Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[CH2:22]([C@H:24]([NH:31][C:32]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:37]=[C:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:35]=1[O:50][CH2:51][CH2:52][NH2:53])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:23].C1CCC(N=C=NC2CCCCC2)CC1.O(C(C)C)C(C)C>C(Cl)Cl>[CH2:22]([C@H:24]([NH:31][C:32]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:37]=[C:36]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:35]=1[O:50][CH2:51][CH2:52][NH:53][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:23]
Reactant: O=C(O)Cc1ccncc1
Reactant: CC[C@H](NC(=O)c1c(OCCN)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: CC[C@H](NC(=O)c1c(OCCNC(=O)Cc2ccncc2)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
0.41 g (2.4 mmol) of 4-pyridylacetic acid hydrochloride were suspended in 80 ml of CH2Cl2; the suspension was cooled to 0° C. and 0.33 ml (2.4 mmol) of TEA, 0.64 g (4.7 mmol) of HOBT and 1.0 g (2.4 mmol) of (S)-N-(α-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide (compound of Description 4) were added. 0.58 g (2.8 mmol) of DCC, dissolved in 10 ml of CH2Cl2, were added dropwise and the reaction mixture was stirred at 0° C. for 1 h and at room temperature overnight. The precipitated dicyclohexylurea was filtered off and the filtrate was washed with 20% citric acid, sat. sol. NaCl and brine, dried over Na2SO4 and evaporated in vacuo to dryness. The crude product was purified by flash column chromatography on 230-400 mesh silica gel, eluting with a mixture of CH2Cl2/MeOH 95:5 containing 0.5% NH4OH (28%), to yield, after trituration with i-Pr2O, 0.85 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[C:21](Cl)[CH:20]=3)=[CH:14][C:13]=2[OH:28])=[O:10])=[CH:4][CH:3]=1.NC1C=CC(OC2C(C)=CC([Cl:44])=CC=2Cl)=CC=1O.BrC1C=CC(CC(O)=O)=CC=1.[F:58][C:59]([F:70])([F:69])[C:60]1[CH:61]=[C:62](B(O)O)[CH:63]=[CH:64][CH:65]=1>>[Cl:44][C:20]1[CH:21]=[C:22]([Cl:26])[CH:23]=[C:24]([CH3:25])[C:19]=1[O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:64]3[CH:63]=[CH:62][CH:61]=[C:60]([C:59]([F:70])([F:69])[F:58])[CH:65]=3)=[CH:3][CH:4]=2)=[C:13]([OH:28])[CH:14]=1
Reactant: Cc1cc(Cl)cc(Cl)c1Oc1ccc(N)c(O)c1
Reactant: Cc1cc(Cl)c(Cl)cc1Oc1ccc(NC(=O)Cc2ccc(Br)cc2)c(O)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C(O)Cc1ccc(Br)cc1
Product: Cc1cc(Cl)cc(Cl)c1Oc1ccc(NC(=O)Cc2ccc(-c3cccc(C(F)(F)F)c3)cc2)c(O)c1

Procedure:
The resin-bound 2-(4-bromo-phenyl)-N-[2-Hydroxy-4-(3,4-dichloro-6-methyl-phenoxy)-phenyl]-acetamide (120 mg, 0.1 mmol, obtained from coupling reaction between the resin bound 2-Amino-5-(2,4-dichloro-6-methyl-phenoxy)-phenol and 4-bromophenyl acetic acid following the general procedure A) was reacted with 3-trifluormethyl-phenyl boronic acid (56.7 mg, 0.3 mmol) as described in the general procedure D followed by cleavage as described in example 1, to afford (27.5 mg) of title compound.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.C(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:7][C:1](=[O:6])[CH:2]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(O)CC(c2ccccc2)O1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 13.67 g methyl acetoacetate, 8.5 g of NaH 60% dispersion in oil, 73.6 mL of 1.6 M n-butyl lithium in hexane, 10 g of benzaldehyde, and 300 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred 15 minutes at -78° C. then allowed to warm to room temperature overnight. A solid was filtered off after concentration (m.p. 145-146° C.). 1H NMR (CDCl3) δ 2.8-3.05 (m, 2 H), 3.5 (d, 1 H), 3.7 (d, 1 H), 5.7 (dd, 1 H), 7.3-7.5 (m, 5 H).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[CH2:42]([O:46][CH2:47][CH2:48][CH2:49][NH2:50])[CH2:43][CH2:44][CH3:45]>C1COCC1>[CH2:42]([O:46][CH2:47][CH2:48][CH2:49][NH:50][C:30]([C:28]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[C:9]([CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][C:11]=2[CH:29]=1)=[O:31])[CH2:43][CH2:44][CH3:45]
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Reactant: CCCCOCCCN
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CCCCOCCCNC(=O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of 3-butoxypropylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 556.3 (M+H)+.
Reaction SMILES: [O:1]1CCN=[C:2]1[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].N1CCCC1=[O:18].ClCC(O)=O>>[N:7]1([CH2:6][C:2]([OH:1])=[O:18])[CH2:11][CH2:10][CH2:9][C:8]1=[O:12]
Reactant: O=C1CCCN1CC1=NCCO1
Reactant: O=C1CCCN1
Agent: O=C(O)CCl
Product: O=C(O)CN1CCCC1=O

Procedure:
1-[(2-oxazolin-2-yl)methyl]-2-pyrrolidone, for example, can be obtained by condensation of pyrrolidone and chloroacetic acid to form 2-pyrrolidone acetic acid, where m=1 in the above formula (II), or, alternatively, by condensing butyrolactone with glycine, and the starting carboxylic acid condensed with ethanolamine and cyclodehydrated to form 1-[(2-oxazolin-2-yl)methyl]-2-pyrrolidone.
Reaction SMILES: [CH3:1][C@H:2]1[C@:14]23[CH:17]=[C:18]([CH3:21])[C@H:19]([OH:20])[C@@:13]2([OH:22])[C@H:12]([OH:23])[C:11]([CH2:24][OH:25])=[CH:10][C@H:9]([C:15]3=[O:16])[C@@H:5]2[C:6]([CH3:8])([CH3:7])[C@@H:4]2[CH2:3]1.O.[C:27]1(C)[CH:32]=CC(S(O)(=O)=O)=C[CH:28]=1.[CH3:38][C:39]([CH3:41])=O>>[CH3:1][CH:2]1[C:14]23[CH:17]=[C:18]([CH3:21])[CH:19]4[O:20][C:39]([CH3:41])([CH3:38])[O:22][C:13]24[CH:12]2[C:11]([CH2:24][O:25][C:27]([CH3:32])([CH3:28])[O:23]2)=[CH:10][CH:9]([C:15]3=[O:16])[CH:5]2[C:6]([CH3:8])([CH3:7])[CH:4]2[CH2:3]1
Reactant: CC(C)=O
Reactant: CC1=C[C@]23C(=O)[C@@H](C=C(CO)[C@@H](O)[C@]2(O)[C@H]1O)[C@H]1[C@@H](C[C@H]3C)C1(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC1=CC23C(=O)C(C=C4COC(C)(C)OC4C24OC(C)(C)OC14)C1C(CC3C)C1(C)C

Procedure:
Ingenol can be converted to ingenol-3,4-acetonide by treatment with 4-toluenesulphonic acid hydrate and acetone to give ingenol-3,4:5,20-diacetonide followed by treatment with perchloric acid in methanol or zinc bromide in dichloromethane and methanol according to the method of Opferkuch et al. (1981). Ingenol-3,4-acetonide could be converted to ingenol-3,4-acetonide-20-trityl ether by treatment with trityl chloride and 4-(N,N-dimethylamino)pyridine in dry pyridine, acylated in an analogous manner to that described in Example 1 or Example 3 to give the ingenol-3,4-acetonide-20-trityl ether 5-acylate then treated with methanolic perchloric acid according to the method of Example 15 or Example 18 to give the ingenol 5-acylate. The ingenol 5-acylate could then be converted to the ingenol-3,4-acetonide 5-acylate by treatment with 4-toluenesulphonic acid hydrate and acetone according to the method of Opferkuch et al. (1981). The ingenol-3,4-acetonide 5-acylate could be converted to the 20-chloro-20-deoxy-3,4-acetonide 5-acylate by the method of Example 15.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][CH:4]=1.C([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])C.[C:25](Cl)(=[O:32])[C:26]1C=CN=C[CH:27]=1.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:25](=[O:32])[C:26]3[CH:22]=[CH:21][N:20]=[C:23]([CH3:24])[CH:27]=3)[S:11][C:7]=2[C:6]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1ccc(-c2cccs2)c2sc(N)nc12
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2cccs2)c2sc(NC(=O)c3ccnc(C)c3)nc12
Yield: 58 %

Procedure:
0.21 g of 4-methoxy-7-thiophen-2-yl-benzothiazol-2-yl-amine (0.0008 Mol) together with 0.27 ml triethylamine (0.002 Mol), 0.01 g of DMAP and 0.20 g isonicotinic acid chloride (0.001 Mol) were heated to reflux for 20 hrs. in dioxane (10 ml). After cooling to room temperature water (20 ml) and sat. NaHCO3 (15 ml) were added. A precipitation formed, which was filtered, washed with water and dried. This crude product was subjected to column chromatography (silicagel, ethyl acetate) to yield the title compound as a yellow solid (58%); F.p.: 203-211° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH:8]([NH:12][C:13](=O)OC(C)(C)C)[CH2:7]2.[CH3:20][OH:21].CCO[CH2:25][CH3:26]>>[C:25]1([CH2:26][N:12]([CH3:13])[CH:8]2[CH2:7][C:6]3[C:11]4=[C:2]([NH:1][C:20](=[O:21])[N:10]4[CH2:9]2)[CH:3]=[CH:4][CH:5]=3)[CH:4]=[CH:3][CH:2]=[CH:11][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1CNc2c(N)cccc2C1
Reactant: CCOCC
Reactant: CO
Product: CN(Cc1ccccc1)C1Cc2cccc3[nH]c(=O)n(c23)C1

Procedure:
This compound was prepared by following the procedure of Example 44 part B, but substituting 1,2,3,4-tetrahydro-N3 -methyl-N3 -(phenylmethyl)quinoline-3,8-diamine for t-butyl (8-amino-1,2,3,4-tetrahydro-3-quinolyl)carbamate. The bulk of the product was converted to the hydrochloride salt, mp 145°-149° C. from methanol/ether.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([O:18][C:19](=[O:25])[NH:20][CH:21]1[CH2:24][NH:23][CH2:22]1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19](=[O:25])[NH:20][CH:21]1[CH2:24][N:23]([CH:10]2[CH2:11][CH2:12][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)[CH2:22]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: O=C1CCC(c2ccccc2)CC1
Product: CC(C)(C)OC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-phenyl-cyclohexanone and azetidin-3-yl-carbamic acid tert-butyl ester using the procedure described in Step D of Example 1.
Reaction SMILES: [CH3:1][CH:2](C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[C:14]([CH2:19][CH:20]1[C:25](=[O:26])[CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:22][CH2:21]1)([O:16]CC)=O.O1C2C=CCCC2CC1=O>C1(C)C=CC=CC=1>[C:27]1([C:23]2[CH2:22][CH2:21][C@H:20]3[CH2:19][C:14](=[O:16])[O:26][C@H:25]3[CH:24]=2)[CH:28]=[CH:29][CH:30]=[CH:2][CH:1]=1
Reactant: CC(C)[O-]
Reactant: CCCCC1=CC(=O)C(CC(=O)OCC)CC1
Agent: O=C1CC2CCC=CC2O1
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: O=C1C[C@@H]2CCC(c3ccccc3)=C[C@@H]2O1
Yield: 83.7 %

Procedure:
The reaction of 7.12 g (34.8 mmoles) of aluminum isopropoxide in 100 ml of toluene with 1.5 g (5.8 mmoles) of 6-(carbethoxymethyl)-3-n-butyl-2-cyclohexen-1-one was conducted in a similar manner to the synthesis of 3a,4,5,7a-tetrahydro-2(3H)-benzofuranone described in Example I. The crude material was purified by crystallization from hexane to yield 1.04 g (84%) of cis 6-phenyl-3a,4,5,7a-tetrahydro-2(3H)-benzofuranone, mp 90°-92° C. NMR and IR confirm the structure of the compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][NH:30][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=1)[CH3:36]
Reactant: CS(=O)(=O)c1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Reactant: CCOC(=O)CN
Product: CCOC(=O)CNc1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1

Procedure:
The product of Example 47, and ethyl glycinate were reacted by the procedure of Example 60 to afford the title compound [4,8-bis-(2-chloro-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-acetic acid ethyl ester. 1H-NMR (CDCl3) δ 1.21 (m, 3H), 3.59 (m, 2H), 4.12 (m, 2H), 5.91 (br s, 1H), 6.41 (m, 2H), 7.25-7.62 (m, 9H). LC MS (m/e)=469 (MH+). Rt=2.12 min
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[N:55]1([C:61]2[CH:68]=[CH:67][CH:66]=[CH:65][C:62]=2[C:63]#[N:64])[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1.FC(F)(F)C(O)=O>ClCCl.C(N(CC)CC)C>[CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30]([N:58]1[CH2:59][CH2:60][N:55]([C:61]2[CH:68]=[CH:67][CH:66]=[CH:65][C:62]=2[C:63]#[N:64])[CH2:56][CH2:57]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: N#Cc1ccccc1N1CCN(C(=O)C2CC(NCc3ccc(F)cc3F)CN2Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.7 %

Procedure:
The mixture of 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (50.0 mg, 0.268 mmol), N-hydroxybenzotriazole (19.0 mg, 0.134 mmol), and 2-piperazin-1-yl-benzonitrile (46.7 mg, 0.25 mmol), triethylamine (0.05 ml) in dry dichloromethane (2 ml) was stirred overnight at rt, and then treated with trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for another 5 h and concentrated. The residue was purified by preparative HPLC on reversed phase eluting with an acetonitrile/water [0.1% aq NH3 (25%)] gradient to afford the title compound (6.7 mg, 9.7%) as a light yellow oil. MS m/e=516.4 [M+H]+.
Reaction SMILES: C1CCCCC1.C([N-]C(C)C)(C)C.[Li+].[C:15]([O:18]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:17])[CH3:16].[C:38]([O:58][CH:59]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)(=[O:57])/[CH:39]=[CH:40]\[C:41]([O:43][CH:44]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42]>C(O)(=O)C.O>[C:15]([CH2:16][CH:40]([CH2:39][C:38]([O:58][CH:59]([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1)=[O:57])[C:41]([O:43][CH:44]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:42])([OH:18])=[O:17]
Reactant: O=C(/C=C\C(=O)OC(c1ccccc1)c1ccccc1)OC(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CC(CC(=O)OC(c1ccccc1)c1ccccc1)C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 28.9 %

Procedure:
The reaction product obtained by conducting the Michael-addition reaction in the same manner as in Example 116 using 5.7 ml of a 1.5M cyclohexane solution of lithium diisopropylamide, 2.6 g of trityl acetate and 3.2 g of dibenzhydryl maleate, was dissolved in a liquid mixture of 20 ml of acetic acid and 5 ml of water, and the solution was left to stand at room temperature overnight and then evaporated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform/methanol=100/1→10/1) to obtain 1.05 g (yield: 29%) of the above-identified compound as white crystalline powder having a melting point of from 105° to 106° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.[N:20]1([C:26]([CH3:31])([CH3:30])[C:27]([NH2:29])=[O:28])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(OC)(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:23]3[CH2:22][CH2:21][N:20]([C:26]([CH3:31])([CH3:30])[C:27]([NH2:29])=[O:28])[CH2:25][CH2:24]3)=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC(C)(C(N)=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: COC(OC)OC
Product: Cc1c(CN2CCN(C(C)(C)C(N)=O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reaction time: 17 h
Yield: 73.6 %

Procedure:
To a solution of 2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (1.00 g, 3.36 mmol) in DCE (50 mL) was added 2-(piperazin-1-yl)isobutyramide (630 mg, 3.69 mmol), trimethyl orthoformate (3.67 mL, 33.58 mmol) and acetic acid (0.19 mL, 3.36 mmol). After stirring at room temperature for 3 h sodium triacetoxyborohydride (1.10 g, 5.03 mmol) was added and the resulting mixture stirred for a further 17 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH/DCM. The resultant residue was triturated with MeOH to give 2-[4-(2-Chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide as a white solid (1.12 g, 74%). LCMS (Method C): RT=2.88 min, [M+H]+ 453
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:17][CH:16]=1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:28]3[CH2:29][CH2:30][N:25]([C:18]4[C:19]5[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=5)[N:15]=[CH:16][CH:17]=4)[CH2:26][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc2c(N3CCNCC3)ccnc2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(c2ccnc3ccccc23)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(4-quinolinyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 64% overall yield. mp 150-151°. FDMS m/e=402 (M+ of free base). α[D]589=−12.41 (c=0.76, methanol)
Reaction SMILES: [C:1]1([CH3:35])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.O>[C:1]1([CH3:35])[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)CCC3)cc1
Temperature: 50 °C
Reaction time: 7.5 h

Procedure:
Ethyl 7-(2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1) was dissolved in THF (94 ml) and lithium hydroxide monohydrate (7.79 g, 186 mmol) in water (94 ml) was added dropwise. The reaction mixture was warmed to 50° C. and stirred for 7.5 hours. The reaction mixture was concentrated in vacuo to remove the THF and diluted with water (500 ml). The pH of the aqueous layer was adjusted to pH 2 with 1 N HCl (100 ml) and extracted with EtOAc (3×500 ml). The combined organic layers were washed with brine (200 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude solid was suspended in TBME/hexane (1:1, 100 ml) and rotated on the rotary evaporator (no vacuum) at RT until crystals formed. The solid was removed by filtration, washed with heptanes (50 ml) and dried at RT overnight. The solid was re-crystallized from a hot mixture of EtOH (211 ml) and water (159 ml). After seeding and stirring for 1 h at 5° C., the crystals were filtered off and the product dried overnight at 40° C. in a vacuum oven to afford the title compound; See Table 4 for characterising data.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:11][N:12]([CH3:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([C:27]#[CH:28])[CH:24]=[CH:25][CH:26]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.[Cu](I)I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:18][N:12]([CH2:11][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:2]=1[C:28]#[C:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:29])[F:30])[CH:22]=1)[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CN(C)Cc1nc2ccccn2c1I
Reactant: C#Cc1cccc(C(F)(F)F)c1
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)Cc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.8 %

Procedure:
In a flask placed under an argon flow, 0.093 g (0.212 mmol) of methyl 2-(((3-iodoimidazo[1,2-a]pyridin-2-yl)methyl)(methyl)amino)acetate were dissolved in 0.5 ml of dimethylformamide with magnetic stirring. To this solution, were added: 0.004 g (0.021 mmol) of copper iodide, 0.037 ml (0.255 mmol) of 3-trifluoromethylphenylacetylene and 0.444 ml (3.18 mmol) of triethylamine. The reaction medium was degassed with argon for 10 min before adding 0.019 g (0.021 mmol) of Pd2(dba)3. The mixture was stirred at r.t. for 16 h before being treated, diluted with 15 ml of ethyl acetate and washed with 2×15 ml of a saturated NaCl aqueous solution. The aqueous phase was extracted with 20 ml of ethyl acetate. The combined organic phases were dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: ethyl acetate 100%). 0.05 g (yield=57%) of methyl 2-(methyl((3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)acetate were obtained as a pale brown solid. LC-MS: m/z=402 (MH+); UV purity at 254 nm=96%. 1H NMR (300 MHz, DMSO) δ 8.75 (d, J=6.7 Hz, 1H), 8.11 (s, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.83-7.59 (m, 3H), 7.55-7.37 (m, 1H), 7.14 (td, J=6.8, 0.9 Hz, 1H), 3.97 (s, 2H), 3.58 (s, 3H), 3.43 (s, 2H), 2.39 (s, 3H).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[O:10])[CH2:5][CH2:4]1)#[N:2].O.[SH-:21].[Na+].Cl.C(NCC)C>CN(C)C=O>[CH3:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[NH:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([C:1](=[S:21])[NH2:2])[CH2:4][CH2:5]1)=[O:10]
Reactant: Cc1ccc(C)c(NC(=O)N2CCC(C#N)CC2)c1
Reactant: [SH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(NC(=O)N2CCC(C(N)=S)CC2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-cyano-N-(2,5-dimethylphenyl)piperidinecarboxamide (i.e. the product of Example 14, Step A) (12.75 g, 49.6 mmol), sodium hydrosulfide hydrate (11.1 g, 150 mmol) and diethylamine hydrochloride (10.9 g, 100 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 3 days. The resulting thick, green suspension was added dropwise into ice water (600 mL). The resulting solid was filtered, washed with water and air-dried to give 12.5 g of the title compound as a tan solid decomposing at 155-156° C.