Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])C)=[C:4]([CH3:11])[CH:3]=1.II.[OH-:14].[Na+].Cl>N1C=CC=CC=1.CCOCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:14])=[C:4]([CH3:11])[CH:3]=1
Reactant: [OH-]
Reactant: CC(=O)c1ccc(O)cc1C
Agent: Cl
Agent: II
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1cc(O)ccc1C(=O)O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4'-Hydroxy-2'-methylacetophenone (15 gm, 0.1 mol) was dissolved in pyridine and iodine (25.4 gm) was added. This mixture was heated to 100° C. for 1 hr and then allowed to stand at room temperature overnight. A thick precipitate was obtained and the mixture was diluted with Et2O before filtering. The solid so obtained was added to 5N NaOH (200 ml) and heated on the steam bath for 1 hr before being cooled and acidified with HCl. This mixture was extracted twice with Et2O and the pooled organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was crystallized from Et2O-hexane to give 9.8 gm of the title compound as a solid.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([OH:9])=[O:8])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23](O)[CH2:22]2.O.N1(O)C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([O:9][C@@H:23]2[CH:24]3[CH2:27][CH2:28][N:21]([CH2:26][CH2:25]3)[CH2:22]2)=[O:8])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: O=C(O)C(Nc1ccccc1)c1csc2ccccc12
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 44.1 %

Procedure:
2-(Benzo[b]thiophen-3-yl)-2-(phenylamino)acetic acid (I18) (295 mg, 1.04 mmol), (R)-quinuclidin-3-ol (159 mg, 1.25 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (191 mg, 1.25 mmol), and DCC (258 mg, 1.25 mmol) were dissolved in dry THF and stirred at room temperature for 15 hours. The solvent was evaporated, and the crude product was dissolved in EtOAc and washed with NaHCO3, water and brine. The organic phase was dried with Na2SO4, filtered and evaporated under vacuum. The crude product was purified by flash chromatography (DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetate (180 mg, 44% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][C:11]([CH3:22])=[CH:12][CH2:13][CH:14]=[C:15]([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[H][H]>S([O-])([O-])(=O)=O.[Ba+2].[Pd+2].S([O-])([O-])(=O)=O.N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][C:11]([CH3:22])=[CH:12][CH2:13][CH:14]=[C:15]([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC(C)=CCC=C(C)CC#CCCCCCCCl
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: c1ccncc1
Product: CCCCCC(C)=CCC=C(C)CC=CCCCCCCCl

Procedure:
A mixture of 5.0 g. of 1-chloro-10,14-dimethylnonadeca-10,13-dien-7-yne 500 mg. of 5% palladium-barium sulfate catalyst and 40 ml. of pyridine is shaken under hydrogen for about 2 hrs. (until the uptake of hydrogen practically ceases). The mixture is then filtered, diluted with water, and extracted with ether. The ether extract is washed with water, dilute hydrochloric acid, and aqueous sodium bicarbonate, then is dried over sodium sulfate and evaporated to leave a residue comprising 1-chloro-10,14-dimethylnonadeca-7,10,13-triene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=1)=[CH:5]2.[C:30](O)(=[O:33])[CH2:31][OH:32].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27]([C:31](=[O:32])[CH2:30][OH:33])[CH2:26][CH2:25]3)[N:21]=1)=[CH:5]2
Reactant: O=C(O)CO
Reactant: Clc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCN4CCNCC4)CS3)cc2c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(CO)N1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
The compound (85 mg, 0.20 mmol) prepared in Example 96 was dissolved in N,N-dimethylformamide (1 ml). Glycolic acid (22 mg, 0.30 mmol), EDC (64 mg, 0.33 mmol) and HOBT (53 mg, 0.39 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (41 mg, Yield 44%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23]C)[CH2:5][NH:6][C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[F:25][C:26]1[CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[C:29]([O:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])=[C:30]([CH:33]=1)[CH:31]=[O:32]>>[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]1[CH:3]=[C:2]([C:28]2[CH:27]=[C:26]([F:25])[CH:33]=[C:30]([CH:31]=[O:32])[C:29]=2[O:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])[C:16]([O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][CH:14]=1)=[O:8])([CH3:11])([CH3:12])[CH3:13]
Reactant: CCOCCOCOc1ccc(CNC(=O)NC(C)(C)C)cc1Br
Reactant: COCCOCOc1c(C=O)cc(F)cc1B1OC(C)(C)C(C)(C)O1
Product: COCCOCOc1ccc(CNC(=O)NC(C)(C)C)cc1-c1cc(F)cc(C=O)c1OCOCCOC
Yield: 54.9 %

Procedure:
Proceeding as in Reference 19, but substituting 1-[3-bromo-4-(2-ethoxyethoxymethoxy)benzyl]-3-tert-butylurea (1.0 g, 2.9 mmol) and 5-fluoro-2-(2-methoxy-ethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (29 mL, 0.1 mM in toluene, 2.9 mmol) gave 1-tert-butyl-3-[5′-fluoro-3′-formyl-6,2′-bis-(2-methoxyethoxymethoxy)biphenyl-3-ylmethyl]-urea (0.854 g).
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[C:13]([O:26]C)=[N:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=3)[CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[C:13](=[O:26])[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=3)[CH:17]=2)=[O:10])=[CH:28][CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncc(-c2ccnc(SC)n2)cc1NC(=O)c1ccc(C(C)(C)C)cc1
Solvent: C1COCCO1
Solvent: O
Product: CSc1nccc(-c2c[nH]c(=O)c(NC(=O)c3ccc(C(C)(C)C)cc3)c2)n1
Temperature: 25 °C
Yield: 25.3 %

Procedure:
4-tert-Butyl-N-[2-methoxy-5-(2-methylsulfanyl-pyrimidin-4-yl)-pyridin-3-yl]-benzamide (120 mg, 0.29 mmol) was dissolved in 1,4-dioxane (6 mL) and water (1.2 mL). Concentrated Hcl (600 μL) was added and the reaction mixture was heated to reflux for 30 minutes. The reaction mixture was cooled down to room temperature and water was added. The obtained precipitate was isolated by filtration and dried under vacuum. The crude solid was purified by flash chromatography to give the title compound as a fawn solid (29 mg, 25% yield). MS (ES+) m/e=395. 1H NMR (DMSO-d6) δH 1.33 (9H, s), 2.58 (3H, s), 7.59 (2H, d), 7.64 (1H, d), 7.88 (2H, d), 8.21 (1H, s), 8.58 (1H, d), 9.11 (1H, s), 9.30 (1H, s), 12.72 (1H, br s).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[SH:10].Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[S:10][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(N)c(S)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N)c(SCc2ccccc2)c1
Yield: 79 %

Procedure:
Following General Procedure A, the title compound (615 mg, 79%) was prepared from 4-amino-3-mercaptobenzonitrile (486 mg, 3.24 mmol), (bromomethyl)benzene (0.38 ml, 3.24 mmol) and K2CO3 (2.2 g, 16.20 mmol) in DMF (10 ml).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]3[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]3[CH:20]=2)[CH:8]=[CH:9][CH:10]=1.[F:21][CH:22]1[CH2:25][N:24]([C:26]([C:28]2[CH:29]=[N:30][N:31]([CH3:36])[C:32]=2[C:33](O)=[O:34])=[O:27])[CH2:23]1>>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]3[N:18]=[C:17]([NH:19][C:33]([C:32]4[N:31]([CH3:36])[N:30]=[CH:29][C:28]=4[C:26]([N:24]4[CH2:23][CH:22]([F:21])[CH2:25]4)=[O:27])=[O:34])[CH:16]=[CH:15][N:14]3[CH:20]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: Cn1ncc(C(=O)N2CC(F)C2)c1C(=O)O
Reactant: Nc1ccn2cc(-c3cccc(OCCF)c3)nc2n1
Product: Cn1ncc(C(=O)N2CC(F)C2)c1C(=O)Nc1ccn2cc(-c3cccc(OCCF)c3)nc2n1

Procedure:
The title compound was prepared in analogy to example 82 from 2-(3-(2-fluoroethoxy)phenyl)imidazo[1,2-a]pyrimidin-7-amine (120 mg) and 4-(3-fluoroazetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (100 mg, 440 μmol). Light brown solid (132 mg, 60%). MS (m/z)=482.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl
Product: O=C(O)CCC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A suspension of 4-(4′-bromo-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester (2.636 g, 0.00759 mol) in 6 M HCl was refluxed for 214 hours and cooled to room temperature. The solids were filtered and washed with 1 M HCl. The filter cake was partitioned between ethyl acetate and 1 M sodium hydroxide. The aqueous layer was washed twice with ethyl acetate and filtered to remove particulates. The filtrate was rotary evaporated to remove residual ethyl acetate. The solution was stirred and acidified to pH 2 with concentrated HCl solution. The resulting precipitate was filtered, washed with water, and dried with house vacuum (air bleed) give 1.97 g of 4-(4′-bromo-biphenyl-4-yl)-4-oxo-butyric acid as a white solid; mp 198-200° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:35]=[CH:34][C:25]2[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.Cl>O1CCOCC1.COCCO>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)=[N:7][C:2]([NH:21][C:22]2[CH:35]=[CH:34][C:25]3[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CC1(C)CCC(=O)Nc2ccc(Nc3ncc(Cl)c(Nc4ccccc4-n4cccn4)n3)cc21
Yield: 81.9 %

Procedure:
Combined (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine (82 mg, 0.268 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (70 mg, 0.343 mmol), 4 N HCl in dioxane (80 ul) and 2-methoxyethanol (4 mL). Heated reaction at 120° C. for 16 hours. Evaporated off solvent and purified with normal phase chromatography to yield a beige solid, 7-[5-Chloro-4-(2-pyrazol-1-yl-phenylamino)-pyrimidin-2-ylamino]-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (104 mg, 82%). LCMS: m/z=474.34 (M+H+), 1H NMR (400 MHz, CD3OD) δ 8.41 (d, 1H, J=8.1 Hz), 8.02 (m, 2H), 7.84 (s, 1H), 7.60 (dd, 1H, J=8.3, 2.3 Hz), 7.52 (m, 2H), 7.42 (m, 1H), 7.30 (m, 1H), 6.91 (d, 1H, J=8.6 Hz), 6.55 (m, 1H), 4.59 (s, 1H), 2.32 (m, 2H), 2.11 (m, 2H), 1.35 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1([O:22][Si](C)(C)C)[C:15]2[NH:14][C:13]3[C:8](=[CH:9][C:10]([C:20]#[N:21])=[CH:11][C:12]=3[C:16]([F:19])([F:18])[F:17])[C:7]=2[CH2:6][CH2:5][CH2:4]1.[OH-].[K+]>C1COCC1.O>[OH:22][C:3]1([C:2]([F:28])([F:1])[F:27])[C:15]2[NH:14][C:13]3[C:8](=[CH:9][C:10]([C:20]#[N:21])=[CH:11][C:12]=3[C:16]([F:17])([F:18])[F:19])[C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: C[Si](C)(C)OC1(C(F)(F)F)CCCc2c1[nH]c1c(C(F)(F)F)cc(C#N)cc21
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(C(F)(F)F)c2[nH]c3c(c2c1)CCCC3(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
1,8-bis(Trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole-6-carbonitrile (100 mg, 0.23 mmol) was dissolved in THF (5 mL) and KOH (66 mg, 1.19 mmol), in H2O (5 mL), was added. The reaction mixture was stirred at room temperature for 1 h, diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude compound which was purified by column chromatography [EtOAc-hexane (17:3) as eluant] to afford the title compound as a white solid (30 mg, 36.58%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.75 (br s, 1H), 8.067 (s, 1H), 7.75 (s, 1H), 2.91-2.86 (m, 1H), 2.80-2.74 (m, 1H), 2.55 (s, 1H), 2.37-2.32 (m, 1H), 2.16-2.05 (m, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[OH:15][CH2:16][C:17]1[CH:18]=[C:19]([S:23]([C:26]2[CH:27]=[C:28]3[C:33](=[C:34]([CH3:36])[CH:35]=2)[N:32]=[CH:31][C:30]([C:37]([NH2:39])=[O:38])=[C:29]3[NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=2)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>>[CH3:1][S:2]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([C:26]2[CH:27]=[C:28]3[C:33](=[C:34]([CH3:36])[CH:35]=2)[N:32]=[CH:31][C:30]([C:37](=[O:38])[NH2:39])=[C:29]3[NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=2)(=[O:25])=[O:24])[CH:18]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(CO)c4)cc23)c1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(COS(C)(=O)=O)c4)cc23)c1
Reaction time: 1 h
Yield: 118.8 %

Procedure:
Methanesulfonyl chloride (0.06 mL, 1.474 mmol) and DIEA (0.243 mL, 1.394 mmol) were added to a stirring solution of Intermediate 134 (330 mg, 0.697 mmol) at rt. The reaction was monitored by LC/MS and additional methanesulfonyl chloride (0.06 mL, 1.474 mmol) and DIEA (0.243 mL, 1.394 mmol) were added after 3 h. The resulting reaction mixture was stirred for an additional 1 h then quenched with satd. NaHCO3 (50 mL). The aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with H2O (100 mL), brine (100 mL), dried over Na2SO4 (s), and concentrated to give the title compound (460 mg) as a yellow solid. The compound was used with no further purification. ES/MS calcd. for C26H26N3O7S2+ 556.1. Found m/z=556.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[CH:13](B(OCCCC)OCCCC)=[CH2:14].[F-].[Cs+]>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.COCCOC.CO>[CH3:8][C:6]1[CH:7]=[C:2]([CH:13]=[CH2:14])[C:3]([CH3:12])=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Br
Reactant: C=CB(OCCCC)OCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: C=Cc1cc(C)c([N+](=O)[O-])cc1C
Temperature: 130 °C

Procedure:
To a microwave reaction vessel was added a mixture of 1-bromo-2,5-dimethyl-4-nitrobenzene (1.15 g, 5.0 mmol), dibutyl vinylboronate (1.16 g, 6.3 mmol), Pd(PPh3)4(289 mg, 0.25 mmol), CsF (2.28 g, 15 mmol) and a mixed solvent (1,2-dimethoxyethane/MeOH=2:1, 15 mL). The mixture was degassed and sealed with N2. The reaction vessel was then heated to 130° C. in a microwave reactor for 15 min. After opening the reaction vessel, the mixture was poured into saturated NH4Cl aqueous solution (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried (MgSO4). After removing the drying agent by filtration, the filtrate was concentrated and purified by flash column chromatography (silica gel, 0-30% EtOAc in hexanes gradient) to provide 1,4-dimethyl-2-nitro-5-vinylbenzene as needlelike crystals; ESMS m/z 178.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH:7]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[S:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3Cl)[CH:15]=2)=[O:13])[CH2:8]1)[S:3]([CH3:6])(=[O:5])=[O:4].[CH3:24][C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([NH2:34])=[CH:29][CH:28]=2>>[CH3:1][N:2]([CH:7]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[S:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[NH:34][C:30]3[CH:31]=[C:32]4[C:27](=[CH:28][CH:29]=3)[NH:26][C:25]([CH3:24])=[CH:33]4)[CH:15]=2)=[O:13])[CH2:8]1)[S:3]([CH3:6])(=[O:5])=[O:4]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CN(C1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1)S(C)(=O)=O
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC(N(C)S(C)(=O)=O)C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (+/−)-methanesulfonic acid methyl-{1-[7-chloro-thieno[3,2-b]pyridine-2-carbonyl]-pyrrolidin-3-yl}-amide and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 484 (MH+); HPLC Rf: 3.69 min.; HPLC purity 91%.
Reaction SMILES: [NH3:1].Br[CH2:3][C:4]1[C:14]([Cl:15])=[C:13]([Cl:16])[CH:12]=[CH:11][C:5]=1[C:6](OCC)=[O:7]>CN(C)C=O>[Cl:15][C:14]1[C:13]([Cl:16])=[CH:12][CH:11]=[C:5]2[C:4]=1[CH2:3][NH:1][C:6]2=[O:7]
Reactant: CCOC(=O)c1ccc(Cl)c(Cl)c1CBr
Reactant: N
Solvent: CN(C)C=O
Product: O=C1NCc2c1ccc(Cl)c2Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ammonia was bubbled through a solution of ethyl 2-bromomethyl-3,4-dichlorobenzoate (25 g, 0.08 mol.) in 250 ml. of dimethylformamide for 1/2 hour at 0° C. The mixture was stirred for one hour at 25° C., poured on crushed ice and filtered. The solid was chromatographed on silica gel eluted ether, ethyl acetate and then acetone to give 4,5-di-chloro-2,3-dihydro-1H-isoindol-1-one.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Cl:7])=[CH:5][CH:6]=1.C([Li])CCC.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>O1CCCC1>[Cl:7][C:4]1[S:3][C:2]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1
Reactant: Clc1ccc(Br)s1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(Cl)s1
Temperature: -80 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A stirred solution of 5.1 mL (0.046 mole) of 2-bromo-5-chlorothiophene in 200 mL of tetrahydrofuran was cooled to -85°C., and 19.7 mL (0.049 mole) of n-butyllithium (0.049 mole-2.5M in hexanes) was added dropwise during a 15 minute period. The reaction mixture temperature was maintained at -85° C. to -80° C. throughout the addition. Upon completion of addition, the reaction mixture temperature was maintained at about -80° C. for one hour. After this time, a solution of 12.5 mL (0.046 mole) of tributyltin chloride in 50 mL of tetrahydrofuran was added to the cold reaction mixture during a 10 minute period. Upon completion of addition, the reaction mixture was stirred at -80° C. for one hour, then it was allowed to warm gradually to ambient temperature. The reaction was quenched with an aqueous solution saturated with ammonium chloride, and then the reaction mixture was extracted with three 150 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 18.4 grams of (5-chlorothien-2-yl)tributyl tin. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=[N:5]1)[CH3:3].[Cl:13]N1C(=O)CCC1=O>CN(C=O)C>[Cl:13][C:7]1[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccnn1C(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)cnn1C(C)C
Temperature: 60 °C
Yield: 93.6 %

Procedure:
A solution of methyl 1-(1-methylethyl)-1H-pyrazole-5-carboxylate (120 mg) in DMF (3 ml) was treated with N-chlorosuccinimide (95 mg) and heated to 60° C. for 18 h under nitrogen. The cooled mixture was partitioned between diethyl ether (20 ml) and water (20 ml), separated and dried over sodium sulphate then evaporated to give the title compound as a pale yellow oil (135 mg).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[ClH:20]>O>[CH2:1]([Cl:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Cl
Reactant: CCCCCCCCCCCCCCCCCCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCl

Procedure:
A 1 l jacketed glass reactor with a glass paddle stirrer and immersed tube for reactant metering is initially charged with 220 g of N-n-octylalkylpyridinium chloride (prepared according to Example 2) and adjusted to a temperature of 150° C. 447 g of n-octadecanol are introduced uniformly via an immersed tube over 5 hours. Gaseous hydrogen chloride is metered in via an immersed tube in a slight stoichiometric excess over the entire reaction time, and the water of reaction formed is simultaneously removed via distillation. The performance of the reaction and the workup of the reaction mixture are analogous to Example 4a. After a total reaction time of 8 h (including 3 hours of postreaction), the conversion based on n-octadecanol is 99.8%.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH3:23][NH:24][CH2:25][CH:26]1[O:31][CH2:30][CH2:29][NH:28][CH2:27]1.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:28]4[CH2:29][CH2:30][O:31][CH:26]([CH2:25][NH:24][CH3:23])[CH2:27]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CNCC1CNCCO1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1

Procedure:
A solution of 8.3 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7.1 g of 2 -(methylaminomethyl)morpholine dihydrochloride and 15.2 g of 1,8-diazabicyclo[5.4.0]undec-7-ene in 166 ml of acetonitrile is refluxed for 8 hours. After ice-cooling, the precipitated crystals are collected by filtration, washed with acetone and recrystallized from dimethylformamide to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-[2-(methylaminomethyl)-morpholino]-4-oxoquinoline-3-carboxylic acid, melting at 257°-259° C. with decomposition. The corresponding hydrochloride melts at 288°-290° C. with decomposition.