Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])S(C(F)(F)F)(=O)=O.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]3[CH:28]=[C:29](O)[CH:30]=[CH:31][C:25]=3[CH:24]=2)=[CH:19][CH:18]=1>N1C=CC=CC=1>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]3[CH:28]=[C:29]([O:1][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])[CH:30]=[CH:31][C:25]=3[CH:24]=2)=[CH:19][CH:18]=1
Reactant: Oc1ccc2cc(-c3ccc(Br)cc3)sc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc2cc(-c3ccc(Br)cc3)sc2c1)C(F)(F)F

Procedure:
Tf2O was added slowly to a mixture of 2-(4-bromo-phenyl)-benzo[b]thiophen-6-ol (200 mg, 0.66 mol) in pyridine (3 mL) at 0° C. with stirring. The mixture was stirred at ambient temperature for 16 hours before quenched with NaHCO3 solution. The mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was used for next step reaction without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9])C=CC=CC=1.[N+:27]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O)([O-:29])=[O:28]>C1C=CC=CC=1>[CH3:9][C:8](=[CH:33][C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)C(C)=Cc1cccc([N+](=O)[O-])c1

Procedure:
To a stirred slurry of 79.8 g. of triphenyl(1-[ethoxycarbonyl]ethylidene)phosphorane in 300 ml. of benzene was added 30.2 g. of 3-nitrobenzaldehyde and the resulting mixture was heated under reflux overnight. The reaction mixture was cooled and the solvent was removed by evaporation in vacuo. The residue was extracted with 300 ml. of isopropyl ether. The isopropyl ether solution was filtered, and the filtrate was evaporated in vacuo. The residue was distilled under reduced pressure, giving 37.6 g. of the title product, b.p. 147°-162° C./0.25 mm Hg. The NMR spectrum (in CDCl3) showed absorptions at 1.4 (t), 2.1 (d), 4.3 (q), 7.4 (m) and 8.1 (m) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:31])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]Br.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[Br:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:31])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCCCOc1ccc(C(=O)Oc2ccc(-c3ccc(O)cc3)cc2)cc1
Reactant: BrCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(-c3ccc(OCCCCCCCCCCCBr)cc3)cc2)cc1
Yield: 97.7 %

Procedure:
A mixture of 3.5 g (8.4 mmol) of 4-Octyloxy-benzoic acid (4′-hydroxy-biphenyl-4-yl) ester, 7.88 g (25 mmol) of 1,11-Dibromoundecane, 3.45 g (25 mmol) of K2CO3 and 50 mL of dry butanone is refluxed for 24 h, then allowed to return to room temperature. The reaction mixture is filtered off and the butanone is distilled off under reduced pressure. The crude product purified by column chromatography on silica gel using CH2Cl2 as eluent gives a pure product as a white solid (5.35 g, 85% yield).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][S:10][C:11]1[CH:12]=[C:13]([C:25]2[NH:26][CH:27]=[CH:28][CH:29]=2)[C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]=2[C:21]=1[C:20]([F:23])=[CH:19][CH:18]=3)(C)(C)C.C1C=C(Cl)C=C(C(OO)=[O:39])C=1.C(OCC)(=O)C>C1COCC1>[NH2:7][CH2:8][CH2:9][S:10]([C:11]1[CH:12]=[C:13]([C:25]2[NH:26][CH:27]=[CH:28][CH:29]=2)[C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]=2[C:21]=1[C:20]([F:23])=[CH:19][CH:18]=3)=[O:39]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCSc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NCCS(=O)c1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 25 °C

Procedure:
A solution of [2-[6-fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-ethyl]-carbamic acid tert-butyl ester (from Example 39 above) (150 mg, 0.35 mmol) in THF (approximately 15 mL) was treated with mCPBA (Acros, 97 mg, 0.42 mmol, 75%) at 0° C. The reaction mixture was allowed to stir and warm up to room temperature overnight. The mixture was poured into ethyl acetate and washed successively with aqueous saturated Na2S2O3 and aqueous saturated K2CO3. The organic layer was dried over Na2SO4, filtered, concentrated and the residue was purified by HPLC (silica gel, 40% ethyl acetate in hexanes). The resulting intermediate was precipitated out of THF with excess of pentane. This material was then dissolved at 0° C. in 50% TFA in CH2Cl2 solution (10 mL) that contained H2O (0.5 mL) and stirred for 2 hours. Upon completion, the reaction mixture was diluted with ethyl acetate and extracted with aqueous ammonium hydroxide. The organic layer was dried over Na2SO4, filtered and concentrated to an orange solid. This solid was dissolved in THF and precipitated with excess of pentane to give 5-(2-amino-ethanesulfinyl)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as an orange solid. (Yield 75 mg, 62%).
Reaction SMILES: [C:1]([CH2:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=O)#[N:2].[CH:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(O)C.[CH3:25][NH:26][NH2:27]>C(OCC)(=O)C>[CH3:25][N:26]1[C:1]([NH2:2])=[CH:3][C:4]([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]2)=[N:27]1.[CH:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: CNN
Reactant: N#CCC(=O)C1CCCCN1
Agent: O=COCc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1nc(C2CCCCN2)cc1N
Yield: 66.2 %

Procedure:
Under nitrogen atmosphere, to a 250 mL three-neck reaction flask were added the compound of Example 11A (16.0 g, 55.9 mmol), ethanol (80 mL) and methylhydrazine (12 mL, 224 mmol). The mixture was refluxed for 5 hr. The reaction was stopped. Ethanol was removed by rotary-evaporation to obtain a crude product. The crude product was subject to column chromatography (eluant: petroleum ether:ethyl acetate=1:1) to give 11.7 g of the title compound. Yield: 66.6%. MS (ESI): m/z 315 (M+H)+
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([Br:25])[C:23]=1O)[C:19]#[N:20]>O1CCOCC1>[Br:25][C:22]1[C:23]2[O:11][C:9]([C:8]3[CH:7]=[CH:6][C:5]([C:4]([O:3][CH3:2])=[O:14])=[CH:13][CH:12]=3)=[N:15][C:16]=2[CH:17]=[C:18]([C:19]#[N:20])[CH:21]=1
Reactant: N#Cc1cc(N)c(O)c(Br)c1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2nc3cc(C#N)cc(Br)c3o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a 3-l round-bottom flask fitted with a stir bar and a Claisen adapter fitted with a thermocouple and a condenser blanketed with nitrogen was added terephthalic acid monomethyl ester chloride (37.3 g) and a solution of 3-amino-5-bromo-4-hydroxybenzonitrile (40 g, Step B) in dioxane (675 ml). The mixture was heated to reflux and stirred at this temperature overnight. The mixture was then cooled to room temperature and the dioxane was removed in vacuo. The flask was fitted with a Dean-Stark trap and p-toluenesulfonic acid monohydrate (35.8 g) and toluene (2.5 l) were added. The mixture was heated to reflux and stirred at this temperature overnight. The mixture was then allowed to cool, transferred to a new 5-l flask, and concentrated to a brown solid. The crude product was triturated with methanol to provide 55.5 g (83%) of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.50 (s, 1H), 8.34 (d, J=8.0 Hz, 2H), 8.29 (s, 1H), 8.19 (d, J=8.0 Hz, 2H), 3.91 (s, 3H).
Reaction SMILES: C([NH:8][C@@H:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][F:11])C1C=CC=CC=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.[ClH:28].C(O)C>CO.[Pd]>[ClH:28].[F:11][CH2:10][C@@H:9]([NH2:8])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[C@@H](CF)NCc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Solvent: CO
Product: CC(C)(C)[C@H](N)CF
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)—N-benzyl-1-fluoro-3,3-dimethylbutan-2-amine (4.12 g, 19.68 mmol) in methanol (50 mL) was added 10% palladium on carbon (2.095 g, 1.968 mmol). The reaction mixture was shaken under H2 atmosphere (60 Psi) for 24 h, a 1.25 M solution of HCl in ethanol (31.5 mL, 39.4 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solid was filtered through Celite, washed with methanol. The filtrate was concentrated to give the title compound (3.1 g). 1H NMR (400 MHz, DMSO-d6) δ 0.96 (s, 9H), 3.11-3.20 (m, 1H), 4.55-4.82 (m, 2H), 8.26 (s, 3H).
Reaction SMILES: [CH:1]([Si:4]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:5][CH2:6][C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[CH:15]=1)([CH3:3])[CH3:2].[I:22]N1C(=O)CCC1=O.O>C(#N)C>[I:22][C:15]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[CH2:6][O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:16]([CH3:18])[CH3:17])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)[Si](OCc1cn2ccccc2n1)(C(C)C)C(C)C
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: O
Product: CC(C)[Si](OCc1nc2ccccn2c1I)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
1.85 g (6.08 mmol) of 2-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine were solubilised in 25 ml of acetonitrile with magnetic stirring, to this solution were added 1.409 g (6.08 mmol) of N-iodosuccinimide. The mixture was stirred at r.t. for 16 h before being treated with 100 ml of water. The aqueous phase was extracted with 3×50 ml of dichloromethane. The combined organic phases were washed with 100 ml of a saturated NaCl aqueous solution, dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. 2.29 g (yield=83%) of 3-iodo-2-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine were obtained as a pale yellow solid. LC-MS: m/z=431 (MH+); UV purity at 254 nm=95%.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[F:34])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CN(C=O)C>[F:34][C:25]1[CH:26]=[C:27]([C:30]([F:32])([F:33])[F:31])[CH:28]=[CH:29][C:24]=1[CH:11]([C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[CH2:10][CH2:9][C:1]#[N:2]
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(C(F)(F)F)cc3F)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(C(F)(F)F)cc3F)c[nH]c12
Temperature: 80 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
726 mg (11.1 mmol) of potassium cyanide were added to 2.65 g (5.57 mmol) of the compound from Example 63A in 128 ml of DMF. The mixture was stirred at 80° C. for 2 h and then concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 1.46 g of the title compound were obtained with a purity of 85% (55% of theory).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]2=O)=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12].C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1>[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][C@H:17]2[NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12]
Reactant: NC1CC1
Reactant: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC2CC2)nc1Cl
Temperature: 50 °C
Reaction time: 15 h
Yield: 15 %

Procedure:
Cyclopropylamine (249 μL, 3.59 mmol) was added to a solution of tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (190 mg, 0.512 mmol) in tetrahydrofuran (6 mL), and the mixture was heated under reflux at 50° C. for four hours. The reaction solution was concentrated under reduced pressure, and then tetrahydrofuran (3 mL) and methanol (3 mL) were added. Cyclopropylamine (71.0 μL, 0.102 mmol), sodium cyanoborohydride (97.0 mg, 1.54 mmol) and acetic acid (293 μL, 5.12 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine, and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography and preparative TLC (eluent: chloroform:methanol=10:1 v/v) to obtain 34 mg of the cis isomer of the title compound (16%) as a pale yellow oily substance and 32 mg of the trans isomer of the title compound (15%) as a pale yellow oily substance.
Reaction SMILES: C1(S([N:10]2[C:22]3[C:21]([N:23]4[C:35]5[C:34]([C:36]([O:38][CH3:39])=[O:37])=[CH:33][CH:32]=[CH:31][C:30]=5[C:29]5[C:24]4=[CH:25][CH:26]=[CH:27][CH:28]=5)=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)(=O)=O)C=CC=CC=1.[OH-].[K+].Cl>CS(C)=O.O>[C:21]1([N:23]2[C:35]3[C:34]([C:36]([O:38][CH3:39])=[O:37])=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22]2[NH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1cccc2c3ccccc3n(-c3cccc4c5ccccc5n(S(=O)(=O)c5ccccc5)c34)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cccc2c3ccccc3n(-c3cccc4c3[nH]c3ccccc34)c12
Temperature: 25 °C

Procedure:
65 g (123 mmol) of methyl 9-benzenesulfonyl-9H-[1,9′]bicarbazolyl-1′-carboxylate and 48 g (856 mmol) of potassium hydroxide in 65 ml of dimethyl sulfoxide and 21 ml of water are heated at 60° C. for 1 h. The mixture is subsequently cooled to room temperature, neutralised using 1 M HCl solution and extracted with dichloromethane. The solvent is evaporated in vacuo, and the residue is purified by chromatography (heptane/ethyl acetate 10:1). Yield: 45 g (116 mmol), 95% of theory.
Reaction SMILES: [C:1]([O:11][CH3:12])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=O.[NH2:13][C@H:14](CO)[CH:15]([CH3:17])[CH3:16]>ClC1C=CC=CC=1>[CH:15]([C@H:14]1[CH2:12][O:11][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[O:8][CH2:9][C@H:14]([CH:15]([CH3:17])[CH3:16])[N:13]=2)=[N:13]1)([CH3:17])[CH3:16]
Reactant: CC(C)[C@H](N)CO
Reactant: COC(=O)CCCCC(=O)OC
Solvent: Clc1ccccc1
Product: CC(C)[C@H]1COC(CCCCC2=N[C@@H](C(C)C)CO2)=N1
Yield: 64.8 %

Procedure:
Under an argon atmosphere, a mixture of dimethyl adipate (3 mmol), (L)-valinol (7.2 mmol), Zn4(OCOCF3)6O (0.3 mmol) and chlorobenzene (5 mL) was refluxed for 6 hours, then concentrated, and purified by silica gel column chromatography to give 1,4-bis((S)-4-isopropyl-1,3-oxazolin-2-yl) butane in 64.8% yield.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:18][C:19]1[CH:28]=[CH:27][C:26]2[NH:25][C:24](=[O:29])[C:23]3[NH:30][CH:31]=[CH:32][C:22]=3[C:21]=2[CH:20]=1.[CH2:33]([C:35]([O-:37])=[O:36])[CH3:34]>CN(C)C=O>[C:8]1([S:14]([NH:18][C:19]2[CH:28]=[CH:27][C:26]3[NH:25][C:24](=[O:29])[C:23]4[NH:30][CH:31]=[CH:32][C:22]=4[C:21]=3[CH:20]=2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:33]([C:35]([O-:37])=[O:36])[CH3:34]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccc(NS(=O)(=O)c3ccccc3)cc2c2cc[nH]c12
Temperature: 40 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
62 μL (0.44 mmol) of triethylamine and then 31 μL (0.24 mmol) of benzenesulfonyl chloride are added to 60 mg (0.22 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 64) suspended in anhydrous dimethylformamide (1 mL). The solution is stirred for 1 h at 40° C. The solvent is evaporated and the raw product obtained is purified by recrystallization from methanol to give 51 mg (57%) of 8-benzenesulfonylamino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11](=O)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][CH2:23][CH2:24][OH:25].CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:1]([O:8][CH2:9][C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:11]([NH:22][CH2:23][CH2:24][OH:25])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: CC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(NCCO)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A solution of (3S)-4-benzyloxy-3-tert-butoxycarbonylamino-2-butanone (4.3 g) in dry MeOH (20 ml) was added to a solution of 2-aminoethanol (2.0 g) and AcOH (1.8 g) in dry MeOH (20 ml). NaBH3CN (1.4 g) was added and the mixture was stirred at ambient temperature overnight. The mixture was concentrated in vacuo and the residue was partitioned between AcOEt and aqueous NaHCO3 solution. The organic layer was washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution. The organic layer was mixed with 1N HCl (50 ml) and the mixture was stirred vigorously for 1 hour. The organic layer was separated, washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4 and concentrated in vacuo to give 4.1 g of (2R, 3RS)-O-benzyl-2-tert-butoxycarbonylamino-3-(2-hydroxyethylamino)butanol as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([S:14][CH2:15][CH3:16])[N:11]=[C:10]([NH2:17])[CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:19][CH:20](OC)OC>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([S:14][CH2:15][CH3:16])[N:11]3[CH:19]=[CH:20][N:17]=[C:10]3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(CBr)OC
Reactant: CCSc1nc(N)cc(-c2ccc(Br)cc2)n1
Solvent: O
Solvent: C1CCOC1
Product: CCSc1nc(-c2ccc(Br)cc2)cc2nccn12
Reaction time: 24 h
Yield: 77.3 %

Procedure:
To a slurry of 6-(4-bromophenyl)-2-(ethylthio)pyrimidin-4-amine (35.00 g, 112.8 mmol) in 20 mL of THF and 200 mL of water was added 2-bromo-1,1-dimethoxyethane (38.14 g, 225.7 mmol) at ambient temperature. The reaction flask was fitted with a condenser and the mixture was allowed to proceed with stirring at reflux overnight. After 24 hours, the reaction mixture was cooled and poured into 400 mL of water. The solid was collected by vacuum filtration. The wet solid was suspended in 500 mL of aqueous saturated sodium bicarbonate and gas evolution was observed. The mixture was stirred at ambient temperature for 10 minutes before it was extracted with DCM (8×500 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was then dried under high vacuum overnight to afford 7-(4-bromophenyl)-5-(ethylthio)imidazo[1,2-c]pyrimidine (31 g, 87.18 mmol, 77.27% yield). MS (apci) m/z=334.0 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:26])[C:14]([CH3:25])([S:16]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH3:15])[O:9][N:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].N12CCCN=C1CCCC[CH2:28]2.CI>>[CH3:28][O:4][C:3](=[O:5])[C:2]([CH3:1])([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:26])[C:14]([CH3:25])([S:16]([CH:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)(=[O:18])=[O:17])[CH3:15])[O:9][N:8]=1)[CH3:6]
Reactant: CC(C)(C(=O)O)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Product: COC(=O)C(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 78.7 %

Procedure:
2-Methyl-2-{5-[2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionylamino]-isoxazol-3-yl}-propionic acid (208 mg, 0.54 mmol) is suspended in acetoitrile (5 mL). 1,8-Diazabicyclo[5,4,0]undec-7-ene (0.096 mL, 0.64 mmol) is added and followed by the addition of methyl iodide (0.073 mL, 1.18 mmol). The reaction mixture is stirred at room temperature for 3.5 h. After this time, the reaction mixture is quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate twice. The combined organics are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (silica, eluent: DCM, MeOH) to provide 171 mg of the title compound. Yield: 79%; m/z 403 [M+H].
Reaction SMILES: CS([Cl:5])(=O)=O.[CH3:6][C:7]1([CH3:23])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:17][CH3:18])[CH:14]=2)[N:9]([CH2:19][CH2:20]O)[C:8]1=[O:22].C(N(CC)CC)C>ClCCl>[Cl:5][CH2:20][CH2:19][N:9]1[C:10]2[C:15](=[CH:14][C:13]([S:17][CH3:18])=[CH:12][CH:11]=2)[CH2:16][C:7]([CH3:23])([CH3:6])[C:8]1=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CSc1ccc2c(c1)CC(C)(C)C(=O)N2CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ccc2c(c1)CC(C)(C)C(=O)N2CCCl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Methanesulfonyl chloride (1.05 ml, 1.56 g, 0.014 mol) was added to a solution of 3,4-dihydro-3,3-dimethyl-1-(2-hydroxyethyl)-6-methylthio-2(1H)-quinolinone (2.88 g, 0.011 mol) and triethylamine (2.27 ml, 1.64 g, 0.016 mol) in dichloromethane (50 ml) at 0° C. under nitrogen and the resultant mixture was stirred for 20 mins. Then the mixture was allowed to warm to room temperature and sirred for 20 hr. The reaction mixture was then washed with water (2×20 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was then dissolved in carbon tetrachloride (30 ml), filtered and the solvent was evaporated in vacuo to afford 1-(2-chloroethyl)-3,3-dimethyl-6-methylthio-2(1H)-quinolinone as an oil which solidified on standing.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:28][CH3:29])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[CH:26]=O)=[O:19])[CH3:13].N1CCCCC1>C(O)C>[CH2:28]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[CH:26]=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[NH:7][C:6]1=[O:11])=[O:19])[CH3:29]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=C1C(=O)Nc2ccc(Br)cc21
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-oxindole (106 mg, 0.5 mmol), 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (126 mg, 1 equiv.) and piperidine (0.2 mL) in ethanol (2 mL) was heated in a sealed tube at 80° C. for 1 hr and then cooled. The precipitate was collected by vacuum filtration, washed with ethanol and ethyl acetate and dried to give the title compound as an orange solid.