Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([N:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]=1[NH2:28])[CH2:2][CH2:3][CH3:4].[C:29](Cl)(=O)[CH3:30].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:6]2[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([N:13]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:7]=2[N:28]=[C:29]1[CH3:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(C)nc(N(Cc2ccccc2)Cc2ccccc2)c1N
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCn1c(C)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc(C)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.6 %

Procedure:
N4 -n-Butyl-6-methyl-N2,N2 -bis(phenylmethyl)pyridine-2,3,4-triamine (0.65 g, 1.7 mmole) was combined with toluene (10 mL) and acetyl chloride (0.12 mL, 1.7 mmole) and stirred at ambient temperature for 15 minutes. Phosphorous oxychloride (0.31 mL) was added and the reaction mixture was heated at reflux overnight. The reaction mixture was evaporated. The residue was purified by silica gel column chromatography eluting with hexane:ethyl acetate (70:30) to provide 0.18 g of the desired product.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[C:42]([O:49][C@H:50]([CH2:52][CH:53]=[CH2:54])[CH3:51])[CH:41]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.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>[CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:43]5[CH:44]=[CH:45][C:40]([F:39])=[CH:41][C:42]=5[O:49][C@H:50]([CH2:52][CH:53]=[CH2:54])[CH3:51])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1B(O)O
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
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+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5ccc(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Temperature: 90 °C
Yield: 66.5 %

Procedure:
To a solution of (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate (0.27 g, 0.462 mmol, 1 equiv) and (S)-(4-fluoro-2-(pent-4-en-2-yloxy)phenyl)boronic acid (207 mg, 0.924 mmol, 2 equiv) in DMF (5 mL, sparged with nitrogen for 10 min) was added Pd(PPh3)4 (53 mg, 0.046 mmol, 0.1 equiv) and 2 M Na2CO3 (0.46 mL, 0.924 mmol, 2 equiv). The reaction was heated at 90° C. for 2.5 h. Upon cooling to ambient temperature, the reaction was diluted with EtOAc, washed with water, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (210 mg, 66%) as a viscous yellow oil. LCMS (ESI, M+1): 684.35.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[NH2:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([OH:26])=[C:21]([CH3:27])[CH:20]=1>>[CH3:25][C:24]1[CH:23]=[C:22]([OH:26])[C:21]([CH3:27])=[CH:20][C:19]=1[NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Reactant: Cc1cc(O)c(C)cc1N
Product: Cc1cc(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)c(C)cc1O

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 4-amino-2,5-dimethylphenol (40 mg, 0.290 mmol) similar to Example 117 and isolated as a white solid (2 mg). 1H NMR (CDCl3): 8.77 (d, J=6.0 Hz, 2H), 8.27 (d, J=6.3 Hz, 2H), 7.05 (s, 1H), 6.86 (s, 1H), 6.77 (s, 1H), 6.47 (s, 1H), 5.25 (bs, 1H), 2.26 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[C:6]=1[C:14]1[C:15]2[NH:22][CH:21]=[C:20]([C:23](O)=[O:24])[C:16]=2[N:17]=[CH:18][N:19]=1)[CH2:2][CH3:3].[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][C@@H:35]([NH2:38])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][C@@H:35]([NH:38][C:23]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:6]4[C:7]5[O:11][CH2:10][O:9][C:8]=5[CH:12]=[CH:13][C:5]=4[O:4][CH2:1][CH2:2][CH3:3])[C:15]=3[NH:22][CH:21]=2)=[O:24])[CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)O)c[nH]c13)OCO2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-propoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A70) and commercially available (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: C1(OC(=O)[N:9]([CH:42]2[CH2:44][CH2:43]2)[CH2:10][C:11]2[N:12]=[C:13]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)[S:14][C:15]=2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)=[C:20]([O:30][CH3:31])[CH:19]=2)C=CC=CC=1.[OH-].[K+]>C(O)CO.O>[CH:42]1([NH:9][CH2:10][C:11]2[N:12]=[C:13]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:36][CH:37]=3)[S:14][C:15]=2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)=[C:20]([O:30][CH3:31])[CH:19]=2)[CH2:43][CH2:44]1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN(C(=O)Oc2ccccc2)C2CC2)ccc1-c1noc(=O)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CNC2CC2)ccc1-c1noc(=O)[nH]1
Yield: 35.9 %

Procedure:
To a solution of 32.6 mg of cyclopropyl-[5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl]-carbamic acid phenyl ester in 2 mL of ethylene glycol was added 2 mL of a saturated solution of potassium hydroxide in water. The resulting mixture was stirred in a sealed tube under microwave irradiation for 25 minutes to 100° C., then 10 additional minutes to 120° C. and finally 15 more minutes to 140° C. It was then extracted with dichloromethane. The organic extracts were washed water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from dichloromethane 100 to dichloromethane 90/methanol 10) to give 9.5 mg of 3-{4-[4-cyclopropylaminomethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([N+:22]([O-])=O)=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[F:21])[C:8]([F:12])=[C:9]([F:11])[CH:10]=1)[CH:2]=[CH2:3].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C.O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[F:21])[C:6]=1[NH2:22])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(F)c(F)c(Nc2ccc(Br)cc2F)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCOc1cc(F)c(F)c(Nc2ccc(Br)cc2F)c1N
Temperature: 70 °C
Yield: 99.3 %

Procedure:
A suspension of (3-allyloxy-5,6-difluoro-2-nitro-phenyl)-(4-bromo-2-fluoro-phenyl)-amine (Intermediate 8, 0.7 g, 1.7 mmol) in ethanol (12 mL) was stirred at 70° C. to obtain a clear solution. To this hot solution, was added a freshly prepared solution of Na2S2O4 (0.9 g, 5.2 mmol) in water (1.9 mL) and stirred the reaction mixture at 90° C. for 1 h. The progress of reaction was monitored by TLC. After completion, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over anhydrous Na2SO4 and concentrated to yield 6-allyloxy-N2-(4-bromo-2-fluoro-phenyl)-3,4-difluoro-benzene-1,2-diamine as a yellow solid (630 mg). 1H-NMR (400 MHz, CDCl3): δ 4.55 (2H, d, J=5.6), 5.32-5.36 (2H, m), 5.42 (1H, d), 6.02-6.08 (1H, m), 6.35 (1H, t, J=8.8), 6.60-6.65 (1H, m), 7.06 (1H, d, J=8.4), 7.23 (1H, dd, J=2.0, 10.4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#N.C(O)=[O:12]>[Al].[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[O:12]
Reactant: Cc1ccc(C#N)cc1Cl
Reactant: O=CO
Agent: [Ni]
Agent: [Al]
Product: Cc1ccc(C=O)cc1Cl

Procedure:
A mixture of 3-chloro-4-methylbenzonitrile (4.0 g, 26.39 mmol), formic acid (72 ml, 75% v/v) and nickel aluminum alloy (50/50, 4.8 g) was stirred and heated under reflux for 2 h. The reaction mixture was then filtered hot through Hyflo, and the residue was washed well with hot ethanol. The filtrate was concentrated under reduced pressure to yield a sticky solid. Distillation of this solid afforded 3-chloro-4-methylbenzaldehyde as a colourless oil, b.p. 73°-74°/0.8 mmHg.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=O)[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH2:38]([O:45][N:46]=[CH:47][CH:48]1[CH2:52][CH2:51][CH2:50][NH:49]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[C:2]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[C:16]([N:49]1[CH2:50][CH2:51][C:47](=[N:46][O:45][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:48]1[CH3:52])=[O:18])([CH3:1])([CH3:3])[CH3:4]
Reactant: C(=NOCc1ccccc1)C1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1C(=NOCc2ccccc2)CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The solution of boc-L-α-cyclohexylglycine (1.27 g, 4.92 mmole), 1-hydroxylbenzotriazole (0.99 g, 7.38 mmole), diisopropylethylamine (2.54 g, 19.68 mmole), and O-benzotriazole-N,N,N,N-tetramethyl-urounium hexafluorophosphate (2.80 g, 7.38 mmole) in dichloromethane (30 ml) is stirred for 15 minutes at room temperature. A solution of pyrrolidine-2-carbaldehyde-O-benzyl-oxime (˜1.00 g, 0.49 mmole) in dichloromethane is added. The reaction solution is stirred for three hours at room temperature and then quenched with saturated NaHCO3 aqueous, extracted with dichloromethane. The organic layer is combined, dried, and concentrated under vacuum. The residue is purified by flash chromatography (silica gel; from 20% to 70% of ethyl acetate in hexane) to provide 1.81 g (83% over 2 steps) of the title compound. M+H+=444.2
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH3:9])[C:3]=1[Cl:10].[Br:11]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][Br:11])[C:3]=1[Cl:10]
Reactant: Cc1c(Cl)ccc(Br)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: Clc1ccc(Br)c(Cl)c1CBr
Yield: 99.7 %

Procedure:
By the method in Preparation 5 and using the reagents 1-bromo-2,4-dichloro-3-methyl-benzene (74.4 g, 310 mmol), N-bromosuccinimide (58.0 g, 326 mmol) and benzoyl peroxide (750 mg) affords the title compound as an amber oil (98.5 g, 99%):
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH:20]C=O)[S:18][CH:19]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.O.[OH-].[Na+]>CO>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH2:20])[S:18][CH:19]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.5 %

Procedure:
A mixture of 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (15.0 g) and conc. hydrochloric acid (9.5 g) in methanol (75 ml) was stirred at ambient temperature for 2.5 hours. Water (100 ml) was added to the reaction mixture and the solution was adjusted to pH 3.0 with 10% aqueous solution of sodium hydroxide under stirring. The precipitates were collected by filtration, washed with water and diisopropyl ether and dried to give 2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (12.7 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:11])[CH2:6][CH2:7][C:8]([O-])=[O:9]>CN(C=O)C>[Cl:3][C:8](=[O:9])[CH2:7][CH2:6][C:5]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: CCCCOC(=O)CCC(=O)[O-]
Solvent: CN(C)C=O
Product: CCCCOC(=O)CCC(=O)Cl
Reaction time: 8 h

Procedure:
Excess thionyl chloride and one drop of DMF are added to monobutyl succinate. The reaction takes place with evolution of gas. The mixture is left to stir with exclusion of moisture overnight and subsequently the excess thionyl chloride is removed by distillation under atmospheric pressure. The remaining crude product is fractionally distilled under 0.05 mbar, and the pure product is obtained at about 70° C. The characterization of the product by IR spectroscopy shows bands at 1800 cm-1 (acid chloride) and 1740 cm-1 (ester) of equal intensity.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[BH4-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3,4-difluorobenzaldehyde (200 mg, 1.41 mmol) in methanol (4 mL) was added NaBH4 (80 mg, 2.1 mmol). The reaction mixture was stirred at rt for 10 min., then diluted with water and extracted with ethyl acetate. The organic part was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude was used into next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C([Li])CCC.[I:25]I.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([N:10]2[C:11]([I:25])=[CH:12][C:8]([N:3]3[C:4]([CH3:7])=[CH:5][CH:6]=[C:2]3[CH3:1])=[N:9]2)=[CH:14][CH:15]=1
Reactant: II
Reactant: Cc1ccc(C)n1-c1ccn(-c2ccc(Cl)cc2)n1
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(I)n(-c2ccc(Cl)cc2)n1
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
Under argon atmosphere, a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-(4-chlorophenyl)-1H-pyrazole (4.98 g) in tetrahydrofuran (40 ml) was cooled to −78° C., n-butyllithium (13.7 ml, 1.6M solution in n-hexane) was added dropwise thereto, and the mixture was stirred for 30 minutes. To this reaction solution was added dropwise a solution of iodine (5.58 g) in tetrahydrofuran (10 ml), the mixture was stirred for 30 minutes. To this reaction solution were added a 20 wt % aqueous solution of sodium sulfite and a saturated aqueous solution of ammonium chloride, the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. To the resulting solid residue was added a mixed solvent of ethyl acetate/n-hexane=1/2, the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (4.19 g).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:11][O:12][C:13]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[O:14]>C(Cl)Cl>[CH3:11][O:12][C:13]([C:15]1[NH:16][CH:17]=[C:18]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH:19]=1)=[O:14]
Reactant: COC(=O)c1ccc[nH]1
Reactant: CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)C(C)C)c[nH]1
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
A mixture of isobutyryl chloride and aluminum chloride in dry DCM were stirred in an inert atmosphere at 0-5° C. for 15 minutes. To this was added a solution of 1H-pyrrole-2-carboxylic acid methyl ester in dry DCM drop wise under stirring at 0-5° C. and stirred further for 4 hours at room temperature. After completion of reaction, reaction mixture was poured into ice water and extracted with DCM, DCM layer was washed with 1N NaOH followed by water and brine. The organic layer was dried over anhydrous sodium sulfate and was evaporated to get 4-isobutyryl-1H-pyrrole-2-carboxylic acid methyl ester (B1-I)
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:31]([O:33][CH2:34][CH3:35])=[CH2:32])CCC>O1CCOCC1>[CH2:34]([O:33][C:31]([C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1)=[CH2:32])[CH3:35]
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Product: C=C(OCC)c1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
To 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (1.0 g, 2.88 mmol) was added 1,4-dioxane (15 mL) and the resulting solution degassed with nitrogen. Pd(TPP)2Cl2 (0.202 g, 0.288 mmol) and tributyl(1-ethoxyvinyl)stannane (5.2 g, 14 mmol) were added under a nitrogen stream and the reaction mixture was heated to 90° C. where it stirred for 16 h. After this time, the reaction mixture was allowed to cool to room temperature. Once at the prescribed temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by neutral alumina column chromatography (20% ethyl acetate, hexane) to yield 2-(1-ethoxyvinyl)-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (940 mg, 85% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.23 (d, 1H, J=4.4 Hz), 7.75-7.85 (m, 2H), 7.70 (dt, 1H, J=2, 7.6 Hz), 7.45-7.58 (m, 5H), 7.20-7.30 (m, 3H), 6.61 (br s, 1H), 4.61 (s, 1H), 4.60 (d, 2H, J=4 Hz), 3.94 (q, 2H, J=6.8 Hz), 1.40 (t, 3H, J=6.8 Hz). LCMS Method Y: retention time 1.952 min, [M+1]=383.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4′-fluoro-biphenyl-4-ol and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (178 mg, 76%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-])=O)(=[O:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4].Cl[Sn]Cl>Cl.CO>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH2:25])(=[O:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccnc2c(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cccc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Product: COC(=O)c1ccnc2c(NS(=O)(=O)c3ccccc3N)cccc12
Yield: 47.2 %

Procedure:
In a similar fashion using route 1 general procedure 4, 8-(2-nitro-benzenesulfonylamino)-quinoline-4-carboxylic acid methyl ester (Intermediate 260) (0.62 g, 1.6 mmol), SnCl2 (1.3 g, 6.4 mmol), 6N HCl (2 drops) and MeOH (15 ml) at 80° C. for 48 h gave the title compound (270 mg, 50%) which was used in the next step without further purification.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[I:9][CH2:10][C:11](O)=[O:12].C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O>[I:9][CH2:10][C:11]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:12]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CI
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(CI)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.7 %

Procedure:
N-Hydroxysuccinimide (1 g, 8.7 mmole), iodoacetic acid (8.7 mmole, 1.6 g), and DCC (8.7 mmole, 1.7 g) were added to 250 mL of EtOAc and the mixture was stirred at room temperature for 5 hours. The mixture was filtered and the filtrate concentrated to dryness in vacuo. The residue was crystallized from ethanol to yield 1.74 g (71%) of white crystals, mp 148-150° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(O[CH:14](OCC)[N:15]([CH3:17])[CH3:16])C>>[CH3:14][N:15](/[CH:17]=[CH:1]/[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH3:16]
Reactant: CCOC(OCC)N(C)C
Reactant: Cc1ccncc1[N+](=O)[O-]
Product: CN(C)/C=C/c1ccncc1[N+](=O)[O-]

Procedure:
Commercially available 4-methyl-3-nitropyridine is condensed with N,N-dimethylformamide diethyl acetal to provide E-4-[2-(N,N-dimethylamino)-1-ethenyl]-3-nitropyridine, which is then subjected to catalytic hydrogenation to give 6-azaindole.
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:36][CH:37]([CH3:39])[CH3:38]>CN(C=O)C.C(OCC)(=O)C>[CH3:18][C@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:16][O:15][CH:12]1[CH2:11][CH2:10][N:9]([C:7]2[O:8][C:4]3[CH:3]=[C:2]([O:1][CH2:36][CH:37]([CH3:39])[CH3:38])[CH:28]=[CH:27][C:5]=3[N:6]=2)[CH2:14][CH2:13]1
Reactant: CC(C)CI
Reactant: C[C@@H](COC1CCN(c2nc3ccc(O)cc3o2)CC1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc2nc(N3CCC(OC[C@H](C)NC(=O)OC(C)(C)C)CC3)oc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.6 %

Procedure:
To a solution of tert-butyl [(1S)-2-{[1-(6-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]oxy}-1-methylethyl]carbamate (150 mg) in DMF (5 mL) were added potassium carbonate (210 mg) and 1-iodo-2-methylpropane (190 mg), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (97 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1)=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1cc(C(=O)c2cc(Cl)ccc2N)ccn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: Cc1cc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ccn1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 123 mg of (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride.