Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([CH3:22])[CH3:21])[N:9]=[C:10]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13](F)[CH:12]=3)[C:3]=12.O.[NH2:24][NH2:25]>CCCCO>[NH2:16][C:15]1[C:14]2[C:13](=[CH:12][C:11]([C:10]3[C:3]4[C:4](=[N:5][CH:6]=[N:7][C:2]=4[NH2:1])[N:8]([CH:20]([CH3:22])[CH3:21])[N:9]=3)=[CH:18][CH:17]=2)[NH:25][N:24]=1
Reactant: NN
Reactant: CC(C)n1nc(-c2ccc(C#N)c(F)c2)c2c(N)ncnc21
Solvent: O
Solvent: CCCCO
Product: CC(C)n1nc(-c2ccc3c(N)n[nH]c3c2)c2c(N)ncnc21
Temperature: 110 °C
Yield: 70 %

Procedure:
4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorobenzonitrile (BA150, 20 mg, 0.07 mmol) was dissolved in n-BuOH (2 ml). Hydrazine monohydrate (0.400 ml) was added and the reaction was heated to 110° C. under an argon atomosphere and left stirring over night. Reaction mixture was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA154 (15 mg, 70% yield). ESI-MS (M+H)+ m/z calcd 309.2, found 309.4.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:26]=[N:27][CH:28]=[N:29][CH:30]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:26]=[N:27][CH:28]=[N:29][CH:30]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: Brc1cncnc1
Product: OC1(c2cncnc2)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 60 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 5-bromopyrimidine, the title compound was formed in 60% yield as a white solid, mp 298°-300° C. (dec). free base: 1H NMR (CDCl3, 250 MHz) 9.12 (s, 1H), 8.86 (s, 2H), 7.26 (m, 2H), 7.18 (m, 2H), 6.94 (m, 4H), 4.29 (s, 1H), 3.49 (s, 2H), 2.96 (m, 2H), 2.70 (dt, J=2.5, 12.0 Hz, 2H), 2.61 (d, J=1.5 Hz, 2H), 2.10 (dt, J=4.6, 13.0 Hz, 2H), 1.89 (s, 1H), 1.76 (m, 2H) MS (CI, CH4) m/z 384 (M+1,100), 412 (M+29,20), 366 (13) hydrochloride salt:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].[Br:16][CH:17]([CH2:20][Br:21])[CH2:18]O>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:18][CH:17]([Br:16])[CH2:20][Br:21])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: OCC(Br)CBr
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Product: O=C(O)c1cc(OCC(Br)CBr)c2ccccc2c1O
Temperature: 90 °C
Yield: 35 %

Procedure:
60 g (0.3 mol) of 1,4-dihydroxy-2-naphthoic acid was added to 150 ml of 2,3-dibromopropanol and, under heating at 90° C. with stirring, hydrogen chloride gas was bubbled in the mixture during a reaction period of 2 hours. The mixture was cooled to 10° to 20° C. and the crystals precipitated were collected by filteration to obtain 42.4 g (35% yield) of 1-hydroxy-4-(β,γ-dibromopropyloxy)-2-naphthoic acid.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[N-:12]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>CN(C=O)C.CCOC(C)=O>[Cl:11][C:4]1[C:5]([C:6]#[N:7])=[CH:8][CH:9]=[CH:10][C:3]=1[CH2:2][NH2:12]
Reactant: N#Cc1cccc(CBr)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cccc(CN)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-(bromomethyl)-2-chlorobenzonitrile (0.87 mmol) in 9 mL DMF was added NaN3 (1.3 mmol) and the resulting brown solution was stirred at RT for 20 min. The reaction mixture was diluted with EtOAc, washed twice with water and brine, dried over MgSO4 and concentrated in vacuo. The crude azide was redissolved in 4.3 mL THF and 0.1 mL water. Triphenylphosphine (1.04 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was acidified with 0.1N HCl solution until pH 3 and it was extracted 3 times with Et2O. The ageous phase was basified with 1M NaOH solution and extracted 3 times with DCM. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as yellowish oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=O.[CH:36]([NH2:39])([CH3:38])[CH3:37]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:39][CH:36]([CH3:38])[CH3:37])[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CSc1nccc(-c2c(-c3ccnc(F)c3)nn3ccccc23)n1
Reactant: CC(C)N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)Nc1nccc(-c2c(-c3ccnc(F)c3)nn3ccccc23)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
2-(2-Fluoro-4-pyridinyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine (0.18 g, 0.53 mmol) was dissolved in dichloromethane (10 mL) and the resulting solution cooled to 0° C. in an ice bath. To this solution was added dropwise 3-chloroperoxybenzoic acid (230 mg, 57–86%) in dichloromethane. This reaction mixture was stirred at 0° C. for 10 minutes. Additional dichloromethane was added and the reaction mixture was extracted with saturated aqueous potassium carbonate. The organic phase was dried over magnesium sulfate, filtered and concentrated to give a foam. This foam was dissolved in isopropylamine and heated to 50° C. for 2 hours. The resulting mixture was concentrated to a solid that was purified by by silica gel chromatography (1:1 ethyl acetate:hexane) give 90 mg (48%) of the title compound as a solid. 1H NMR (CDCl3): δ 8.56 (d, 1H), 8.31 (m, 2H), 8.19 (d, 1H), 7.52 (m, 1H), 7.40 (t, 1H), 7.33 (broad s, 1H), 7.02 (t, 1H), 6.45 (d, 1H), 5.20 (m, 1H), 4.20 (m, 1H), 1.31 (d, 5H); 19F NMR (CDCl3): 8–67.68; MS m/z 349 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][C:14]#[CH:15])[C:6](=[O:16])[C:5]2=[O:17].[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27](=[O:29])[CH3:28])=[CH:19]1.CNC>CO>[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27](=[O:29])[CH2:28][C:5]2([OH:17])[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=3)[N:7]([CH2:11][CH2:12][CH2:13][C:14]#[CH:15])[C:6]2=[O:16])=[CH:19]1
Reactant: CC(=O)c1c[nH]c2ccccc12
Reactant: C#CCCCN1C(=O)C(=O)c2cc(C)ccc21
Agent: CNC
Solvent: CO
Product: C#CCCCN1C(=O)C(O)(CC(=O)c2c[nH]c3ccccc23)c2cc(C)ccc21
Temperature: 100 °C

Procedure:
To a clean dry Biotage microwave vial equipped with a stir bar was added the 5-methyl-1-(pent-4-yn-1-yl)indoline-2,3-dione (0.015 grams, 0.066 mmol), 1-(1H-indol-3-yl)ethanone (0.19 grams, 0.12 mmol, purchased from Fisher scientific) and 0.2 mL of methanol. 9.0 μL of dimethyl amine (40% by weight in water) was then added and the solution was placed in a Biotage initiator and heated at 100° C. for thirty minutes. The solution was then concentrated and purified on a Teledyne ISCO using hexanes and ethyl acetate. Yield, 20%. 1H-NMR δ 9.15 (bs, 1H), 8.33 (m, 1H), 7.69 (s, 1H), 7.39 (m, 1H) 7.38 (m, 1H), 7.27 (m, 2H), 7.10 (d, 1H), 6.84 (d, 1H), 5.58 (bs, OH), 3.81 (p, 2H), 3.49 (d, 1H), 3.24 (d, 1H) 2.28 (m, 5H), 2.01 (t, 1H), 1.92 (m, 2H).
Reaction SMILES: C([Li])CCC.[C:6]1([CH2:12][C:13]2[NH:17][C:16](=[O:18])[O:15][N:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O1CCCC1.[C:24](=[O:26])=[O:25]>CCCCCC>[O:18]=[C:16]1[O:15][N:14]=[C:13]([CH:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:24]([OH:26])=[O:25])[NH:17]1
Reactant: O=c1[nH]c(Cc2ccccc2)no1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)C(c1ccccc1)c1noc(=O)[nH]1
Reaction time: 2 h

Procedure:
169.2 g. (0.328 moles + 20 percent) of a 15 percent solution of butyl lithium in hexane is cooled to -60° under a nitrogen atmosphere. At this temperature, a solution of 28.9 g. (0.164 moles) of 3-(phenylmethyl)-1,2,4-oxadiazol-5(4H)-one in 360 ml. of anhydrous tetrahydrofuran is added dropwise with stirring over a period of about 2 hours. A proportionate stream of carbon dioxide is passed through the resulting suspension for a period of 2 hours. The cold bath is removed and the solution is permitted to come to room temperature. The solution is concentrated in a rotary evaporator, the residue is treated with water, the aqueous solution is extracted with ether and the aqueous phase is acidified with 2N hydrochloric acid. This acidified aqueous phase is extracted several times with ether. The combined ether phases are dried with magnesium sulfate and the ether is evaporated. The residue is crystallized by trituration with petroleum ether. 23.9 g. of 4,5-dihydro-5-oxo-α-phenyl-1,2,4-oxadiazole-3-acetic acid are obtained, m.p. 140°-141° (dec.). The product is purified by dissolving in a small amount of water with the addition of sodium bicarbonate and again precipitating with dilute hydrochloric acid. The precipitated product melts at 142°-143° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:19]([NH2:21])=[O:20])[CH2:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.[Cl-].[NH4+].C(O)C.O>[Fe]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([NH2:21])=[O:20])[CH2:14][CH:13]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C2=CCN(CC(N)=O)CC2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(C2=CCN(CC(N)=O)CC2)ccc1N
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2-[4-(3-Methoxy-4-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetamide (240 mg, 0.82 mmol), iron (138 mg, 2.47 mmol), ammonium chloride (22.0 mg, 0.412 mmol) in ethanol (7 mL, 100 mmol) and water (3 mL, 200 mmol) was heated at 80° C. After 3 h, MS showed product with no SM. The mixture was cooled, solvent was evaporated and was diluted with aq. Na2CO3 solution and EtOAc. The mixture was filtered through a pad of celite, extracted from EtOAc, combined organic was washed with brine. After drying, the solvent was evaporated to give the product, 2-[4-(4-Amino-3-methoxy-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetamide, as a foam (195 mg, 91%). The product was taken to the next step without further purification. MS: 262 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[CH3:11][C:12]([CH3:14])=O>>[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[C:5](=[C:12]([CH3:14])[CH3:11])[C:4](=[O:9])[O:3]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)=O
Product: CC(C)=C1C(=O)OC(C)(C)OC1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 1 starting from acetone and 2,2-dimethyl-1,3-dioxane-4,6-dione.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][C:22]3[CH:35]=[CH:34][C:25]([CH:26]=[C:27]4[S:31][C:30](=[O:32])[NH:29][C:28]4=[O:33])=[CH:24][CH:23]=3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(OCC)(=O)C>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][O:21][C:22]3[CH:35]=[CH:34][C:25]([CH2:26][CH:27]4[S:31][C:30](=[O:32])[NH:29][C:28]4=[O:33])=[CH:24][CH:23]=3)=[CH:17][CH:18]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Oc2ccc(CCOc3ccc(C=C4SC(=O)NC4=O)cc3)cc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)Oc2ccc(CCOc3ccc(CC4SC(=O)NC4=O)cc3)cc2)cc1
Reaction time: 4 h
Yield: 41.4 %

Procedure:
1.2 g (2.35 mmole) 5-(4-[2-(4-(4-methoxyphenylsulfonyloxy)phenyl)ethoxy]benzylidene)thiazolidine-2,4-dione was mixed with 200 ml warm ethyl acetate, 2 ml acetic acid and 1.2 g Pd/C (5%, 50% water) and hydrogenated for 4 hours at room temperature. 1.2 g more of the catalyst was added after 2 hours. The catalyst was filtered off and the solvent was evaporated in vacuo. The crude product was purified by chromatography on silica gel using dichloromethane/diisopropyl ether (gradient) as eluent to give 0.5 g of the desired product.
Reaction SMILES: [CH:1]1([NH2+:7][CH:8]2[CH2:13]CCCC2)CCCCC1.[C:14]([NH:24][C@H:25]([C:35]([O-:37])=[O:36])[CH2:26][CH:27]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O-:30])=[O:29])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[CH:38]1([NH2+]C2CCCCC2)CCCCC1.C(Cl)Cl>C1(C)C=CC=CC=1>[CH3:38][N:7]([CH3:1])[CH:8]([O:36][C:35](=[O:37])[C@H:25]([CH2:26][CH:27]([C:31]([CH3:32])([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[NH:24][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH3:13]
Reactant: C1CCC([NH2+]C2CCCCC2)CC1
Reactant: CC(C)(C)C(C[C@H](NC(=O)OCc1ccccc1)C(=O)[O-])C(=O)[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(OC(=O)[C@H](CC(C(=O)O)C(C)(C)C)NC(=O)OCc1ccccc1)N(C)C
Temperature: 50 °C
Yield: 89.1 %

Procedure:
To 1.20 g N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-dicyclohexyl ammonium salt, 20 ml methylene chloride and 2.1 ml solution of dimethylamioethyl-chloride in the amount of 0.5 g, which stoichiometrically corresponds to two times molar volume, in toluene were added to be subjected to reflux in oil bath at 50° C. for 35 hrs. After cooling down to the room temperature, the reaction mixture was similarly treated as in Step Example 1 to obtain N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-α-dimethylaminoethyl ester in the amount of 842 mg (yield; 89.1%).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[NH:5][C:4]=1[C:10]([OH:12])=[O:11])#[N:2].[CH3:13][Si](C=[N+]=[N-])(C)C.CCOCC>C1COCC1>[CH3:13][O:11][C:10]([C:4]1[NH:5][C:6]([CH2:8][CH3:9])=[CH:7][C:3]=1[C:1]#[N:2])=[O:12]
Reactant: CCc1cc(C#N)c(C(=O)O)[nH]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1cc(C#N)c(C(=O)OC)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Cyano-5-ethyl-1H-pyrrole-2-carboxylic acid (Intermediate 31) (500 mg) was dissolved in anhydrous THF (5 ml) and cooled to 0° C. (Trimethylsilyl)diazomethane/ether (2 ml) was added. The mixture was stirred at room temperature under nitrogen gas for 1 h. The solvent was removed in vacuo and MeOH was added. The mixture was stirred for a further 15 min, the solvent was removed in vacuo and the solid was dried under vacuum to give the title compound (580 mg).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[Na].[NH2:6][CH2:7][C:8]([OH:10])=[O:9]>>[C:1]([CH2:2][CH2:3][N:6]([CH2:3][CH2:2][C:1]#[N:4])[CH2:7][C:8]([OH:10])=[O:9])#[N:4]
Reactant: C=CC#N
Reactant: NCC(=O)O
Agent: [Na]
Product: N#CCCN(CCC#N)CC(=O)O

Procedure:
Bis-cyanoethyl glycine was prepared in conventional manner by reacting two mols acrylonitrile with one mol sodium salt of glycine in essentially the same manner used in preparing the catalyst of Example 2, except that the sodium salt was neutralized at the end of the reaction.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4].I[C:30]1[N:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]2=[N:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[N:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]3=[N:32][CH:31]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4]
Reactant: COC(=O)c1sc(B2OC(C)(C)C(C)(C)O2)cc1OC(C)c1ccccc1Cl
Reactant: Ic1cnc2ccccn12
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: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2cnc3ccccn23)cc1OC(C)c1ccccc1Cl

Procedure:
3-[1-(2-Chloro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophene-2-carboxylic acid methyl ester (150 mg, 0.37 mmol, 1.0 Eq.), 3-Iodo-imidazo[1,2-a]pyridine (108 mg, 0.44 mmol, 1.2 Eq.) and Pd(PPh3)4 (42 mg, 0.04 mmol, 0.1 Eq.) were dissolved in toluene (1.6 mL) and EtOH (0.4 mL). 2M K2CO3 (0.55 mL, 1.10 mmol, 3.0 Eq) and the reaction heated under microwave conditions at 140° C. for 15 minutes. The reaction was partitioned between EtOAc (10 mL) and water (10 mL) and the aqueous phase extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (50% EtOAc/petroleum Ether) to give the sub-title compound as am off-white solid (61 mg, 0.15 mmol, 40%); 1H NMR (400 MHz, CDCl3) δ 1.77 (3H, d), 3.96 (3H, s), 5.86 (1H, q), 6.89 (1H, s), 7.28-7.43 (4H, m), 7.67 (1H, dd), 7.72-7.78 (1H, m), 7.83 (1H, s), 8.32 (2H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:12])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(C=O)c(Cl)c1

Procedure:
Combine 2,6-dichloro-4-hydroxy-benzaldehyde (120 g, 628.24 mmol) and potassium carbonate (173.65 g, 1256.5 mmol) in 900 mL dimethylformamide and treat with iodomethane (107 g, 753.9 mmol). Stir the reaction at room temperature for 3 hours. Filter off solids and pour into 6 L of water. Filter solids, wash several times with water, air dry and dissolve in ethyl acetate. Wash with water, followed by brine and then dry over sodium sulfate. Filter and concentrate under vacuum to ˜100 mL volume, at which point, solids start to crash out. Filter then concentrate down the filtrate to yield a second crop. Wash with hexane, combine all solids and vacuum dry to yield 112.3 g of off-white, solid: 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 6.90 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C@@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH2:21])=[CH:17][CH:16]=1.F[C:30]1[S:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1>N1C=CC=CC=1>[S:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[NH:21][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][NH:9][C:10]=3[N:1]=2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(OCCCc2ccc3c(n2)NCCC3)cc1
Reactant: Fc1nc2ccccc2s1
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](Cc1ccc(OCCCc2ccc3c(n2)NCCC3)cc1)Nc1nc2ccccc2s1
Temperature: 25 °C

Procedure:
A mixture constituted by 1-4 (150 mg, 0.4 mmole) and 2-fluorobenzothiazole (75 mg; 0.5 mmole) in 3 ml of pyridine is agitated at ambient temperature then heated under reflux for minutes, followed by evaporating under reduced pressure and purifying by chromatography eluting with an AcOEt/CH2Cl2 mixture 50/50 in order to obtain 90 mg of the expected 2-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:40])[CH:5]=[C:6]([Cl:39])[C:7]=1[CH2:8][C@@H:9]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[CH:25]=1)[O:10][C:11](=[O:23])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1.[H-].[Na+].I[CH3:44]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:40])[CH:5]=[C:6]([Cl:39])[C:7]=1[CH2:8][C@@H:9]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[CH:25]=1)[O:10][C:11](=[O:23])[N:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)[CH3:44]
Reactant: CI
Reactant: COc1ccc(NC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(N(C)C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,4-dimethoxyphenylcarbamoyloxy)ethyl)pyridine 1-oxide (127.5 mg, 0.21 mmol) in anhydrous THF (4 ml) and cooled at 0° C., sodium hydride (10.21 mg, 0.255 mmol) and iodomethane (0.016 ml, 0.255 mmol) were sequentially added. The cold bath was removed and the mixture was stirred at RT for 2 hours. Then the reaction was quenched with iced water and extracted with EtOAc. The combined organic layer were washed with brine, dried over Na2SO4 and evaporated. Purification of the resulting crude by flash chromatography on silica gel (DCM:MeOH 100:2) afforded the desired product as a white solid (95 mg, 0.155 mmol, 72.8% yield, [α]D=+21.41, c 0.569, DCM)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[CH:18][CH:17]=1.O.O.Cl[Sn]Cl.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[NH2:12][C:6]1[N:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[CH:20][CH:21]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2
Reactant: CC(C)(C#N)c1ccc(Nc2c([N+](=O)[O-])nnc3ccc(Br)cc23)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1ccc(Nc2c(N)nnc3ccc(Br)cc23)cc1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
Under N2, an orange solution of 2-(4-(6-bromo-3-nitrocinnolin-4-ylamino)phenyl)-2-methylpropanenitrile (2.5 g, 6.06 mmol) and SnCl2.2H2O (5.21 g, 24.26 mmol) in EtOAc (50 mL) was heated at 45° C. for 3 h. After cooling to r.t., the pH of the mixture was adjusted to 8 with saturated Na2CO3. The mixture was filtered through a Buchner funnel, and the filtrate was collected and concentrated to give 2-(4-(3-amino-6-bromocinnolin-4-ylamino)phenyl)-2-methylpropanenitrile (1.6 g, yield 69%). MS (m/z): 384 (M+H)+.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9][CH2:8][CH2:7][C:6]2=1.[CH:25](N(C(C)C)CC)(C)C.CI.Cl>C1COCC1>[ClH:1].[Br:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([N:16]([CH3:25])[CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9][CH2:8][CH2:7][C:6]2=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Brc1ccc2[nH]c3c(c2c1)CCCC3NCCc1ccccc1
Agent: Cl
Solvent: CI
Solvent: C1CCOC1
Product: CN(CCc1ccccc1)C1CCCc2c1[nH]c1ccc(Br)cc21
Reaction time: 12 h

Procedure:
6-Bromo-N-methyl-N-(2-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt was prepared from 6-bromo-N-(2-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt (0.05 g, 0.12 mmol), diisopropylethyl amine (0.04 mL, 0.25 mmol) and methyl iodide (0.008 mL, 0.12 mmol) in THF (2.0 mL). The reagents were added to a round bottom flask and allowed to stir for 12 hrs. at room temperature under inert atmosphere. The solvent was evaporated, ethyl acetate was added (10 mL), the organics were washed with water (2.0 mL) and sat. NaCl (2.0 mL), dried over Na2SO4, filtered and evaporated to leave an oily residue. Purification by flash chromatography with gradient 10-50% ethyl acetate/hexanes eluent afforded a clear oil that was converted to the HCl salt to give a white solid (0.01 g, 20%). 1H-NMR (CDCl3): δ 8.30 (s, 1H), 7.53 (d, 2H), 7.38-7.10 (m, 5H), 6.89 (d, 1H), 4.09 (m, 1H), 3.04-2.95 (m, 1H), 2.90-2.80 (m, 2H), 2.70-2.55 (m, 3H), 2.48 (s, 3H), 2.11-1.99 (m, 2H), 1.70-1.60 (m, 2H).