Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH:8]2[CH2:10][CH2:9]2)[N:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16][CH2:15]1>>[CH:8]1([CH2:7][N:6]2[C:2]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:16][CH2:15]3)=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=[N:5]2)[CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1cnn(CC2CC2)c1Cl
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Product: CC(C)(C)OC(=O)NCC1CCN(c2c([N+](=O)[O-])cnn2CC2CC2)CC1
Yield: 95 %

Procedure:
Reaction of 5-chloro-1-cyclopropylmethyl-4-nitro-1H-pyrazole and tert-butyl piperidin-4-ylmethylcarbamate gave tert-butyl (1-(1-(cyclopropylmethyl)-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate as a pale yellow gum (0.57 g, 95%). 1H NMR (400 MHz, CDCl3) δ 8.07-8.03 (m, 1H), 4.63 (s, 1H), 3.91 (d, J=7.1 Hz, 2H), 3.40-3.32 (m, 2H), 3.13-3.06 (m, 2H), 2.95 (d, J=11.5 Hz, 2H), 1.81 (d, J=12.9 Hz, 2H), 1.46 (s, 9H), 1.42-1.14 (m, 3H), 0.95-0.82 (m, 1H), 0.63-0.57 (m, 2H), 0.42-0.35 (m, 2H)
Reaction SMILES: N[CH:2]([CH3:29])[CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH3:30][S:31]([O:34]S(C)(=O)=O)(=O)=[O:32].[N:39]1C=CC=CC=1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:5]([CH2:4][CH2:3][CH2:2][CH2:29][NH:39][S:31]([CH3:30])(=[O:34])=[O:32])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: c1ccncc1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CC(N)CCn1c(CCCOc2ccccc2)nc2c(N)nc3ccccc3c21
Product: CS(=O)(=O)NCCCCn1c(CCCOc2ccccc2)nc2c(N)nc3ccccc3c21

Procedure:
Using the general method of Example 255, except that pyridine was used in place of acetonitrile, 1-(3-aminobutyl)-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.1 mmol) was reacted with an excess of methanesulfonic anhydride to provide 1.36 g of N-{4-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide as a solid, m.p. 156.4-157.1° C. Analysis: Calculated for C24H29N5O3S: %C, 60.48; %H, 6.34; %N, 14.69; Found: %C, 60.75; %H, 6.36; %N, 14.31.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH3:22])=[N:19]2)=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>CN(C=O)C>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH:22]=[CH:6][C:5]3[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=3)[C:1]#[N:2])=[N:19]2)=[CH:14][CH:13]=1
Reactant: N#Cc1cccc(C=O)c1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Yield: 82.9 %

Procedure:
Under the protection by nitrogen, meta-cyanobenzaldehyde (137.6 g, 1.05 mol), 7-chloroquinaldine (177 g, 1.0 mol) and sodium acetate (82 g) are added into 200 ml of acetic anhydride and 800 ml of dimethyl fomamide (DMF), and the resulted mixture solution is stirred and heated to reflux for 24 hours. After distilling the most solvent, 300 ml of water is added into the residue, and then extracted by ethyl acetate (500 ml×3), washed with saturated saline water, dried with anhydrous sodium sulfate and condensed in the vacuum. The resulted residue is then purified through Flash Column Chromatography to obtain 241 g of the title compound, with a yield of 83%.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25].[F:30][C:31]([F:41])([F:40])[O:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>>[F:30][C:31]([F:40])([F:41])[O:32][C:33]1[CH:34]=[CH:35][C:36]([N:37]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[C:17]([F:29])([F:28])[F:16])(=[O:26])=[O:25])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:38][CH:39]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1C(F)(F)F)CC2

Procedure:
Off white solid. MS (ESI): 523.11 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethyl-benzenesulfonyl chloride and 4-(trifluoromethoxy)-aniline.
Reaction SMILES: C(OP(C[N:10]1C2C3C=CC=C(C(F)(F)F)C=3C([N+]([O-])=O)=CC=2NC(=O)C1=O)(=O)OCC)C.[CH2:33]([O:35][P:36]([CH2:41][N:42]1[C:51]2[CH:50]=[C:49]([N+:52]([O-:54])=[O:53])[C:48]3[C:55]([C:59](F)(F)F)=[CH:56][CH:57]=[CH:58][C:47]=3[C:46]=2[NH:45][C:44](=[O:63])[C:43]1=[O:64])(=[O:40])[O:37][CH2:38][CH3:39])[CH3:34]>>[CH2:33]([O:35][P:36]([CH2:41][N:42]1[C:51]2[CH:50]=[C:49]([N+:52]([O-:54])=[O:53])[C:48]3[C:55]([C:59]#[N:10])=[CH:56][CH:57]=[CH:58][C:47]=3[C:46]=2[NH:45][C:44](=[O:63])[C:43]1=[O:64])(=[O:40])[O:37][CH2:38][CH3:39])[CH3:34]
Reactant: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2c3cccc(C(F)(F)F)c3c([N+](=O)[O-])cc21)OCC
Reactant: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c3c(C(F)(F)F)cccc3c21)OCC
Product: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2c3cccc(C#N)c3c([N+](=O)[O-])cc21)OCC

Procedure:
(6-nitro-7-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]quinoxalin-1-yl)-methanephosphonic acid diethyl ester and (6-nitro-7-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]quinoxalin-4-yl)-methanephosphonic acid diethyl ester
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.FC1C=CC(S(N(CC)C(=C)C(NCC2C=CN=C(C3C=CC(OC(F)(F)F)=CC=3)C=2)=O)(=O)=O)=CC=1>C(O)C.ClC1SC(S(N(CC)C(=C)C(NCC2C=CN=C(C3C=CC(OC(F)(F)F)=CC=3)C=2)=O)(=O)=O)=CC=1>[Cl:10][C:4]1[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Reactant: C1COCCN1
Agent: C=C(C(=O)NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(Cl)s1
Agent: C=C(C(=O)NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Solvent: CCO
Product: N#Cc1cc(Cl)nc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
2,6-dichloropyridine-4-carbonitrile 24 (4 gr, 23.13 mmol) was dissolved in 100 ml of ethanol. To the solution were added TEA (1 equiv., 3.22 ml), morpholine (1 equiv., 2 ml) and the mixture was stirred at 70° C. for 4 hours. (TLC AcOEt 3/petroleum ether 7). The solvent was evaporated and the residue was dissolved with ethyl acetate, washed with water and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude was crystallized from ethyl acetate and petroleum ether to give a beige solid. (4.6 g, 89% yield) 1HNMR (DMSO, 400 MHz) δ 3.58 (4H, m), 3.64 (4H, m), 7.10 (1H, s), 7.32 (1H, s)
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([Cl:10])=[O:9])[CH2:4][CH2:3]1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([Br:31])=[CH:18][C:19]=1[NH:20][CH:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][CH2:22]1)=[O:14].N1C=CC=CC=1.CO>C1(C)C=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([Cl:10])=[O:9])[CH2:4][CH2:3]1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([Br:31])=[CH:18][C:19]=1[N:20]([CH:21]1[CH2:22][CH2:23][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:29][CH2:30]1)[C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4]1)=[O:9])=[O:14]
Reactant: COC(=O)c1sc(Br)cc1NC1CCC2(CC1)OCCO2
Agent: C[C@H]1CC[C@H](C(=O)Cl)CC1
Agent: C[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Temperature: 5 °C
Reaction time: 16 h

Procedure:
The 1M solution of trans-4-methylcyclohexyl carboxylic acid chloride is added to a solution of 5-bromo-3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester (24.79 g, 65 mmol) in toluene (25 mL) followed by pyridine (5.78 mL, 71.5 mmol). The resulting mixture is then stirred for 16 h at reflux. The reaction mixture is diluted with toluene (60 mL) and cooled down to 5° C. After the addition of pyridine (12 mL) and MeOH (5.6 mL), the mixture is stirred 2 h at 5° C. The white suspension is filtered off and the toluene is added to the mother liquor. The organic phase is washed with 10% citric acid, aq. Sat NaHCO3, dried (Na2SO4) and concentrated. The residue is triturated in boiling hexane (1500 mL). The reaction mixture is allowed to cool down to room temperature. The reaction flask is immersed into ice bath, and stirred for 30 min; white solid is filtered off, and washed with cold hexane (225 mL). The solid is purified by silica gel column chromatography using 20% EtOAc:hexane as eluent to furnish the final compound 5-bromo-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (10.5 g, 32%).
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([C:6]([N:8]2[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:7])[CH:2]=1.NC1[S:15][C:16]2C=C[CH:20]=[CH:19][C:17]=2N=1>C(#N)C>[S:15]1[C:16]2[CH:17]=[CH:19][CH:20]=[CH:9][C:10]=2[N:11]=[C:12]1[NH:8][C:6]([N:3]1[CH:2]=[CH:1][N:5]=[CH:4]1)=[O:7]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2ccccc2s1
Solvent: CC#N
Product: O=C(Nc1nc2ccccc2s1)n1ccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.3 %

Procedure:
To CDI (1.6 g, 10 mmol) in acetonitrile (30 mL) was slowly added 2-aminobenzothiazole (1.0 g, 6.6 mmol) and allowed to stir at rt for 48 hours. The reaction mixture was filtered, washed with acetonitrile, and dried to provide 1.44 g (88%) of the desired product N-(benzo[d]thiazol-2-yl)-1-imidazole-1-carboxamide (1M): LC/MS (APCI): m/z 245.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][CH2:38][CH2:39][CH2:40][CH2:41][OH:42]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][OH:42])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Product: O=C(NCCCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1 H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-amino-1-butanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.25-1.85 (m, 12 H), 2.35-2.45 (m, 2 H), 3.40 (ddd, J=18.53, 12.53, 6.42 Hz, 8 H), 4.15-4.23 (m, 4 H), 4.44 (t, J=5.16 Hz, 1 H), 7.14 (t, J=8.95 Hz, 2 H), 7.37-7.43 (m, 2 H), 7.99 (s, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.31 (t, J=6.11 Hz, 1 H), 17.21 (s, 1 H); ES+ MS: 539 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:10]2)=[C:5]([CH2:20][CH3:21])[CH:4]=1)#[CH:2].C(O)(=O)C1C=CC=CC=1.[CH2:31]([O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][C:38](I)=[CH:37][CH:36]=1)[CH3:32]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:13]([O:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:38]3[CH:39]=[CH:40][C:35]([C:34]([O:33][CH2:31][CH3:32])=[O:42])=[CH:36][CH:37]=3)=[CH:4][C:5]=2[CH2:20][CH3:21])[CH2:11][CH2:10]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OCc3ccccc3)CC2)c(CC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(CC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-ethyl-benzene (Intermediate 90, 90.0 mg, 0.33 mmol) and ethyl-4-iodo benzoate (Reagent A, 100.0 mg, 0.36 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (77 mg, 0.11 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 100.0 mg (72%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[C:12]2[S:11][C:10](=[O:13])[NH:9][C:8]=2[C:7]([O:14]C)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.N1C=CC=CC=1>CN1CCCC1=O.O>[C:1]([C:4]1[C:12]2[S:11][C:10](=[O:13])[NH:9][C:8]=2[C:7]([OH:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C(C)=O)c2sc(=O)[nH]c12
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of 7-acetyl4-methoxy-1,3-benzothiazol-2(3H)-one (1.2 g), pyridine hydrochloride (2.77 g), in dry 1-methyl-2-pyrrolidone(6 ml), was heated at 190° C. in a microwave reactor for 90 min. The reaction mixture was cooled to room temperature, and diluted with water. The precipitated solid was collected by filtration, washed with water and dried under vacuum at 40° C. to give the title compound (1.07 g). LCMS RT=2.46 min.
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@:10]1([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:11][C@H:12]2[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])C1C=CC=CC=1.[H][H]>CO.C(O)(=O)C.[Pd]>[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[N:16]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@@:10]1([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:11][C@H:12]2[S:24]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@@]2(c3ccccc3)[C@H](NCc3ccccc3)CC[C@@H]1N2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: N[C@@H]1CC[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccccc1)N2Cc1ccccc1
Yield: 48.8 %

Procedure:
(1R*,2R*,5S*,6R*)-2-benzylamino-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octane (Description 4; 8.34 g, 16 mmol) was dissolved in methanol (150 mL) and acetic acid (150 mL), then treated with 10% palladium on activated charcoal (2 g). The suspension was then hydrogenated at 50 psi hydrogen for 16 hours, then filtered. The filtrate was concentrated in vacuo, and the oil remaining suspended in saturated aqueous sodium hydrogen carbonate solution (250 mL). This was extracted with ethyl acetate (2×250 mL) and the extracts were dried (MgSO4), then concentrated. Purification by silica chromatography yielded the title compound as a gum (3.37 g, 7.8 mmol).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:36])[CH2:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])=[CH:20][C:19]=3[F:37])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2].O=[C:39](NC1C=CC=CC=1)[CH2:40]C(O)=O>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([CH:26]4[CH2:40][CH2:39][N:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:27]4=[O:28])=[O:36])=[CH:20][C:19]=3[F:37])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)c1
Reactant: O=C(O)CC(=O)Nc1ccccc1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)C5CCN(c6ccccc6)C5=O)cc4F)c3s2)c1
Yield: 40 %

Procedure:
Following the procedure described above for the synthesis of compound 5d (scheme 4), but replacing acid 1 with the acid 205, title compound 204 was obtained in 40% yield. 1H NMR (DMSO-d6) δ (ppm): 10.72 (s, 1H), 8.49 (d, J=5.7 Hz, 1H), 8.06 (d, J=1.0 Hz, 1H), 7.96-7.90 (m, 2H), 7.72 (s, 1H), 7.67-7.65 (m, 2H), 7.53-7.49 (m, 2H), 7.41-7.37 (m, 2H), 7.16 (t, J=7.2 Hz, 1H), 6.70 (d, J=5.5 Hz, 1H), 4.06 (q, 2H), 3.93 (m, 2H), 3.77 (t, J=8.2 Hz, 1H), 4.42 (m, 2H), 1.40 (t, 3H). MS (m/z): 542.0 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]([O:26]C3CCCCO3)[CH2:11][O:12][CH2:13][CH2:14]OS(C3C=CC(C)=CC=3)(=O)=O)[CH:8]=[CH:9][C:2]1=2.[CH3:33][NH2:34].C(OCC)C.[ClH:40].C(O)C>C(O)C.CC(C)=O>[ClH:40].[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]([OH:26])[CH2:11][O:12][CH2:13][CH2:14][NH:34][CH3:33])[CH:8]=[CH:9][C:2]1=2
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(OC2CCCCO2)c2ccc3sccc3c2)cc1
Reactant: CN
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Solvent: CCOCC
Product: CNCCOCC(O)c1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In 15 ml of ethanol was dissolved 1.5 g of 1-(benzo[b]thiophen-5-yl)-1-(2-tetrahydropyranyloxy)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethane. To the solution was added 4.9 ml of a 40% aqueous methylamine solution. The resulting mixture was refluxed for 1 hour. The reaction mixture was added to a mixture of 20 ml of ice water and 20 ml of diethyl ether. The organic layer was separated. The aqueous layer was extracted with 20 ml of diethyl ether. The extract was combined with the previously separated organic layer. To the combined organic layer was added 20 ml of water. The resulting mixture was adjusted to pH 1.5 with 6N hydrochloric acid and stirred at room temperature for 20 minutes. The aqueous layer was separated. The organic layer was extracted with 10 ml of water. The extract was combined with the previously separated aqueous layer. To the combined aqueous layer was added 30 ml of methylene chloride. The resulting mixture was adjusted to pH 11 with a 10% aqueous sodium hydroxide solution. The organic layer was separated. The aqueous layer was extracted with 15 ml of methylene chloride. The extract was combined with the previously separated organic layer and the combined organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was dissolved in 7 ml of acetone. To the solution was added 0.5 ml of a 5N dry hydrogen chloride-ethanol solution. The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 7 ml of diethyl ether. The resulting crystals were collected by filtration to obtain 0.5 g of 1-(benzo[b]thiophen-5-yl)-2-(N-methylaminoethoxy)ethanol hydrochloride (compound No. 347).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[O:21][CH:22]=[CH:23][N:24]=1)CCC>COCCOC.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>[CH3:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:20]1[O:21][CH:22]=[CH:23][N:24]=1)[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Cc1cccc2cc(C=O)c(-c3ncco3)nc12
Temperature: 100 °C
Yield: 34.3 %

Procedure:
To a solution of 2-chloro-8-methylquinoline-3-carboxaldehyde (250 mg, 1.21 mmol) in DME (3 mL) was added 2-(tributylstannyl)oxazole (0.31 mL, 1.76 mmol) and Pd(PPh3)4 (70 mg, 0.06 mmol). The reaction mixture was heated in a microwave at 100° C. for 45 minutes. More Pd(PPh3)4 (50 mg, 0.04 mmol) was added to the mixture, which was heated at 100° C. for 2 h. Purification by column chromatography (SiO2, 0-100% EtOAc in heptane) gave the title compound as a cream solid (99 mg, 34%). δH (DMSO-d6) 10.85 (s, 1H), 8.91 (s, 1H), 8.52 (d, J 0.6 Hz, 1H), 8.12 (d, J 8.1 Hz, 1H), 7.86 (d, J 7.0 Hz, 1H), 7.64-7.72 (m, 2H), 2.81 (s, 3H). LCMS (ES+) 239 (M+H)+, RT 3.65 minutes (Method 3).
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[O:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:33]4[CH:34]=[CH:35][O:31][CH:32]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: OB(O)c1ccoc1
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: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cccc(-c2c(-c3ccoc3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 80 °C
Yield: 80.3 %

Procedure:
A mixture of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (70 mg, 0.134 mmol) (Example 33), 3-furanylboronic acid (22.43 mg, 0.20 mmol), sodium carbonate (28.3 mg, 0.267 mmol) and tetrakis(triphenylphosphine)palladium(0) (15.44 mg, 0.013 mmol) in acetonitrile (1 mL) and water (250 μl) was heated at 80° C. under nitrogen for 1.5 h. The reaction mixture was cooled to RT and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in isohexane, afforded the title compound (55 mg). LCMS (A) m/z: 511 [M+1]+, Rt 1.51 min (acidic), Rt 0.98 min (basic).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:48][C:49]1[NH:50][C:51]2[C:56]([C:57]=1[CH2:58][C:59](O)=[O:60])=[CH:55][CH:54]=[CH:53][CH:52]=2>CN(C)C=O.ClCCl>[CH3:2][O:3][C:4](=[O:18])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:59](=[O:60])[CH2:58][C:57]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[NH:50][C:49]=2[CH3:48])=[CH:9][CH:8]=1
Reactant: Cc1[nH]c2ccccc2c1CC(=O)O
Reactant: COC(=O)/C=C/c1ccc([C@@H]2CCCN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc([C@@H]2CCCN2C(=O)Cc2c(C)[nH]c3ccccc23)cc1
Reaction time: 16 h
Yield: 92 %

Procedure:
To a stirred solution of (E)-3-((S)-4-pyrrolidin-2-yl-phenyl)-acrylic acid methyl ester hydrochloride (0.3 g, 1.12 mmol) in N,N-dimethylformamide (20 mL) was added sequentially triethylamine (0.5 mL, 3.58 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.24 g, 1.25 mmol), 1-hydroxybenzotriazole (0.17 g, 1.25 mmol) and 2-methylindole-3-acetic acid (0.235 g, 1.24 mmol). The reaction was stirred for 16 h and diluted with dichloromethane, and the solution was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (2% methanol in dichloromethane) to obtain (E)-3-(4-{(S)-1-[2-(2-methyl-1H-indol-3-yl)-acetyl]-pyrrolidin-2-yl}-phenyl)-acrylic acid methyl ester as a colorless oil (0.42 g, 1.03 mmol, 93% yield).
Reaction SMILES: [C:1]([C:3]1[O:7][N:6]=[CH:5][CH:4]=1)#[N:2].[NH2:8][C:9]1[S:10][C:11]([CH3:19])=[CH:12][C:13]=1[C:14](OCC)=O.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:14]1[C:13]2[CH:12]=[C:11]([CH3:19])[S:10][C:9]=2[N:8]=[C:1]([C:3]2[O:7][N:6]=[CH:5][CH:4]=2)[N:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1ccno1
Reactant: CCOC(=O)c1cc(C)sc1N
Product: Cc1cc2c(Cl)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 5-cyanoisoxazole and 2-amino-5-methyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(isoxazol-5-yl)-6-methyl-thieno-[2,3-d]-pyrimidine