Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1.C(N(CC)CC)C.[NH2:29][C:30]1[C:38]([CH3:39])=[CH:37][C:36]([Cl:40])=[CH:35][C:31]=1[C:32](O)=[O:33]>C(#N)C>[Cl:40][C:36]1[CH:37]=[C:38]([CH3:39])[C:30]2[N:29]=[C:12]([C:10]3[N:9]([C:15]4[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=4)[N:8]=[C:7]([Cl:6])[CH:11]=3)[O:14][C:32](=[O:33])[C:31]=2[CH:35]=1
Reactant: O=C(O)c1cc(Cl)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
To a solution of methanesulfonyl chloride (6.96 g, 61.06 mmol) in acetonitrile (150 mL) was added dropwise a mixture of the carboxylic acid product from Step D (15.0 g, 58.16 mmol) and triethylamine (5.88 g, 58.16 mmol) in acetonitrile (150 mL) at −5° C. The reaction mixture was then stirred for 30 minutes at 0° C. Then, 2-amino-3-methyl-5-chlorobenzoic acid from Example 6, Step A (10.79 g, 58.16 mmol) was added, and stirring was continued for an additional 10 minutes. A solution of triethylamine (11.77 g, 116.5 mmol) in acetonitrile was then added dropwise while keeping the temperature below 10° C. The reaction mixture was stirred 60 minutes at 0° C., and then methanesulfonyl chloride (6.96 g, 61.06 mmol) was added. The reaction mixture was then warmed to room temperature and stirred for an additional 2 hours. The reaction mixture was then concentrated, and the crude product was chromatographed on silica gel using methylene chloride as eluent to afford the title product as a yellow solid (9.1 g).
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.C[O:32][C:33]1[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[C:39]([O:46]C)=[C:38]2[C:34]=1[CH2:35][CH:36]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:37]2>O>[CH3:45][O:44][C:40]1[C:39](=[O:46])[C:38]2[CH2:37][CH:36]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:35][C:34]=2[C:33](=[O:32])[C:41]=1[O:42][CH3:43]
Reactant: CCOC(=O)CCCCCCCC1Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCCCCCCC1CC2=C(C1)C(=O)C(OC)=C(OC)C2=O
Reaction time: 0.25 h
Yield: 16.2 %

Procedure:
A water (1.0 ml) solution of CAN (336 mg, 0.613 mmols) was dropwise added to an acetonitrile (2.0 ml) solution of ethyl 8-(4,5,6,7-tetramethoxyindan-2-yl)octanoate (100 mg, 0.245 mmols) with cooling with ice and stirring was continued for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) followed by recrystallization from hexane to obtain the entitled compound (15 mg) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[N:7]([CH:11]=[CH:12][N:13]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[I:14]N1C(=O)CCC1=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:6]2[N:7]([C:11]([I:14])=[CH:12][N:13]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cccn2ccnc12
Solvent: CC#N
Product: COC(=O)c1cccn2c(I)cnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of imidazo[1,2-a]pyridine-8-carboxylic acid methyl ester (3.24 g, 18.3 mmol) and N-iodosuccinimide (NIS) (4.11 g, 18.3 mmol) in acetonitrile (50 mL) is stirred at room temperature. After 2 hours, the reaction mixture is quenched with saturated aqueous Na2S2O3 and extracted with EtOAc (3×100 mL). The combined organic layers are washed with water, brine, dried over Na2SO4 and concentrated. The crude material is purified by silica gel chromatography eluting with 80% EtOAc in hexanes to afford 3-iodo-imidazo[1,2-a]pyridine-8-carboxylic acid methyl ester. Mp: 99-110° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([CH2:12][N:13]([CH3:18])[C:14](=[O:17])[CH:15]=[CH2:16])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].CN(CC1SC2C=CC=CC=2C=1C)C(=O)C=C.Br[C:37]1[CH:38]=[C:39]2[C:44](=[N:45][CH:46]=1)[NH:43][C:42](=[O:47])[CH2:41][CH2:40]2.BrC1C=NC2NC(=O)C(C)(C)NCC=2C=1>>[CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([CH2:12][N:13]([CH3:18])[C:14](=[O:17])/[CH:15]=[CH:16]/[C:37]3[CH:46]=[N:45][C:44]4[NH:43][C:42](=[O:47])[CH2:41][CH2:40][C:39]=4[CH:38]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)[CH3:2]
Reactant: C=CC(=O)N(C)Cc1cccc2c1ccn2CC
Reactant: O=C1CCc2cc(Br)cnc2N1
Agent: C=CC(=O)N(C)Cc1sc2ccccc2c1C
Agent: CC1(C)NCc2cc(Br)cnc2NC1=O
Product: CCn1ccc2c(CN(C)C(=O)/C=C/c3cnc4c(c3)CCC(=O)N4)cccc21
Yield: 46 %

Procedure:
The title compound was prepared according to the procedure of Example 2, except substituting (N-((1-ethyl-1H-indol-4-yl)methyl)-N-methylacrylamide) for N-methyl-N-(3-methyl-benzo[b]thiophen-2-ylmethyl)acrylamide and 6-bromo-3,4-dihydro-1,8-naphthyridin-2(1H)-one for 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one. The title compound (329 mg, 46%) was obtained as an off-white solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.62-10.58 (m, 1H), 8.38-7.98 (m, 2H), 7.57-7.53 (m, 1H), 7.42-7.08 (m, 4H), 6.92-6.78 (m, 1H), 6.51 (s, 1H), 5.05-4.88 (m, 2H), 4.22-4.19 (m, 2H), 3.04-2.85 (m, 5H), 2.55-2.50 (m, 2H), 1.35 (t, J=7.2 Hz, 3H); ESI MS m/z 389 [C23H24N4O2+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[CH:5]=[CH:4][CH:3]=1.[OH-].[K+].I[CH2:19][CH2:20][CH3:21]>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[CH2:19][CH2:20][CH3:21])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: Cc1cccc(Nc2cccc(C)n2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCN(c1cccc(C)n1)c1cccc(C)n1
Reaction time: 1 h
Yield: 911.6 %

Procedure:
To a flask were added 1.0 g 6-methyl-N-(6-methylpyridin-2-yl)pyridin-2-amine, 0.84 g of pulverized potassium hydroxide and 15 ml of N,N-dimethylformamide. After stirring for 1 hour under nitrogen, the mixture was cooled to 5 C and 0.85 g of 1-iodopropane were added. The mixture was allowed to warm to 22 C and stirred for 16 hours. After quenching with 15 ml water, the product was extracted twice with diethyl ether and washed with water. Following removal of solvent, the product was purified by silica gel chromatography using 10% ethyl acetate in hexane to give 11.0 g of a colorless oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[CH:7][NH:6][C:5]=2[C:9]([OH:11])=O)[CH2:3][CH2:2]1.[C:12](Cl)(=O)[C:13](Cl)=O>ClCCl.CN(C)C=O>[CH:1]1([C:4]2[CH:8]=[CH:7][NH:6][C:5]=2[C:9]([NH:6][C:5]2[CH:4]=[CH:1][CH:2]=[CH:3][C:12]=2[CH3:13])=[O:11])[CH2:2][CH2:3]1
Reactant: O=C(O)c1[nH]ccc1C1CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)c1[nH]ccc1C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 186.6 %

Procedure:
To a suspension of the 3-cyclopropyl-1H-pyrrole-2-carboxylic acid (50 mg, 0,33 mmol) in dry dichloromethane (0.4 mL) was added a solution of oxalyl chloride (0.04 mL, 0,37 mmol) in 0.3 mL of dichloromethane atroom temperatureand 3 drops of N,N-dimethylformamide. After 1.5 h at this temperature, the mixture was concentrated under vacuum and the residue was redissolved in dichloromethane (1 mL). To this solution was added a solution of o-toluidine in dichloromethane (0,2 mL) and the mixture was stirred at room temperature overnight. The reaction was worked-up diluting with dichloromethane and washing with sodium bicarbonate (2×) and brine. The organic phase was dried and concentrated to give 74 mg of the title compound (88% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:9][C:8]2[N:10]=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:13][C:7]=2[NH:6][C:5]1=[O:38].[C:39](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[C:33]([O:32][C:31](=[O:37])[NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:11]3[C:12]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[CH:13][C:7]4[N:6]([CH3:39])[C:5](=[O:38])[CH:4]([CH2:3][CH2:2][OH:1])[O:9][C:8]=4[N:10]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][CH2:29]1)([CH3:35])([CH3:34])[CH3:36]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)C(CCO)O4)cc2)CCC1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(CCO)Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 1-(4-(3-(2-hydroxyethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (40 mg, 0.078 mmol) in DMF(1 ml) was added potassium carbonate (32 mg) and methyl iodide (13.2 mg, 0.093 mml) were added. The reaction mixture was stirred at room temperature for 4 h.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([O:23]CC)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.CO.[OH-].[Li+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:15])[CH:11]=[C:10]([C:21]([OH:23])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(C(=O)N2CCCC2)cc(-c2ccc(Br)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(C(=O)N2CCCC2)cc(-c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 4′-bromo-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylate (3.3 g, 8.2 mmol), MeOH (100 mL), water (20 mL), and lithium hydroxide (0.90 g, 38 mmol) was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was acidified with 1N aq. HCl to pH 2-3 and extracted with EtOAc (2×100 mL). The combined organic layers were dried (Na2SO4) and concentrated to afford a white foam. LC-MS: 376.1 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>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.C1COCC1>[NH2:11][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: Nc1cc(Br)cnc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1
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: C1CCOC1
Product: Nc1cc(-c2ccccc2)cnc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To 5-bromo-3-amino-2-nitropyridine (190 mg, 0.872 mmol) in a dry microwave reaction tube were added phenylboronic acid (159 mg, 1.31), K2CO3 (361 mg, 2.61 mmol) and Pd(PPh3)4 (101 mg, 0.087 mmol) and the reaction flask was evacuated and flushed with N2 four times. To this solid reaction mixture was added anhydrous THF (2 mL) and the reaction mixture was degassed by applying vacuum and flushing with N2 five times and sealed in N2 atmosphere. The reaction mixture was then heated 120° C. for 2 h. After this time, LC/MS analysis of the reaction mixture should essentially show the desired product. Reaction mixture was concentrated in vacuo and to the residue was added MeOH and stirred for 30 min. All the solids were collected by filtration and washed thoroughly with MeOH and water MS: cal'd 216 (M+H)+, exp 216 (M+H)+
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].ClC[C:16]1[CH:17]=[N:18][O:19][C:20]=1[C:21]1[S:22][C:23]([Cl:27])=[C:24]([Cl:26])[CH:25]=1.Cl>O1CCCC1.O>[Cl:26][C:24]1[CH:25]=[C:21]([C:20]2[O:19][N:18]=[CH:17][C:16]=2[CH2:3][CH2:2][C:1]([OH:9])=[O:8])[S:22][C:23]=1[Cl:27]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCc1cnoc1-c1cc(Cl)c(Cl)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1cnoc1-c1cc(Cl)c(Cl)s1
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
To a solution of diethyl malonate (3.55 g) in tetrahydrofuran (50 ml) was gradually added sodium hydride (60%, oil, 710 mg) at 0° C. The mixture was stirred for 10 min and a solution of 4-chloromethyl-5-(4,5-dichloro-2-thienyl)isoxazole (2.38 g) in tetrahydrofuran (50 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in a mixture of 6N hydrochloric acid (60 ml) and acetic acid (90 ml), and the solution was heated under reflux for 8 hr. The reaction mixture was concentrated, and water was added to the residue to give colorless crystals (2.04 g, yield 79%) of 3-[5-(4,5-dichloro-2-thienyl)-4-isoxazolyl]propionic acid. The crystals were recrystallized from ethyl acetate-hexane to give a colorless prism. melting point: 142–143° C.
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].C(O)(=[S:21])C>ClCCl>[SH:21][CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]
Reactant: O=C(CCCl)c1ccccc1
Reactant: CC(O)=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCS)c1ccccc1
Reaction time: 1 h
Yield: 59.4 %

Procedure:
Triethylamine (1.49 mL, 10.7 mmol, 1.50 equiv) was added to a solution of 3-chloropropiophenone (1.20 g, 7.12 mmol, 1 equiv) in dichloromethane (100 mL) at 23° C. Thioacetic acid (602 μL, 8.54 mmol, 1.20 equiv) was then added dropwise to the solution. After 1 h, the reaction mixture was concentrated in vacuo. The crude residue was dissolved in tetrahydrofuran (50 mL) and aqueous hydrochloric acid (6 N, 50 mL) was added to the solution. Thee reaction mixture was then heated to reflux. After 36 h, the reaction was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate solution (400 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL), and the combined organic layers were dried over sodium sulfate, were filtered, and were concentrated under reduced pressure. The crude reaction mixture was purified by flash column chromatography on silica gel (eluent: 20% ethyl acetate in hexanes) to afford 3-mercaptopropiophenone (E2-30, 703 mg, 59.4%) as a colorless oil. 1H NMR (500 MHz, CDCl3, 20° C.): δ 7.93 (d, J=7.5, 2H, COPh-o-H), 7.55 (t, J=7.5, 1H, COPh-p-H), 7.45 (app-t, J=7.5, 2H, COPh-m-H), 3.31 (t, J=7, 2H, CH2CH2SH, 2.89 (dt, J=8.5, 6.0, 2H, CH2CH2SH), 1.74 (t, J=8.5, 1H, SH). 13C NMR (125.8 MHz, CDCl3, 20° C.): δ 198.2 (C═O), 136.8 (COPh-ipso-C), 133.6 (COPh-p-C), 128.9 (COPh-m-C), 128.2 (COPh-o-C), 42.7 (CH2CH2SH), 19.1 (CH2CH2SH). FTIR (thin film) cm−1: 3061 (w), 2941 (w), 1683 (s), 1597 (m), 1580 (m) 1448 (m). HRMS (ESI) (m/z): calc'd for C9H11OS [M+H]+: 167.0525. found 167.0526. TLC (20% ethyl acetate in hexanes), Rf: 0.28 (UV, CAM).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[O:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27]>C1COCC1.CCOC(C)=O>[CH3:13][C:12]([Si:9]([CH3:11])([CH3:10])[O:8][C:4]1[CH:3]=[C:2]([C:25](=[O:26])[CH2:24][CH2:23][C:22]([OH:27])=[O:21])[CH:7]=[CH:6][CH:5]=1)([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Reactant: O=C1CCC(=O)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)CCC(=O)O)c1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
Under argon, to a solution of [(3-bromophenyl)oxy](1,1-dimethylethyl)-dimethylsilane (1.5 g, 5.22 mmol) in THF (60 mL) at −78° C., was added dropwise n-BuLi (3.6 mL, 1.6 M in hexanes), 20 min after the addition, this solution was added to a solution of dihydro-2,5-furandione (630 mg, 6.26 mmol) in THF (10 mL) under argon at −78° C. 15 min later, the reaction mixture was slowly warmed to rt overnight. The reaction mixture was diluted with EtOAc (50 mL), then extracted with NaOH (20 ml, 1.0 N). Aquaous layer was acidified with HCl (1.0N) until pH=2, then extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a colorless crystal (546 mg, 54%). MS (ES+) m/e 195 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([S:10]([NH:13][C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[O:15])(=[O:12])=[O:11])=[CH:4][N:3]=1.[Na].C(C1C=CC=CC=1)(=[O:28])C1C=CC=CC=1.ClC1C=CC=C(C(OO)=O)C=1>C1COCC1>[CH3:18][CH:17]([NH:16][C:14]([NH:13][S:10]([C:5]1[C:6]([S:8]([CH3:9])=[O:28])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1)(=[O:12])=[O:11])=[O:15])[CH3:19]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CSc1nc(N)ncc1S(=O)(=O)NC(=O)NC(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)NC(=O)NS(=O)(=O)c1cnc(N)nc1S(C)=O
Yield: 84 %

Procedure:
2-Amino-N-[[(1-methylethyl)amino]carbonyl]-4-(methylthio)-5-pyrimidinesulfonamide (3.0 g, 9.84 mmol) was dissolved in dry (freshly distilled from sodium/benzophenone) THF (60 mL) and m-chloroperbenzoic acid (MCPBA) (2.55 g, 11.81 mmol, 80% 1.2 eq) was added as a solid. The reaction turned yellow and a white solid precipitated out of solution. After 90 minutes the reaction was diluted with ethyl ether (60 mL) and the white solid was filtered, washed with THF, then with ether three times and air dried for 2 hours, to yield 2.64 g (8.22 mmol, 84%) of product, m.p. 140° C. (dec.). The product was unstable to heat but could be stored under nitrogen in the freezer for weeks.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1.[S:13]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.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>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][S:13][CH:14]=2)[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1
Reactant: COc1cc(I)cc([N+](=O)[O-])c1
Reactant: OB(O)c1ccsc1
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
Product: COc1cc(-c2ccsc2)cc([N+](=O)[O-])c1
Temperature: 160 °C
Yield: 91.9 %

Procedure:
To a solution of 1-iodo-3-methoxy-5-nitro-benzene (1.0 g, 3.59 mmol) in ethanol (18 mL) in a microwave tube were added tetrakis(triphenylphosphine)palladium(0) (837 mg, 0.72 mmol), thiophen-3-ylboronic acid (748 mg, 5.55 mmol), and potassium carbonate (496 mg, 3.58 mmol) at room temperature. The mixture was heated to 160° C. under closed microwave conditions for 30 minutes. After cooling to room temperature, the colored mixture was filtered and the filter cake was washed with water. The filtrate was diluted with 1.0 N HCl and the organic compound was extracted into ethyl acetate (2×50 mL). The combined organic extracts were washed with brine solution (100 mL) and dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by using an ISCO 80 g column, eluting with 0-10% ethyl acetate in hexanes to obtain 3-(3-methoxy-5-nitro-phenyl)-thiophene (776 mg, 92%) as a light yellow oil: EI(+)-HRMS m/e calculated for C11H9NO3S (M+)+ 235.0303, found 235.0298.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]2[CH:39]=[CH:40][N:41]=[C:34]2[CH:33]=[C:32]3[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:28])=[CH:23][CH:22]=1>C1COCC1.O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([C:11]2[N:7]([CH3:6])[CH:8]=[N:9][CH:10]=2)([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]2[CH:39]=[CH:40][N:41]=[C:34]2[CH:33]=[C:32]3[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[OH:28])=[CH:25][CH:26]=1
Reactant: Cn1ccnc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1ccccc1)cc1nccn12
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1ccccc1)cc1nccn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.1 %

Procedure:
n-Butyllithium (0.0129 mol) was added slowly at −70° C. under N2 flow to a solution of 1-methylimidazole (0.0129 mol) in THF (25 ml). The mixture was stirred for 30 min. Chlorotriethylsilane (0.0129 mol) was added. The mixture was allowed to warm to room temperature and then cooled to −70° C. n-Butyllithium (0.0129 mol) was added. The mixture was stirred at −70° C. for 1 hour, then allowed to warm to −15° C. and cooled to −70° C. A solution of (±)-α-(4-chlorophenyl)-5-phenylimidazo[1,2-a]quinoline-7-methanone (0.0107 mol) in THF (12 ml) was added. The mixture was stirred at −70° C. for 1 hour. Water was added The mixture was extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel. The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 0.9 g (18%) of (±)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-5-phenylimidazo[1,2-a]quinoline-7-methanol (compound 11).
Reaction SMILES: [Br-].[CH2:2]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4].CC(C)([O-])C.[K+].[CH:37]([CH:39]1[CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH2:40]1)=O.O>C1COCC1>[CH2:2]([C:5]1[CH:30]=[CH:29][C:8]([CH:9]=[CH:37][CH:39]2[CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH2:40]2)=[CH:7][CH:6]=1)[CH2:3][CH3:4]
Reactant: CCCc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=CC1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1ccc(C=CC2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
Suspension of 114 g of 4-n-propylbenzyltriphenyl phosphonium bromide in 500 ml of THF was stirred under nitrogen gas stream and 32.3 g of potassium-t-butoxide was added thereto at room temperature. After stirred at room temperature for 1 hour, a solution of 31.2 g of 4-formylcyclohexanone in 200 ml of THF was added dropwise to the suspension. After stirred at room temperature for 2 hours, 1 l of water was added thereto and then it was extracted with 1 l of ethyl acetate. Organic layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off under a reduced pressure, and then 500 ml of heptane was added thereto. Precipitate thus separated was filtered off and purified by a column chromatography over a silica gel by using ethyl acetate/heptane (1/5) as an eluent, and the solvent was distilled off under a reduced pressure to obtain 42 g of 4-(2-(4-n-propylphenyl)ethenyl)cyclohexanone.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:26]=[CH:25][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:22]([CH3:24])[CH3:23])[N:19]=[CH:20][N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.[C:27](O)(=[O:31])[C@H:28]([CH3:30])[OH:29]>>[OH:29][C@@H:28]([CH3:30])[C:27]([N:1]1[CH2:4][CH:3]([C:5]2[CH:26]=[CH:25][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:22]([CH3:24])[CH3:23])[N:19]=[CH:20][N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1)=[O:31]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: C[C@H](O)C(=O)O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)[C@H](C)O)C3)ccc1-2

Procedure:
Following the procedure for 318, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene free base 235 and L-(+)-lactic acid were reacted to give 323 isolated as an off-white solid after freeze-drying (42 mg, 29%). LCMS: RT=10.71 min, [M+H]+=440. 1H NMR δ (ppm) (CDCl3): 8.40-8.33 (1 H, m), 7.90 (1 H, s), 7.10 (1 H, t, J=6.16 Hz), 6.99 (1 H, d, J=8.83 Hz), 5.91-5.83 (1 H, m), 4.62-4.36 (5 H, m), 4.21 (3 H, m), 4.18-4.08 (1 H, m), 3.93-3.84 (1 H, m), 3.40 (2 H, t, J=5.01 Hz), 1.61 (6 H, d, J=6.62 Hz), 1.34 (3 H, d, J=6.57 Hz)