Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[F:20])[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[F:27][C:28]([F:39])([F:38])[C:29]1([CH2:32]OS(C)(=O)=O)[CH2:31][CH2:30]1>>[CH:1]1([N:4]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:32][C:29]3([C:28]([F:39])([F:38])[F:27])[CH2:31][CH2:30]3)[CH2:23][CH2:22]2)[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[F:20])[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2cc(C(=O)N(C3CCNCC3)C3CC3)on2)c(F)c1
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Product: N#Cc1ccc(-c2cc(C(=O)N(C3CC3)C3CCN(CC4(C(F)(F)F)CC4)CC3)on2)c(F)c1

Procedure:
The title compound is prepared from 3-(4-cyano-2-fluoro-phenyl)-isoxazole-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide and methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester following a procedure analogous to that described for Example 3. LC (method 4): tR=1.35 min; Mass spectrum (ESI+): m/z=477 [M+H]+.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.OC[C:14]1[C:19]([OH:20])=[C:18](CO)[CH:17]=[C:16]([CH3:23])[CH:15]=1.O.O.[C:26](O)(=O)C(O)=O>CCOCCOC(C)=O>[C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:26]=[CH:23][C:16]1[CH:17]=[CH:18][C:19]([OH:20])=[CH:14][CH:15]=1
Reactant: Cc1cc(CO)c(O)c(CO)c1
Reactant: O=C(O)C(=O)O
Agent: Oc1cccc2ccccc12
Solvent: O
Solvent: CCOCCOC(C)=O
Product: C=Cc1ccc(O)cc1

Procedure:
A mixture comprising of 72.lg 1-naphthol, 84.1 g 2,6-bis(hydroxymethyl)-p-cresol, 5.0 g oxalic acid dihydrate and 150 ml ethyl cellosolve acetate in a 0.5-L resin kettle, equipped as in Example 1, was heated to initiate the condensation reaction substantially forming the 1-naphthol-methylene-p-cresol block segments. An exothermic reaction resulted, reaching a peak temperature of about 120° C. The reaction mixture was allowed to reflux for about 2 hours, 108.1 g m-cresol and 48.8 g of 36.9 percent formaldehyde were added, and the condensation mixture again allowed to reflux for about 2 hours. The volatiles present in the reaction mixture were removed by distillation and stripping as described in Example 1. About 201 g of resin having a Tg of about 121° C. and a Mn of 1940 Daltons was obtained.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:7]2[O:8][C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C@H:6]2[O:5][C@@H:4]2[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@H:3]12.[H-].[Na+].[S:22](Cl)(=[O:25])(=[O:24])[NH2:23]>CN(C=O)C>[CH3:12][C:9]1([CH3:13])[O:8][C@H:7]2[C@H:2]([O:1][S:22](=[O:25])(=[O:24])[NH2:23])[C@H:3]3[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@H:4]3[O:5][C@@H:6]2[CH2:11][O:10]1
Reactant: CCOC(=O)C1[C@@H]2[C@@H](O)[C@@H]3OC(C)(C)OC[C@H]3O[C@H]12
Reactant: NS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1[C@@H]2[C@@H](OS(N)(=O)=O)[C@@H]3OC(C)(C)OC[C@H]3O[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Compound 6a (0.28 g, 1.0 mmol) was added to a dry 3-neck flask containing NaH (60% dispersion in mineral oil, 0.12 g, 3.1 mmol) in DMF (10 mL) at 0° C. After 30 min at 0° C., sulfamoyl chloride (0.36 g, 3.1 mmol) was added in portions, and the reaction was stirred for an additional 1 hour at 0° C. The reaction mixture was quenched with H2O at 0° C. and diluted with ice cold H2O (20 mL) and dichloromethane (50 mL). The aqueous layer was removed, and the organic layer was washed with ice cold water (2×20 mL) and brine (1×20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Column chromatography (SiO2, a gradient of pure hexanes to a 2:3 ratio of ethyl acetate in hexanes) followed by preparative TLC (SiO2, 7:13 ratio of ethyl acetate in hexanes) on the crude mixture afforded a yellow glass (0.28 g, 0.80 mmol) 77% yield. 1H NMR (500 MHz, CDCl3): δ 4.98 (s, 2H), 4.75 (d, 1H, J=8.5 Hz), 4.15 (q, 2H, J=7.5 Hz), 3.99 (dd, 1H, J=8.0, 3.0 Hz), 3.88-3.82 (m, 2H), 3.69 (dd, 1H, J=11.0, 10.0 Hz), 3.22 (ddd, 1H, J=10.0, 10.0, 5.5 Hz), 2.18 (dd, 1H, J=5.0, 3.0 Hz), 1.96-1.94 (m, 1H), 1.50 (s, 3H), 1.40 (s, 3H) 1.27 (t, 3H, J=7.5 Hz) (FIG. 19). 13C NMR (500 MHz, CDCl3): δ 100.2, 77.9, 71.2, 63.3, 61.9, 61.3, 58.8, 31.0, 29.0, 22.6, 20.8, 19.2, 14.2 (FIG. 20). HRMS (m/z): [M+H]+ calculated for C13H22NO8S, 352.1061. found 352.1061. Anal. calculated for C13H21NO8S: C, 44.44; H, 6.02. Found C, 44.54; H, 5.80.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[NH4+].[N+:16]([CH2:19][CH3:20])([O-:18])=[O:17]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[C:19]([N+:16]([O-:18])=[O:17])[CH3:20]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CC(=Cc1ccc(Cl)cc1Cl)[N+](=O)[O-]
Temperature: 25 °C
Yield: 51.9 %

Procedure:
A mixture of 2,4-dichlorobenzaldehyde (1.45 g, 8.3 mmol), ammonium acetate (0.64 g, 8.3 mmol) and nitroethane (6 g, 80 mmol) was heated under reflux for 6 hr. The mixture was allowed to cool to room temperature and ethyl acetate was added. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. Recrystallization from ethanol gave 2,4-dichloro-1-(2-nitro-1-propenyl)benzene (yellow needle crystals, yield; 1.0 g, 52%).
Reaction SMILES: CN([P+](O[N:12]1N=[N:19][C:14]2C=CC=C[C:13]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[C:28]([C:31]1[CH:36]=[N:35][N:34]2[CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:39]=[C:33]2[C:32]=1[NH:46][C@@H:47]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:48](O)=[O:49])(=[O:30])[NH2:29].NCC#N.C(N(CC)CC)C>CN(C=O)C>[C:13]([CH2:14][NH:19][C:48](=[O:49])[C@@H:47]([NH:46][C:32]1[C:33]2[N:34]([CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:39]=2)[N:35]=[CH:36][C:31]=1[C:28]([NH2:29])=[O:30])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)#[N:12]
Reactant: NC(=O)c1cnn2cc(-c3ccccc3)cc2c1N[C@H](C(=O)O)c1ccccc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCNC(=O)[C@@H](Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
BOP reagent (17.2 mg, 0.039 mmol) was added in one portion to a solution of (S)-2-(3-carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-ylamino)-2-phenylacetic acid (Example 122, 10 mg, 0.026 mmol), 2-aminoacetonitrile (1.82 mg, 0.032 mmol) and triethylamine (0.011 ml, 0.078 mmol) in DMF (0.01 ml). The reaction was allowed to stir at rt for 1 hour before being purified by reverse-phase Prep HPLC (condition A). The fraction containing the major product was concentrated on the rotovap to remove the MeOH and the aqueous slurry of the product was neutralized by addition of ˜1 mL of saturated aq sodium bicarbonate. Sonication of the slurry followed by vacuum filtration and air drying in the funnel afforded the title compound (7 mg, 60% yield). HPLC (condition B): retention time=1.57 min. LCMS (condition B): MH+ m/z 425.2. 1H NMR (500 MHz, MeOD) δ ppm 8.33 (1H, s), 8.07 (1 H, d, J=1.66 Hz), 7.86 (1 H, s), 7.75 (4 H, dd, J=7.63, 2.08 Hz), 7.60 (2H, t, J=7.49 Hz), 7.49-7.57 (3 H, m), 7.41 (1 H, t, J=7.35 Hz), 7.31 (1 H, d, J=1.66 Hz), 6.11 (1 H, s), 4.22-4.44 (1 H, m), 3.17 (2 H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)[O:22][C@@H:13]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:40]=[N+:41]=[N-:42].[Na+]>CS(C)=O>[N:40]([CH2:28][C@H:23]1[O:22][C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C@@H:25]([OH:26])[C@@H:24]1[OH:27])=[N+:41]=[N-:42]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@H](OCc3ccccc3)[C@H](NC(=O)OCc3ccccc3)[C@@H](O)[C@@H]2O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@H]1O[C@H](OCc2ccccc2)[C@H](NC(=O)OCc2ccccc2)[C@@H](O)[C@@H]1O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A solution of 32.14 g benzyl 2-benzyloxycarbonylamino-2-desoxy-6-O-(p-tolylsulfonyl)-a-D-glucopyranoside in 75 ml of dimethyl sulfoxide was treated at room temperature with 7.5 g of sodium azide and stirred at 90° C. for 3 hours. The mixture was then poured on to ice/water. Separated crystals were filtered off under suction, washed with water and dried. There was obtained benzyl 6-azido-2-benzyloxycarbonylamino-2,6-didesoxy-a-D-glucopyranoside, [a]+119.60° (c 0.5; dioxan), MS: m/z 428 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl>[CH3:16][O:15][C:13]([CH:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:12]1[S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31])=[O:14]
Reactant: COC(=O)C1CCC(c2ccc(F)cc2)N1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl (2RS,5SR)-5-(4-fluoro-phenyl)-pyrrolidine-2-carboxylate (2.27 g, 10.2 mmol) and triethylamine (2.13 ml, 15.3 mmol) in dichloromethane (60 ml) was added at 0° C. toluene-4-sulfonyl chloride (2.32 g, 12.2 mmol). The mixture was stirred at RT for 16 h, evaporated, dissolved in water (50 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with water (40 ml), brine (40 ml), dried (MgSO4) and evaporated. The crude product was purified by crystallization from diethyl ether/hexane to give the title compound, off-white solid, m.p. 91° C. and MS: m/e=378.3 (M+H+).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:28]=[C:27]([CH2:29][N:30]4[CH2:35][CH2:34][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]4)[S:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:41]1[N:46]2[CH:47]=[CH:48][N:49]=[C:45]2[C:44]([CH3:50])=[CH:43][CH:42]=1>O1CCOCC1.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.S1C=CC=C1C([O-])=O.[Cu+]>[CH3:50][C:44]1[C:45]2[N:46]([CH:47]=[CH:48][N:49]=2)[C:41]([C:11]2[N:12]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:8]3[N:28]=[C:27]([CH2:29][N:30]4[CH2:35][CH2:34][CH:33]([C:36]([OH:39])([CH3:37])[CH3:38])[CH2:32][CH2:31]4)[S:26][C:9]=3[N:10]=2)=[CH:42][CH:43]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)sc2n1
Reactant: Cc1ccc(Br)n2ccnc12
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cc1ccc(-c2nc(N3CCOCC3)c3nc(CN4CCC(C(C)(C)O)CC4)sc3n2)n2ccnc12
Temperature: 150 °C
Yield: 87.5 %

Procedure:
A mixture of 2-[1-(7-morpholin-4-yl-5-(tributylstannanyl)thiazolo[5,4-d]pyrimidin-2-ylmethyl)piperidin-4-yl]propan-2-ol (118 mg, 0.18 mmol), 5-bromo-8-methylimidazo[1,2-a]pyridine (45 mg, 0.21 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol) and copper(I) thiophene-2-carboxylate (7 mg, 0.035 mmol) in dioxane (2 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the desired product was eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to give 244 as an off-white solid (80 mg, 89%). LCMS (Method G) RT 5.09 min; [M+H+ 508. 1H NMR (400 MHz, CHCl3-d): δ 9.22 (s, 1 H); 7.93 (d, J=7.4 Hz, 1 H); 7.75 (d, J=1.3 Hz, 1H); 7.14 (d, J=7.4 Hz, 1 H); 4.43 (m, 4 H); 3.90 (m, 4 H); 3.87 (s, 2 H); 3.10 (d, J=11.5 Hz, 2 H); 2.73 (s, 3 H); 2.23 (t, J=11.5 Hz, 2 H); 1.78 (m, 2 H); 1.55-1.41 (m, 2 H); 1.35 (m, 2 H); 1.22 (s, 6 H)
Reaction SMILES: [CH3:1][NH2:2].CO.O.[O:6]1[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7]1>>[CH3:1][NH:2][CH2:7][CH:8]([OH:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CN
Reactant: CCCCCCCCCCC1CO1
Solvent: CO
Solvent: O
Product: CCCCCCCCCCC(O)CNC
Reaction time: 24 h
Yield: 85.3 %

Procedure:
Two-thousand one-hundred and seventy grams of methylamine were introduced into 4550 ml of methanol at room temperature, whereupon there were dropped in 1288 grams of 1,2-epoxydodecane within 30 minutes at 20° C with stirring and water cooling and the mixture was allowed to stand for 24 hours with occasional stirring. After drawing off the excess methanol the residue was rectified. There were obtained 1284 grams (85.3% of theory) of N-methyl-N-(2-hydroxydodecyl) amine having a boiling point at 0.4 mm Hg of 130° C and a melting point of 67°-68° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:17]([OH:19])=O)[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O.C(N(CC)CC)C>[CH3:21][O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:25][C:17](=[O:19])[C@@H:12]([CH2:13][C:14](=[O:16])[NH2:15])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: NC(=O)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(N)=O)NC(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 72 h

Procedure:
Nα -Benzyloxycarbonyl-D-asparagine, 5.325 g., and 3.814 g. of leucine methyl ester hydrochloride are dissolved in 50 ml. of dimethylformamide. The solution is cooled to 5° C. and treated slowly with 3.0 ml. of diphenylphosphorylazide in 10 ml. of dimethylformamide and 5.9 ml. of triethylamine in 10 ml. of dimethylformamide. The reaction is stirred with ice cooling for two and a half hours and at room temperature for three days. The mixture is filtered and the filtrate evaporated to dryness under reduced pressure. The residue is crystallized from ethyl acetate; 2.5 g.; m.p. 191°-193° C.; [α]D25 -14.4° (c 1.015, DMF). A further quantity of material, 1.25 g., is obtainable from the mother liquor of the crystallization.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=2)[O:3]1.[NH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:14])=[O:13])[CH:8]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC1(C)CCc2cc(S(=O)(=O)Cl)ccc2O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To the solution of 2,2-dimethylchroman-6-sulfonyl chloride (3.165 g, 10.92 mmol) in DCM (50 mL) at −30° C. was added tert-butyl 2-aminoacetate (2.308 mL, 16.39 mmol), Hunig'sBase (3.82 mL, 21.85 mmol), and catalytic amount of DMAP. The mixture was stirred at 25° C. overnight while the reddish orange color of the reaction mixture turned bright yellow. The crude reaction mixture was diluted with EtOAc, washed with dilute aqueous hydrochloric acid solution, then aqueous NaHCO3 solution and brine. The organic layer was dried over MgSO4 and removed on a rotavapor to give a creamy powder. The crude material was purified by silica chromatography (15-30% EtOAc/Hexanes) to yield 3.6 grams of an off white powder (88%). 1H NMR (500 MHz, CDCl3) δ 7.58 (d, J=2.1 Hz, 1H), 7.55 (dd, J=8.6, 2.3 Hz, 1H), 6.81 (t, J=10.6 Hz, 1H), 4.90 (s, 1H), 3.64 (d, J=5.1 Hz, 2H), 2.81 (t, J=6.7 Hz, 2H), 1.81 (t, J=6.7 Hz, 2H), 1.35 (s, 9H), 1.34 (s, 6H). LRMS [ESI, (M−H)−] m/z calcd for C17H24NO5S 354.14, found 354.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[CH3:7].[NH2:13][C@@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][C@@H:15]1[O:25][CH2:26][CH:27]=[CH2:28].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([NH:13][C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][C@@H:15]2[O:25][CH2:26][CH:27]=[CH2:28])=[O:10])[NH:5][C:6]=1[CH3:7]
Reactant: Cc1[nH]c(C(=O)O)c(C#N)c1Cl
Reactant: C=CCO[C@H]1CN(C(=O)OCC)CC[C@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=CCO[C@H]1CN(C(=O)OCC)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 16, 562 mg, 3.07 mmol) and ethyl (3S,4R)-4-amino-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate (Intermediate 18, 700 mg, 3.07 mmol) in dichloromethane (150 mL) were added HOBt (470 mg, 3.07 mmol) and N-methyl morpholine (1.01 mL, 9.21 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (1.05 g, 5.52 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with the addition of 2 N HCl (100 mL). The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL) and brine, and dried over anhydrous sodium sulphate, filtered, and concentrated under vacuum. Purification by column chromatography (silica, 35% ethyl acetate in pet ether) afforded Ethyl (3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate 1.1 g (90%) as brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.[C:16](=O)(O)[O-].[Na+]>CO.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([O:13][CH3:16])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C)(C)CC(=O)O)c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(C)(C)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
3-(3-Methoxyphenyl)-3-methylbutanoic acid 85.D (0.22 g, 1.1 mmol) was dissolved in MeOH (11 mL) and a catalytic amount (˜5 drops) of sulfuric acid was added. The solution was heated to reflux and stirred overnight. The reaction was cooled to room temperature and saturated sodium bicarbonate was added to neutralize the reaction. The mixture was then concentrated and the residue taken up in EtOAc and washed with water (2×30 mL), 1M lithium chloride solution (1×30 mL) and brine (1×30 mL) and dried over magnesium sulfate to give the desired product methyl 3-(3-methoxyphenyl)-3-methylbutanoate 85.E (0.227 g, 97% yield). MS ESI (pos.) m/e: 240.1 (M+H2O)+.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.O=S(Cl)[Cl:12]>C(Cl)Cl>[Cl:12][CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ncccc1CO
Solvent: ClCCl
Product: Cc1ncccc1CCl
Reaction time: 4 h

Procedure:
To a stirred solution of 3-hydroxymethyl-2-methylpyridine (1.00 g, 8.13 mmol) from step 1 above in CH2Cl2 (40 mL) at ambient temperature was added SOCl2 (9.5 g, 80 mmol). The mixture was stirred for 4 h, and the solvent and excess SOCl2 were evaporated under reduced pressure. The residue was partitioned between CH2Cl2 (50 mL) and saturated aqueous NaHCO3 (100 mL). The organic layer was separated, and the aqueous layer was washed with additional CH2 Cl2 (2×40 mL). The combined organic layers were evaporated under reduced pressure to give 3-chloromethyl-2-methyl-pyridine as a solid which was used in the next step without purification (TLC: Rf = 0.85 (95:5 CH2Cl2 :MeOH); FAB MS m/z 142 (M+ +H)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:24])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: Cc1ccc(C(=O)O)cc1
Product: Cc1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc1

Procedure:
Reacting 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole with 14.0 mg (0.10 mMol) 4-methylbenzoic acid at 70° C., 12.0 mg (69%) of the title compound were recovered.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[C:27]4[C:22](=[CH:23][C:24]([C:28]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[O:29])=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:36]([O:38]C)=[O:37])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([N:18]3[C:27]4[C:22](=[CH:23][C:24]([C:28]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[O:29])=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:36]([OH:38])=[O:37])[CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(C(=O)N5CCOCC5)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(C(=O)N5CCOCC5)ccc43)nc2c1
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-[6-[(morpholin-4-yl)carbonyl]-1,2,3,4-tetrahydroquinolin-1-yl]quinoxaline-6-carboxylate (107 mg, 0.20 mmol) in methanol (30 ml) and water (2.0 ml) was added sodium hydroxide (32 mg, 0.8 mmol) with stifling overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (20 ml) and adjusted to pH 4 with hydrogen chloride (3 N). The solids were collected by filtration to afford 2-(4-fluorophenyl)-3-[6-[(morpholin-4-yl)carbonyl]-1,2,3,4-tetrahydroquinolin-1-yl]quinoxaline-6-carboxylic acid as a light yellow solid (90 mg, 86%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].Br[CH:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15].CCN(C(C)C)C(C)C>C(#N)C>[CH3:8][NH:7][C:5]([C:4]1[CH:3]=[C:2]([NH:1][CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: CNC(=O)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(Nc1cccc(C(=O)NC)c1)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
3-Amino-N-methylbenzamide (371 mg, 2.47 mmol), ethyl 2-bromo-2-phenylacetate (0.29 ml, 1.64 mmol), and DIPEA (0.43 ml, 2.47 mmol) were dissolved in acetonitrile (5 ml) and stirred under microwave irradiation into a sealed vial at 100° C. for 60 minutes (UPLC-MS: complete conversion). Acetonitrile was evaporated, and the crude residue was purified by flash chromatography (DCM/EtOAc=8/2) to obtain ethyl 2-(3-(methylcarbamoyl)phenylamino)-2-phenylacetate (475 mg, 92% yield).