Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[C:5](=[N:6][C:7](=[O:16])[C:8](=[O:15])[N:9]=2)[CH:4]=1.[N+]([O-])(O)=O.[C:21]([OH:24])(=[O:23])[CH3:22]>>[C:21]([O:24][C:4]1[C:5]2[C:10]([CH:11]=[C:12]([O:13][CH3:14])[C:3]=1[O:2][CH3:1])=[N:9][C:8](=[O:15])[C:7](=[O:16])[N:6]=2)(=[O:23])[CH3:22]
Reactant: COc1cc2c(cc1OC)=NC(=O)C(=O)N=2
Reactant: CC(=O)O
Solvent: O=[N+]([O-])O
Product: COc1cc2c(c(OC(C)=O)c1OC)=NC(=O)C(=O)N=2
Temperature: 25 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
6,7-Dimethoxy-2,3-quinoxalinedione (45) (222 mg, 1.0 mmol) was dissolved in glacial acetic acid (10 mL) at 100° C. (oil bath). The oil bath was removed and fuming nitric acid (53 μL, 1.2 mmol; Baker) was added dropwise to the solution. The reaction mixture was then stirred at room temperature for 24 h. The mixture was filtered and washed with water to give a white solid, giving 150 mg (54%) of the title compound; mp 321-322° C.; 1H NMR (DMSO-d6, 300 MHz) δ 2.300 (s, 3H), 3.619 (s, 3H), 3.746 (s, 3H), 6.661 (s, 1H), 11.700 (s, 1H), 11.832 (s, 1H). EIMS m/e 280 (M+, 30), 238 (100). Anal. Calcd for C12H12N2O6 : C, 51.43; H, 4.32; N, 10.00. Found: C, 51.29; H, 4.04; N, 9.90. (HPLC purity>99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]([C:17]([O:19][CH3:20])=[O:18])[N:4]([CH3:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]O)[CH:9]=2)=[CH:6][N:7]=1.N1C=CC=CC=1.S(Cl)([Cl:29])=O>C1COCC1>[NH2:1][C:2]1[CH:3]([C:17]([O:19][CH3:20])=[O:18])[N:4]([CH3:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][Cl:29])[CH:9]=2)=[CH:6][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C1C(N)=NC=C(c2cccc(CO)c2)N1C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)C1C(N)=NC=C(c2cccc(CCl)c2)N1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
Methyl 3-amino-6-(3-hydroxymethylphenyl)-N-methylpyrazine-2-carboxylate (75 mg, 0.3 mmol) was taken into THF (2 mL) followed by addition of pyridine (120 uL, 1.5 mmol) and the solution was cooled to 0° C. Thionyl chloride (42 uL, 0.6 mmol) was added to the mixture by syringe followed by warming to room temperature. The mixture was then stirred for two hours and partitioned with ethyl acetate and 1 M aqueous hydrochloric acid. The organic layer was washed with water (1x) then brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated followed by silica gel flash chromatography using ethyl acetate:hexanes (1:1) as eluent. The pure fractions were combined and concentrated then dried in vacuo to give methyl 3-amino-6-(3-chloromethylphenyl)-N-methylpyrazine-2-carboxylate (30 mg, 37% yield) as a yellow solid: MS (EI) for C13H13N3O2Cl: 278, 280 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].OC(C(F)(F)F)=O.[C:34]1([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][C:41]2=[O:46])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN1C(=O)CCC1>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:43]4[CH2:44][CH2:45][N:40]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:41](=[O:46])[CH2:42]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: O=C1CNCCN1c1ccccc1
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(c4ccccc4)C(=O)C3)nn12
Temperature: 180 °C
Reaction time: 5 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 50 mg, 0.145 mmol), KF (84 mg, 1.450 mmol), 1-phenylpiperazin-2-one TFA salt (133 mg, 0.435 mmol) were suspended in NMP (483 μL). The RM was stirred at 180° C. for 5 h. The mixture was purified by preparative UPLC with acetonitrile and water (+0.1% TFA) The fractions were collected and acetonitrile was removed. It was taken up with MeOH and passed through an SPE cartridge of PL-HCO3 MP from polymer lab. The solvent was removed and a brown solid was obtained (tR 1.0 min (conditions 4), MH+=485).
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)[N:27]1[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]1)[CH3:7]
Reactant: CCOC(=O)C(Br)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CN1CCNCC1
Product: CCOC(=O)C(c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)N1CCN(C)CC1

Procedure:
The compound was synthesized as in Example 17 from Intermediate 11 (2.3 g, 6.2 mmol) and N-methylpiperazine (1.60 g, 16 mmol). This gave 1.1 g (46%) of pure product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]#[CH:9].[C:11]1([CH3:18])[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[CH3:18][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[O:17][CH2:9][C:8]#[CH:7]
Reactant: Cc1ccccc1O
Reactant: C#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1ccccc1C
Temperature: 25 °C

Procedure:
245 g of potassium carbonate and 75 ml of propargyl chloride are added to a solutions of 96 g of o-cresol in 1500 ml of acetonitrile. The mixture is now heated for 14 hours at 65°, cooled to room temperature, and filtered with suction, and the filtrate is evaporated. The residue is taken up in 150 ml of ethyl acetate, the mixture is filtered with suction and the filtrate is evaporated. This gives 134 g of the total compound as a pale brown oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18].Br[CH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25]>>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25])[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Reactant: N#Cc1cccc(CBr)c1
Agent: Cl
Product: Cc1c(-c2cccnc2)n(Cc2cccc(C#N)c2)c2ccc(Cl)cc12

Procedure:
5-Chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 2) and 3-bromomethyl-benzonitrile are processed according to the method described in Example 11 to give 3-(5-chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile. 1H NMR (400 MHz, MeOD) δ ppm 2.25 (s, 3H), 5.36 (s, 2H), 7.03 (d, J=7.8 Hz, 1H), 7.14 (s, 1H), 7.18 (dd, J=8.6, 2.0 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.36 (t, J=7.7 Hz, 1H), 7.49-7.56 (m, 2H), 7.62 (d, J=2.0 Hz, 1H), 7.81 (dt, J=7.8, 1.9 Hz, 1H), 8.47 (d, J=2.3 Hz, 1H), 8.58 (dd, J=5.1, 1.8 Hz, 1H). HRMS (ESI) m/z 358.1102 [(M+H)+ Calcd for C22H17ClN3, 358.1111].
Reaction SMILES: N1C=CC=C([C:7]([O:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=O)C=1.[Li].[CH3:19][OH:20]>Cl>[N:12]1[CH:13]=[CH:14][CH:15]=[C:16]([C:19]([C:16]2[C:11]([C:10]([O:9][CH3:7])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:20])[CH:11]=1
Reactant: CO
Reactant: O=C(OC(=O)c1ccccn1)c1cccnc1
Agent: Cl
Agent: [Li]
Product: COC(=O)c1ncccc1C(=O)c1cccnc1
Temperature: 85 °C

Procedure:
A mixture of 2.5 g of crude lithium 3-picolinoylpicolinate 16 was dissolved in 40 mL of 1.25 N HCl in methanol and heated in a sealed tube at 85° C. for 2 h. After cooling, the excess solvent and reagent were removed under reduced pressure and the crude material was partitioned between 20 mL of ethyl acetate and 20 mL of saturated aqueous sodium carbonate. The aqueous layer was further extracted with 2×20 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by normal-phase flash chromatography eluting with 50-100% ethyl acetate in hexane over 29 minutes. Like fractions containing product were pooled and concentrated under reduced pressure to give methyl 3-picolinoylpicolinate 7 (240 mg, 0.99 mmol), LCMS: (M+H)+, 243.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]([OH:11])[CH2:9][OH:10])[CH3:2].C[Si](Cl)(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].Cl>C(OCC)(=O)C.C(N(CC)CC)C>[CH2:1]([O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[O:6][CH:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:8]([O:11][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:9][OH:10])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1ccccc1OC(c1ccccc1)C(O)CO
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOc1ccccc1OC(c1ccccc1)C(CO)OS(C)(=O)=O
Temperature: -17 °C
Reaction time: 0.25 h
Yield: 102.9 %

Procedure:
3-(2-Ethoxyphenoxy)-2-hydroxy-3-phenylpropanol from Example 2 (0.288 g, 1 mmole) and triethylamine ((0.15 mL, 1.1 mmole) were dissolved in ethyl acetate (5 mL) and cooled to −17° C. Trimethylsilyl chloride (0.13 mL, 1.0 mmole) dissolved in ethyl acetate (2 mL) was added over 10 minutes keeping the temperature below −15° C. a white precipitate formed during this addition. The mixture was stirred below −15° C. for 15 minutes. Triethylamine (0.15 mL, 1.1 mmole) was added, followed by methanesulfonyl chloride (0.085 mL, 1.1 mmole) dissolved ethyl acetate (2 mL) keeping the temperature below −15° C. The mixture was stirred below −15° C. for 15 minutes. Hydrochloric acid (2N, 2 mL) was added and the mixture was allowed to warm to 20-25° C. and stirred for 30 minutes. The phases were separated and the organic phase was washed with saturated aqueous sodium chloride solution (5 mL) and dried over sodium sulfate. The solution was evaporated to yield 0.377 g of an oil. The oil was chromatographed on silica (230-400 mesh) eluting with 1:1 hexane-ethyl acetate. The product-containing fractions were concentrated to yield 0.33 g (91%) of the title compound as an oil that solidified on standing; mp 83-86° C.; 1H NMR (400.13 MHZ, CDCl3) d 1.66 (t, J=8.2 Hz, 3H), 2.85 (s, 3H), 4.14-4.35 (m, 4H), 5,12 (m, 1H), 5.52 (d, J=6.1 Hz), 6.8-7.15 (m, 4H), 7.5-7.7 (m, 5H); 13C NMR (100.62 MHZ, CDCl3) d 14.73, 37.80, 62.19, 64.27, 81.40, 84.04, 112.88, 117.19, 120.67, 122.86, 127.40, 128.77, 128.86, 137.02, 146.40, 149.30; MS (ei ) m/e 366.
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH2:14][NH2:15])=[CH:8][CH:7]=1)[CH2:3][CH3:4].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].[OH-].[Na+].O>CCOCC>[CH3:1][CH:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12][CH2:13][CH2:14][NH:15][C:17](=[O:18])[O:19][CH2:20][CH3:21])=[CH:10][CH:11]=1)[CH2:3][CH3:4]
Reactant: CCOC(=O)Cl
Reactant: CCC(C)Oc1ccc(SCCN)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)NCCSc1ccc(OC(C)CC)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2-[4-(1-methylpropoxy)phenylthio]-ethylamine (2.21 g, 8.65 mmol) in 25 ml of ether, at 0° and under N2, is added ethyl chloroformate (0.52 g, 4.76 mmol) by syringe, followed by addition of 10% aqueous sodium hydroxide (3.5 ml) and additional ethyl chloroformate (0.51 g, 4.76 mmol). After 15 min., the reaction is worked up by addition of water and extraction with ether. The combined organic phases are washed with 1N sulfuric acid, with water and with brine, dried and filtered, the filtrate is concentrated in vacuo and the product is purified by prep. TLC to give ethyl N-{2-[4-(1-methylpropoxy)-phenylthio]ethyl}carbamate (compound 76, Table A).
Reaction SMILES: [2H]C(Cl)(Cl)Cl.[CH3:6][N:7]([CH3:24])[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([O:16]CC1C=CC=CC=1)=[O:15]>>[CH3:6][N:7]([CH3:24])[C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=[O:15]
Reactant: CN(C)C1CCCCC1C(=O)OCc1ccccc1
Agent: [2H]C(Cl)(Cl)Cl
Product: CN(C)[C@H]1CCCC[C@H]1C(=O)O

Procedure:
A mixture of the amino acid prepared in Part C (31.2 g., 0.15 mole), diphenyl phosphoryl azide (41.3 g.; 0.15 mole), and triethylamine (30.4 g., 0.30 mole) in 750 ml. benzene was refluxed with stirring for 1 hour. Benzyl alcohol (48.7 g., 0.45 mole) was added and the mixture refluxed overnight. The mixture was extracted with 10% HCl. The extract was washed with ether, made basic with 40% KOH, and extracted with ether. The organic layer was washed with water and saturated NaCl solution, dried, and evaporated. The residual oil was distilled to give 8.5 g. (20% yield) mixture of carbamate and benzyl ester, b.p. 130-50°/0.01 mm. The nmr (CDC13) was consistent with a mixture of benzyl N-(2-dimethylaminocyclohexyl) carbamate and benzyl 2-dimethylaminocyclohexanecarboxylate.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([Cl:22])[CH:13]=1)=[CH:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[K+]>C(O)C.O>[Cl:22][C:14]1[CH:13]=[C:12](/[C:5](=[CH:6]\[CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)/[C:4]([OH:23])=[O:3])[CH:17]=[CH:16][C:15]=1[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: CCOC(=O)C(=CC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of the isomeric mixture of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-acrylic acid ethyl ester [500 mg, 1.40 mmol, (E):(Z)=2:1] in ethanol (16 mL) was treated with a solution of potassium hydroxide (393.6 mg, 7.00 mmol) in water (3.7 mL). The yellow solution was stirred for 3 h at 25° C. and then concentrated in vacuo to remove the ethanol. The remaining aqueous layer was acidified to pH=2 with a 1N aqueous hydrochloric acid solution and then extracted with methylene chloride (3×15 mL). The combined organic layers were then dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate plus 1% acetic acid) afforded (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-acrylic acid (458 mg, 99%, 95% is the E isomer) as a white foam: FAB-HRMS m/e calcd for C15H17ClO4S (M+H)+329.0614, found 329.0628.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[NH:16][N:15]=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:41]=[CH:40][C:39]([CH:42]([CH:44]([C:50](=O)[CH2:51][CH2:52][CH3:53])[C:45](OCC)=[O:46])[CH3:43])=[CH:38][CH:37]=1)#[N:29].C(OCC)(=O)C>CCN(C1C=CC=CC=1)CC.O>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([N:11]3[C:45](=[O:46])[C:44]([CH:42]([C:39]4[CH:40]=[CH:41][C:36]([C:31]5[C:30]([C:28]#[N:29])=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:37][CH:38]=4)[CH3:43])=[C:50]([CH2:51][CH2:52][CH3:53])[N:16]4[N:15]=[CH:14][CH:13]=[C:12]34)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: c1cc(NC2CCC3(CC2)OCCO3)[nH]n1
Reactant: CCCC(=O)C(C(=O)OCC)C(C)c1ccc(-c2ccccc2C#N)cc1
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Yield: 139.1 %

Procedure:
A solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine (0.59 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.080 mL) and ethyl 2-[1-(2′-cyanobiphenyl-4-yl)ethyl]-3-oxohexanoate (0.5 g) in diethylaniline (3 mL) was stirred at 180° C. for 2 hr. The mixture was allowed to cool, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.0 g, 74%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>O.Cl.C(Cl)(Cl)Cl>[NH:5]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1)[NH2:1]
Reactant: O=N[O-]
Reactant: COc1ccc(N)cn1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(NN)cn1
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
Sodium nitrite (3.795 g) in water (20 mL) was added dropwise to 5-amino-2-methoxypyridine (6.207 g) in concentrated hydrochloric acid (50 mL) for 80 minutes with ice cooling, followed by stirring at a constant temperature for 30 minutes. Tin(II) chloride dihydrate (39.5 g) in concentrated hydrochloric acid (30 mL) was added dropwise to the reaction mixture at an internal temperature of about 10° C. for 60 minutes, followed by stirring at room temperature for 12.5 hours. Under cooling with ice, sodium hydroxide (54 g) in water (200 mL) and chloroform were added to the reaction mixture. After insoluble substances in the resultant mixture were removed by filtration, the mixture was partitioned. The aqueous layer was extracted with chloroform twice. The organic layers were combined, and dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, to thereby give the title compound as crystals (4.23 g, 60%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:2]1.[Br:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:27])=[C:22]([CH:26]=1)[C:23](Cl)=[O:24].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:27])=[C:22]([CH:26]=1)[C:23]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][N:4]([C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])[C:5]=2[CH:10]=1)=[O:24]
Reactant: O=C(N1CCOc2ccccc21)C(F)(F)F
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)N(C(=O)C(F)(F)F)CCO2)c1cc(Br)ccc1Cl
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a stirred solution of 1-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-2,2,2-trifluoro-ethanone (6.5 g, 28.1 mmol) in dichloromethane (45 mL) was added 5-bromo-2-chlorobenzoyl chloride (8.54 g, 33.7 mmol) in dichloromethane (35 mL) and AlCl3 (5.61 g, 42.2 mmol) at 0° C. After 2 h, the reaction mixture was brought to room temperature and stirred overnight. The reaction was quenched by pouring over crushed ice and extracted with dichloromethane (2×50 mL). The organic layer was washed with aq. NaHCO3 (30 mL), H2O (20 mL), and the solvent evaporated to get the crude product which was purified by silica gel column chromatography to give 1-[6-(5-bromo-2-chloro-benzoyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone (10.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:18](Cl)=[O:19].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18]([C:10]2[O:9][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:11]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cc2ccccc2o1
Reactant: Nc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To 1.72 g of 4-bromoaniline was added to 1.89 g of benzofuran-2-carboxylic acid chloride in 35 mL of dichloromethane cooled in ice bath, followed by the addition of 4.9 mL of triethylamine. The reaction was stirred at room temperature overnight and then diluted with dichloromethane. The dichloromethane layer was washed with water, 1N HCl, water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide 2.61 g of N-(4-bromophenyl)-1-benzofuran-2-carboxamide as a yellow solid. Yield 72%. m.p. 178-180° C.; MS: 314.1(M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[C:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1>CO.C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1
Reactant: COC(=O)c1ccccc1C=C1CCN(C)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
A mixture of 2-(1-methyl-piperidin-4-ylidenemethyl)-benzoic acid methyl ester (from Intermediate B12 step 1) (130 mg; 0.53 mmol; 1 eq.) and 10% Pd/C (˜50% H2O) (34 mg) in MeOH (1 mL) and THF (1 mL) was stirred at room temperature for 3 hours under a H2 atmosphere (10 bars). The catalyst was filtered off and the solution concentrated in vacuo. Purification by column chromatography (heptane/EA) afforded the title compound (97 mg, 74%) as a white solid. UPLC/MS: (MS+) 248.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3(O)[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([I:11])[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.C(N(S(F)(F)[F:38])CC)C>ClCCl.O1CCOCC1>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([F:38])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([I:11])[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(F)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cold (0° C.) solution of 1-(5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 8A) (330 mg, 0.563 mmol) in dichloromethane (6 mL) and dioxane (6 mL) was added diethylaminosulfur trifluoride (0.149 mL, 1.127 mmol) in a single portion via syringe. The reaction was stirred at 0° C. for 2 hours and was then quenched by the addition of saturated sodium bicarbonate solution and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×). The combined organics were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of hexane to 25% ethyl acetate in hexane, to give the title compound. 1H NMR (300 MHz, DMSO-d6) 8.51 (s, 1H), 8.24 (d, J=2.8 Hz, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 7.24 (s, 1H), 2.80-2.63 (m, 4H), 2.37 (s, 3H), 2.09-1.96 (m, 1H), 1.94-1.85 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.CN(C)C=O.[H-].[Na+].[CH:21]([Si:24](Cl)([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])([CH3:23])[CH3:22]>O>[CH3:1][N:2]([CH3:13])[CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:21]([CH3:23])[CH3:22])[CH:5]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CN(C)Cc1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(CN(C)C)c2cccnc21
Temperature: 20 °C
Reaction time: 12 h
Yield: 58.9 %

Procedure:
Into a round bottom flask 7-Azagramine 2 (5.38 g, 30.7 mmol), N,N-dimethylformamide (25.0 mL), and sodium hydride (1.35 g, 33.8 mol) were combined. Into the reaction was added triisopropylsilyl chloride (6.8 mL, 0.032 mol). The reaction was stirred at 20° C. for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with biotage to give compound 4 (6.0 g, yield=58.8%) as a colorless oil.