s, 1H); 7.93 (d, J=8.7 Hz, 1H); 7.50 (dd, J=8.5, 5.4 Hz, 2H); 7.42 (dd, J=8.7, 1.8 Hz, 1H); 7.24 (t, J=8.5 Hz, 2H); 5.64 (s, 1H); 4.22 (s, 2H). LRMS m/z (M+H)+ 359.2 found, 359.4 required.