Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.Cl[C:33]([C@@H:35]([O:37]C(=O)C)[CH3:36])=[O:34]>>[OH:37][C@@H:35]([CH3:36])[C:33]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)=[O:34]
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)[C@H](C)O)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A181) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH2:14][CH2:13][CH2:12][CH:11]=3)=[C:7]([C:15](O)=[O:16])[C:6]=2[CH:18]=1.C1C=CC2N(O)N=[N:31][C:29]=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.CN>CN(C=O)C>[Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH2:14][CH2:13][CH2:12][CH:11]=3)=[C:7]([C:15]([NH:31][CH3:29])=[O:16])[C:6]=2[CH:18]=1
Reactant: CN(c1cc2oc(C3=CCCC3)c(C(=O)O)c2cc1Br)S(C)(=O)=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(C2=CCCC2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A solution of 5-bromo-2-(cyclopent-1-en-1-yl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylic acid (3.5 g, 7.70 mmol), HOBT (1.6 g, 11.55 mmol) and EDCI (2.2 g, 11.55 mmol) in dry DMF (40 mL) was stirred at 25° C. After 2 hours, Et3N (2.4 g, 23.11 mmol) and MeNH2 (1.6 g, 23.11 mmol) were added to the mixture and then stirred overnight. The solvent was removed by vacuum, the mixture was washed with H2O (50 mL) and extracted with EtOAc (50 mL*3), and dried over Na2SO4. After concentration, the residue was purified by column chromatography (DCM) to give the product of 5-bromo-2-(cyclopent-1-en-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (2 g, yield: 56%). 1H-NMR (CDCl3, 400 MHz) δ 8.00 (s, 1H), 7.59 (s, 1H), 6.70 (t, J=3.2 Hz, 1H), 5.95 (s, 1H), 3.31 (s, 3H), 3.30 (s, 3H), 3.06 (s, 3H), 2.76˜2.81 (m, 2H), 2.58˜2.62 (m, 2H), 2.07 (t, J=7.6 Hz, 2H). MS (M+H)+: 427/429.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.I[CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH:31]([CH3:33])[CH3:32])[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CC(C)I
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C(C)C)c2nc(C)nn12
Temperature: 100 °C
Reaction time: 5 h
Yield: 28 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.8 g), 2-iodopropane (0.4 mL), potassium carbonate (0.55 g) and N,N-dimethylacetamide (10 mL) was stirred at 100° C. for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.24 g, 28%).
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[CH2:8][N:7]([C@H:9]3[CH2:14][S:13](=[O:15])[CH:12]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[C:17]=4[F:24])[C@@H:11]([NH:25]C(=O)OC(C)(C)C)[CH2:10]3)[CH2:6][C:5]=12.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[N:1]1[NH:2][CH:3]=[C:4]2[CH2:8][N:7]([C@H:9]3[CH2:14][S:13](=[O:15])[CH:12]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[C:17]=4[F:24])[C@@H:11]([NH2:25])[CH2:10]3)[CH2:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3c[nH]nc3C2)CS(=O)C1c1cc(F)cc(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1C[C@@H](N2Cc3c[nH]nc3C2)CS(=O)C1c1cc(F)cc(F)c1F
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
tert-Butyl N-[(3S,5R)-5-(4,6-dihydro-2H-pyrrolo[3,4-c]pyrazol-5-yl)-1-oxo-2-(2,3,5-trifluorophenyl)thian-3-yl]carbamate was dissolved in a mixture of TFA (0.02 mL) and methylene chloride (0.2 mL). After stirring at RT for 105 min, the solvents were evaporated and the residue was freeze-dried from a mixture of benzene and ethanol to give the title compound as a white solid.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[C:8]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].N1C=CC=CC=1>C(Cl)Cl>[Cl:7][CH:5]([O:4][C:2]([N:18]1[CH2:17][CH2:16][N:15]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:20][CH2:19]1)=[O:3])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (Oakwood, 1.46 g, 1.1 mL, 10.2 mmol) was reacted with 1-Boc-piperazine (Alfa Aesar, 1.5756 g, 8.37 mmol) and pyridine (870 mg, 0.89 mL, 11.0 mmol) in methylene chloride (10 mL) from −78° C. for 1 h and then at room temperature overnight to give piperazine-1,4-dicarboxylic acid tert-butyl ester 1-chloro-ethyl ester. A portion of piperazine-1,4-dicarboxylic acid tert-butyl ester 1-chloro-ethyl ester (682 mg, 1.67 mmol) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (201.4 mg, 0.327 mmol) in the presence of cesium carbonate (743.4 mg, 2.28 mmol) in dimethylformamide (7 mL) overnight to give 1-tert-butyl 4-(1-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)ethyl)piperazine-1,4-dicarboxylate as an off-white lyophilized solid (259.9 mg, 91% yield). MS (ES+) m/z calcd. for C34H36Cl2F2N4O4: [(M+H)+]: 872, found: 872
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][Br:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(ccn2C(=O)c2ccccc2)c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccccc1)n1ccc2cc(CBr)ccc21
Yield: 76.2 %

Procedure:
A suspension of the product of Step A (5.5 g 23.4 mmol) in 10 mL of CCl4 was heated to reflux. N-bromosuccinimide (4.6 g, 25.7 mmol) and several crystals (approximately 100 mg) of azoisobutyronitrile (AIBN) were added. The resultant solution was stirred at reflux for 4 hours. The solution was cooled, diluted with 1.5 L of CH2Cl2 and washed with 400 mL of H2O and 400 mL of brine. The organic phase was dried over MgSO4, filtered and concentrated to a brown oil. The resultant oil was flash chromatographed eluting with 10:1 hexane/ethyl acetate to afford the titled compound (5.6g, 80%) as a yellow powder.
Reaction SMILES: CN(/[CH:4]=[C:5]1\[CH2:6][C:7]([C:14]2[C:22]3[C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[O:19][C:18]=3[C:17]([O:27][CH3:28])=[CH:16][CH:15]=2)([C:12]#[N:13])[CH2:8][CH2:9][C:10]\1=O)C.[CH2:29]([N:33]=[C:34]([NH2:36])[NH2:35])[C:30]([OH:32])=[O:31].[OH-].[Na+]>CO>[C:12]([C:7]1([C:14]2[C:22]3[C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[O:19][C:18]=3[C:17]([O:27][CH3:28])=[CH:16][CH:15]=2)[CH2:8][CH2:9][C:10]2[N:36]=[C:34]([NH:33][CH2:29][C:30]([OH:32])=[O:31])[N:35]=[CH:4][C:5]=2[CH2:6]1)#[N:13]
Reactant: NC(N)=NCC(=O)O
Reactant: COc1ccc(C2(C#N)CCC(=O)/C(=C/N(C)C)C2)c2c1oc1ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C2(C#N)CCc3nc(NCC(=O)O)ncc3C2)c2c1oc1ccccc12
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A mixture of the compound obtained in example 6 (100 mg, 0.267 mmol), guanidine acetic acid and sodium hydroxide (54 mg, 1 mol) in 10 ml of methanol was stirred at 60-70° C. for 8 hrs. Methanol was evaporated under vacuum and the reaction mass was diluted with 10 ml of water. The aqueous layer was washed with ether, acidified with 0.1 N HCl to pH 2 and extracted with ethyl acetate. The organic layer was washed with water followed by brine, and concentrated under vacuum. The crude product was crystallized form hexane to give 60 mg (52.45% yields) of a yellow colored solid.
Reaction SMILES: C([O:5][C:6]([C:8]1[S:9][C:10]([C:24]2[S:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[CH:25]=2)=[CH:11][C:12]=1[NH:13][S:14]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[S:28]1[C:24]([C:10]2[S:9][C:8]([C:6]([OH:7])=[O:5])=[C:12]([NH:13][S:14]([C:17]3[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH:11]=2)=[CH:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]1=2
Reactant: Cc1ccccc1S(=O)(=O)Nc1cc(-c2cc3ccccc3s2)sc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1S(=O)(=O)Nc1cc(-c2cc3ccccc3s2)sc1C(=O)O
Yield: 99 %

Procedure:
5-Benzo[b]thiophen-2-yl-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester was hydrolyzed to the acid using TFA as described for example 2 providing 5-Benzo[b]thiophen-2-yl-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid (24 mg, 99% yield). 1H NMR (DMSO-D6, 400 MHz) 10.19 (s, 1H), 8.0 (d, J=7.7 Hz, 1H), 7.79-7.74 (m, 1H), 7.86 (s, 1H), 7.84-7.81 (m, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.53-7.36 (m, 4H), 7.32 (s, 1H), 2.58 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[N:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CO)cn1
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(Br)cc2)cn1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
4-Bromophenol (1.37 g, 7.90 mmol) was added to a solution of (6-methoxypyridin-3-yl)methanol (1.0 g, 7.16 mmol) in THF (100 mL). Triphenylphosphine (1.88 g, 7.19 mmol) was added followed by triethylamine (0.727 g, 7.19 mmol). The resulting solution was cooled to 0° C. and DIAD (1.45 g, 7.19 mmol) was added by drop-wise addition and was maintained at 0° C. for 30 minutes, then warmed to room temperature and stirred for two days. The reaction was quenched by addition of water and extracted with ether (2×100 mL). The organic layer was washed with water (2×100 mL) then brine (1×100 mL), dried (MgSO4), filtered and concentrated to give a yellow oil. The crude material was purified by flash column chromatography on a Biotage SNAP cartridge Kp-sil 100g column (hexanes/ethyl acetate 9:1) to give a white solid. Mass/Yield—1.78 g/84% TLC (hexanes/ethyl acetate=8:2) Rf=0.12, UV active. LCMS MS ES+294.4/296.4. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.93 (s, 3 H) 4.93 (s, 2 H) 6.72-6.78 (m, 1 H) 6.81-6.86 (m, 2 H) 7.33-7.42 (m, 2 H) 7.58-7.65 (m, 1 H) 8.18 (s, 1 H).
Reaction SMILES: [C:1]([C:4]1[C:27](=[O:28])[O:26][C:7]2=[N:8][C:9]([N:12]3[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]3)=[CH:10][CH:11]=[C:6]2[CH:5]=1)(=[O:3])[CH3:2].[Br:29]Br>C(Cl)(Cl)Cl>[Br:29][CH2:2][C:1]([C:4]1[C:27](=[O:28])[O:26][C:7]2=[N:8][C:9]([N:12]3[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:14][CH2:13]3)=[CH:10][CH:11]=[C:6]2[CH:5]=1)=[O:3]
Reactant: CC(=O)c1cc2ccc(N3CCCN(C(=O)OC(C)(C)C)CC3)nc2oc1=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc3cc(C(=O)CBr)c(=O)oc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.5 %

Procedure:
tert-Butyl 4-(3-acetyl-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl)-1,4-diazepane-1-carboxylate (350 mg, 0.903 mmol) in 10 mL of chloroform was treated with bromine (1M in CHCl3, 0.9 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The precipitated solid was filtered and the mother liquor was concentrated. The residue was purified on silica gel to yield tert-butyl 4-(3-(2-bromoacetyl)-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl)-1,4-diazepane-1-carboxylate (132.2 mg, 32%). MS m/z 489 [M+Na]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8]([CH3:11])C=O.[F:12]/[CH:13]=[C:14](\[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)/CO.O>C1(C)C=CC=CC=1>[NH2:8][CH2:11]/[C:14](=[CH:13]/[F:12])/[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1
Reactant: OC/C(=C/F)CCc1ccc(F)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: NC/C(=C/F)CCc1ccc(F)cc1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Combine oxalyl chloride (25.2 g, 0.198 mol) and toluene (200 mL). Cool to -5° C. Add N,N-dimethylformamide (15.0 g, 0.21 mol) as a solution in toluene (20 mL). Warm to 25° C. After 30 minutes, add a solution of (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol (24.7 g, 30% by weight in toluene, 0.124 mol). After 18 hours, add water (500 mL) and stir for 30 minutes. Separate the organic layer, dry over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][O:31][CH2:30]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][O:31][CH2:30]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: BrCCC1CCCOC1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 213 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(2-bromoethyl)tetrahydro-2H-pyran.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](OC)(=[O:13])[C:11]#[CH:12]>CO>[CH2:1]([NH:9][C:10](=[O:13])[C:11]#[CH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: C#CC(=O)OC
Solvent: CO
Product: C#CC(=O)NCCCCCCCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred, cooled (-30° C.) solution of 18.42 g (0.143 mol) of n-octylamine in 25 ml of aqueous methanol was added 10 g (0.119 mol) of methyl propiolate dropwise. After the addition the reaction mixture was allowed to warm to room temperature and stir for 12 h. The reaction mixture was poured into ice-cold 10% aqueous hydrochloric acid and extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium bicarbonate, brine, and dried over magnesium sulfate. Filtration and removal of solvents gave a crude mixture which was purified by column chromatography (Merck 60® silica gel, 25% ethyl acetate/hexane eluant) to give N-octylpropiolamide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.ClC1C=C(NS(C)(=O)=O)C=CC=1C(O)=O>>[Cl:1][C:2]1[CH:11]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([NH:22][C:21]1[CH:23]=[CH:24][C:18]([Cl:17])=[C:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH:20]=1)=[O:6]
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)cc1Cl
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Agent: CS(=O)(=O)Nc1ccc(C(=O)O)c(Cl)c1
Product: CS(=O)(=O)Nc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
4.2 g of methyl 2-chloro-4-(methylsulfonamido)benzoate was hydrolyzed via Procedure M. 1 g of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 1.35 g of 2-chloro-4-(methylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonamido)benzamide. MS (Q1) 436.1 (M)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][S:12]([CH2:15][CH2:16][C:17]([NH:20]C(=O)OCC1C=CC=CC=1)([CH3:19])[CH3:18])(=[O:14])=[O:13])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][S:12]([CH2:15][CH2:16][C:17]([CH3:19])([NH2:20])[CH3:18])(=[O:14])=[O:13])[CH3:2]
Reactant: CCOCCOCCOCCS(=O)(=O)CCC(C)(C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOCCOCCOCCS(=O)(=O)CCC(C)(C)N
Reaction time: 1.5 h

Procedure:
A solution of benzyl 4-(2-(2-(2-ethoxyethoxy)ethoxy)ethylsulfonyl)-2-methylbutan-2-ylcarbamate (119.8 mg, 0.2691 mmol) in MeOH (3 ml) was put under N2 and 10% Pd/C (12.6 mg) was added. The vessel was pressurized with H2 (1.3 atm) and the suspension stirred vigorously for 1.5 h. The suspension was filtered through a PTFE (0.45 um) filter and concentrated in vacuo, and the residue used without any further purification. LRMS (ESI/APCI): 312 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]#[C:8][C:9]([OH:11])=O.ClC(OCC(C)C)=O.CN1CCOCC1.[Br:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([NH2:45])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([NH:45][C:9](=[O:11])[C:8]#[C:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: COCCOCC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COCCOCC#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 0.72 g of 4-(2-Methoxy-ethoxy)-but-2-ynoic acid and 0.57 mL of isobutyl chloroformate in 15 mL of tetrahydrofuran at 0° C. was added 0.5 mL of N-methylmorpholine followed by 1.2 g of solid N-(3-bromophenyl)-4,6-quinazolindiamine. Stirring was continued for 1 hr at 0° C. and 30 min at room temperature. The mixture was stored over night at −10° C. The mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic solution was dried over magnesium sulfate. The solvent was removed and the residue was chromatographed on silica gel eluting with ethyl acetate, choroform, and methanol solvent mixtures to give 0.55 g of 4-(2-Methoxy-ethoxy)-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide as a yellow solid: mass spectrum (m/e): M+H 454.9, 456.9.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>C(Cl)Cl>[CH:3]1([CH2:2][N:26]2[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]2)[CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCC1CCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CC2CCC2)CC1
Temperature: 35 °C
Reaction time: 2 h
Yield: 8.8 %

Procedure:
Bromomethylcyclobutane (0.200 g, 1.34 mmol, 1 eq) was suspended in DCM (2 mL). DIPEA (0.59 mL, 3.35 mmol, 2.5 eq) was added dropwise, followed by N-Boc-piperazine (0.550 g, 2.95 mmol, 2.2. eq), and the reaction mixture was stirred at 35° C. for 2 h. The crude product was purified by column chromatography on a Biotage SP1 system (DCM/EtOAc; v/v 1:1) to give the title compound (0.030 g, 8.8%); 1H-NMR (500 MHz, CDCl3): δ 1.46 (s, 9H, C(CH3)3), 1.64-1.74 (m, 2H), 1.76-1.96 (m, 2H), 2.02-2.12 (m, 2H), 2.37 (t, J=5.0 Hz, 4H, piperazine N(CH2)2), 2.43 (d, J=7.0 Hz, 2H, NCH2), 2.55 (m, 1H, cyclobutyl CH), 3.43 (t, J=5.0 Hz, 4H, piperazine N(CH2)2); GC-MS (Cl, m/z): Rt=3.77 min—255 [(M+H)+, 100%].
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[NH:19][C:20]1[CH:21]=[N:22][C:23](F)=[CH:24][CH:25]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:29][O-:30].[Na+]>CO>[C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:10]1[N:19]([C:20]2[CH:21]=[N:22][C:23]([O:30][CH3:29])=[CH:24][CH:25]=2)[C:13]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[O-]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccc(F)nc1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-n2c([C@H](C)NC(=O)OC(C)(C)C)nc3ccc(F)cc32)cn1
Temperature: 120 °C
Yield: 27 %

Procedure:
A suspension of {(S)-1-[4-fluoro-2-(6-fluoropyridin-3-ylamino)phenylcarbamoyl]ethyl}carbamic acid tert-butyl ester (196 mg, 0.50 mmol) in 0.5M NaOMe in MeOH (2.0 mL, 1.0 mmol) was heated at 120° C. using microwave irradiation for 15 min. The crude reaction mixture was diluted with MeOH and loaded onto an Isolute®SCX-2 cartridge then washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) to afford the title compound as a pink oil (52 mg, 27%). LCMS (Method C): RT 3.42 min [M+H]+ 387.2.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=2[O:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.[Li+].[OH-]>CO.C(Cl)Cl.O>[Cl:23][C:21]1[CH:20]=[C:19]([CH3:24])[C:18]([O:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)=[C:17]([CH:22]=1)[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:30]
Reactant: CCOC(=O)C1(NC(=O)c2cc(Cl)cc(C)c2OC2CCC2)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Cl)cc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1OC1CCC1
Reaction time: 20 h
Yield: 75 %

Procedure:
A 100 mL flask containing 2-(5-chloro-2-cyclobutoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (0.3 g, 0.7 mmol) is charged with 1,4-dioxane (4 mL) and MeOH (4 mL). A stirring bar is added and stirring is initiated. After dissolution, water (2 mL) is added followed by the LiOH (74 mg, 1.77 mmol). After 20 h, tlc analysis (silica, 10% MeOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜6 mL). The contents of the flask are poured into a separatory funnel containing EtOAc (30 mL). The layers are separated. The aqueous layer is extracted with EtOAc (20 mL). The combined organic extracts are washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated. Pumping to constant weight gives 0.21 g of a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:17])[O:6][C:7]2[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]([OH:16])[C:8]=2[C:9]=1[CH3:10].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[OH:16][C:11]1[C:8]2[C:9]([CH3:10])=[C:4]([CH2:3][CH2:2][N:29]3[CH2:28][CH2:27][N:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][CH3:18])[CH2:31][CH2:30]3)[C:5](=[O:17])[O:6][C:7]=2[CH:14]=[C:13]([OH:15])[CH:12]=1
Reactant: Cc1c(CCCl)c(=O)oc2cc(O)cc(O)c12
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(CCc2c(C)c3c(O)cc(O)cc3oc2=O)CC1
Yield: 23 %

Procedure:
Process B; starting materials: 3-(2-chloroethyl)-5,7-dihydroxy-4-methyl-2H-1-benzopyran-2-one (Example 36) and 1-(2-methoxyphenyl)piperazine; yield 23% of crude crystalline product.