Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]1[CH3:34])([CH3:27])[CH3:26]>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:31]3[CH2:32][CH2:33][N:28]([CH:25]([CH3:27])[CH3:26])[C@H:29]([CH3:34])[CH2:30]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: CC(C)N1CCNC[C@H]1C
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C(C)C)[C@H](C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-isopropyl-2-methylpiperazine. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.93 (br. s., 3H) 1.01 (br. s., 2H) 1.16 (br. s., 5H) 2.43 (s, 1H) 2.47 (s, 3H) 2.61 (d, J=12.20 Hz, 1H) 2.75-2.98 (m, 1H) 3.07 (br. s., 1H) 3.29 (br. s., 2H) 4.39 (br. s., 1H) 7.47-7.62 (m, 3H) 7.68 (s, 1H) 7.95-8.11 (m, 2H) 8.44 (s, 1H); ESI-MS m/z [M+H]+ 445.3.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]2[N:16]=[C:15]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][N:22]=3)(=[O:20])=[O:19])[C:14]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])=[C:13]([O:39][CH3:40])[N:12]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[OH-].[Na+].Cl>>[CH:27]([C:24]1[CH:25]=[CH:26][C:21]([S:18]([NH:17][C:15]2[C:14]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])=[C:13]([O:39][CH3:40])[N:12]=[C:11]([C:9]3[CH:8]=[CH:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=3)[N:16]=2)(=[O:19])=[O:20])=[N:22][CH:23]=1)([CH3:29])[CH3:28]
Reactant: COC(=O)c1cc(-c2nc(NS(=O)(=O)c3ccc(C(C)C)cn3)c(Oc3ccccc3OC)c(OC)n2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccnc(C(=O)O)c2)nc1OC
Reaction time: 1 h

Procedure:
To a solution of 56.6 mg of 4-[4-(5-isopropyl-pyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carboxylic acid methyl ester, product of example 43, there were added at RT 0.5 ml of 1N NaOH and the solution was stirred for 1 h until the reaction was complete according to TLC analysis. It was then poured into cold diluted HCl and the product was extracted into EtOAc. The organic layer was washed with water, dried over Na2SO4 and the solvent removed in vacuo. The solid residue was washed with ether then dried in a high vacuum to give 4-[4-(5-isopropyl-pyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carboxylic acid as a light yellow crystalline solid. ISN mass spectrum, m/e 550.1 (M−1 calculated for C26H25N5O7S: 550).
Reaction SMILES: [Li+].[OH-].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]CC)=[O:13])=[CH:7][C:6]=1[O:17][CH3:18])#[N:4].CO>C1COCC1>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][C:6]=1[O:17][CH3:18])#[N:4]
Reactant: CCOC(=O)Cc1ccc(C#N)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CC(=O)O)ccc1C#N

Procedure:
Aqueous LiOH (0.096 g, 2.9 mmol, in 2 mL of water) was added to a stirred solution of ethyl (4-cyano-3-methoxyphenyl)acetate (0.50 g, 2.9 mmol) in THF:CH3OH) 5:1 (23 mL), and the solution was stirred at room temperature overnight. After acidification to pH 3 with 1 N HCl, the aqueous was extracted with AcOEt (2×50 mL). The organic phase was washed with brine, dried (MgSO4), and evaporated under reduced pressure to give the (4-cyano-3-methoxyphenyl) acetic acid, which was used in the next step without further purification. NMR (500 MHz, DMSO-d6), δ 12.52 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.17 (s, 1H), 7.0 (d, J=7.8.0 Hz, 1H), 3.89 (s, 3H), 3.69 (s, 2H); LC/MS (M+1)+=192.16; tR=0.52 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:16]1[N:17]=[C:18]2[CH:25]=[CH:24][CH:23]=[N:22][C:19]2=[N:20][CH:21]=1)=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:16]1[N:17]=[C:18]2[CH:25]=[CH:24][CH:23]=[N:22][C:19]2=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CNc1cnc2ncccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cnc2ncc(NCC3CCCCN3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2 (Pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester (0.48 g) was dissolved in dichloromethane (3 ml), cooled (ice bath) and treated with trifluoroacetic acid (2 ml). The mixture was stirred for 3 hours at room temperature, solvent removed at reduced pressure and the residue co-evaporated with toluene to give the title compound (0.45 g).
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][NH2:27])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[O:29]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][NH:27][C:30](=[O:32])[CH3:31])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCN)c2c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12

Procedure:
The title compound was prepared in analogy to Example 63-1 in Scheme 25 by using N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,3-diamine (prepared in analogy to Example 9-3) and acetic anhydride. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.00-7.97 (m, 1 H), 7.81 (d, J=7.2 Hz, 1 H), 7.76-7.64 (m, 2 H), 7.46-7.42 (m, 2 H), 7.30-7.28 (m, 1 H), 5.99 (s, 1 H), 5.14 (s, 2 H), 4.54 (brs, 2 H), 3.58 (t, 2 H), 3.36 (m, 4 H), 2.42 (s, 3 H), 2.00 (s, 3 H), 1.94-1.87 (m, 2 H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH:20]1([C@@H:26]([NH2:28])[CH3:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([C@@H:26]([NH:28][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH3:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C[C@H](N)C1CCCCC1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)C1CCCCC1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 1) was reacted with (S)-1-cyclohexylethylamine according to the procedure described in EXAMPLE 11, Step C to afford the title compound. Mass Spectrum (ESI): 322.3 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.63 (s, 1H); 8.30 (br s, 1H); 8.23 (br, s, 1H); 7.88 (d, J=7.3 Hz, 1H); 7.43 (m, 2H); 6.80 (d, J=5.2 Hz, 1H); 4.10 (m, 1H); 1.69-1.91 (m, 4H); 1.10-1.35 (m, 10H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].Cl>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:13]=[CH:12]/[C:11]([OH:15])=[O:14])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: C=CC(=O)O
Reactant: COc1cc(I)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC#N
Product: COc1cc(/C=C/C(=O)O)ccc1Br
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-bromo-4-iodo-2-methoxybenzene (L. A. Hasvold et al., US 2004/0254159) in MeCN (1.1 M) was added acrylic acid (1.24 eq.), TEA (2.5 eq.) and palladium acetate (0.03 eq). The reaction mixture was heated to 90° C. for 40 min, cooled to RT and poured into 1N HCl. After sting for 30 min, the solid was filtered, heated to reflux in EtOH (2.3 M), allowed to cool to RT and stirred overnight. The solid was filtered and washed with 1:1 EtOH:hexane to give the desired product 119. LRMS ESI+ (M+H)+ 257.0.
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][CH2:6][CH3:7])[CH:3]=[O:4].[CH2:8]([O:10][C:11](=[O:15])[CH2:12][N+:13]#[C-:14])[CH3:9]>>[CH2:8]([O:10][C:11]([CH:12]1[CH:3]([C:2]([CH2:5][CH2:6][CH3:7])=[CH2:1])[O:4][CH:14]=[N:13]1)=[O:15])[CH3:9]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C=C(C=O)CCC
Product: C=C(CCC)C1OC=NC1C(=O)OCC

Procedure:
The starting material is manufactured as follows: Reaction of 2-methylene-pentanal with isocyanoacetic acid ethyl ester analogously to Example 1 yields 5-(penten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester. By hydrolysis of the 5-(penten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester in a manner analogous to that described in Example 15, 2-formylamino- 3-hydroxy-4-propyl-4-pentenoic acid ethyl ester is obtained. Reaction of the 2-formylamino-3-hydroxy-4-propyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethyl phosphite in a manner analogous to that described in Example 1 yields E-2-formylamino-4-propyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1)=[O:13].Br[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:31][CH:30]=1>>[CH3:24][O:23][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[O:1][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:31][CH:30]=2)[C:6]([O:8][CH3:9])=[O:7])=[O:13])[CH2:16]1)=[O:22]
Reactant: COC(=O)c1ccc(O)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Reactant: BrCCOc1ccc(OCCCCOc2ccccc2)cc1
Product: COC(=O)c1ccc(OCCOc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 22 from the (+)-B-enantiomer of methyl 4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate (see Example IX, method 2) and 1-(2-bromoethoxy)-4-(4-phenoxybutoxy)benzene.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[C:8]([CH2:19][CH2:20][CH3:21])=[CH:9][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:22].F[C:24]1[CH:33]=[CH:32][C:27]([C:28]([NH:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.C1CCN2C(=NCCC2)CC1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:31][NH:30][C:28](=[O:29])[C:27]1[CH:32]=[CH:33][C:24]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:10]3[CH:9]=[C:8]([CH2:19][CH2:20][CH3:21])[C:6]4[O:7][CH:2]([CH3:1])[C:3](=[O:22])[NH:4][C:5]=4[CH:11]=3)[CH2:18][CH2:17]2)=[CH:25][CH:26]=1
Reactant: CNC(=O)c1ccc(F)cc1
Reactant: CCCc1cc(CN2CCNCC2)cc2c1OC(C)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CCCc1cc(CN2CCN(c3ccc(C(=O)NC)cc3)CC2)cc2c1OC(C)C(=O)N2
Temperature: 120 °C
Reaction time: 4 h
Yield: 18.6 %

Procedure:
In a 20 mL scintillation vial was added 2-methyl-6-(piperazin-1-ylmethyl)-8-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one 358E (67 mg, 0.221 mmol) and 4-fluoro-N-methylbenzamide (50.7 mg, 0.331 mmol) in DMSO (1.104 mL) and stirred at 120° C. for 4 h. DBU (0.133 mL, 0.883 mmol) was added and the reaction mixture was stirred at 120° C. for 18 h. The reaction was concentrated in vacuo to remove DBU, and then K2CO3 (61.0 mg, 0.442 mmol) was added. The mixture was heated overnight at 120° C. The reaction was subsequently filtered and the crude material was purified by prep HPLC 20-45% acetonitrile in water. The appropriate fractions were collected and concentrated in vacuo to give the title compound as a yellow solid (18 mg, 0.041 mmol, 18.67% yield). 1H NMR (DMSO-d6, 400 MHz): δ=10.89 (s, 1H), 10.73 (br. s., 1H), 8.04 (br. s., 1H), 7.75 (d, J=8.8 Hz, 1H), 7.24 (s, 1H), 7.11 (s, 1H), 6.95-7.04 (m, 2H), 6.87 (d, J=2.0 Hz, 1H), 4.66-4.72 (m, 1H), 4.64 (d, J=6.6 Hz, 2H), 3.26 (t, J=7.1 Hz, 2H), 3.03 (q, J=6.7 Hz, 2H), 2.30-2.45 (m, 3H), 1.61-1.67 (m, 2H), 1.55 (d, J=6.8 Hz, 5H), 1.40 (d, J=6.8 Hz, 3H), 0.86-0.93 ppm (m, 3H). ESI-MS: m/z 437.4 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-].[CH3:16][N:17](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][CH:3]=[C:2]2[C:16]#[N:17])=[CH:7][CH:8]=1
Reactant: COc1ccc2cccc(Br)c2c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Cl-]
Product: COc1ccc2cccc(C#N)c2c1
Temperature: 120 °C
Reaction time: 15 h
Yield: 51 %

Procedure:
A mixture of 1-bromo-7-methoxy-naphthalene (3.26 g, 13.8 mmol), Zn(CN)2 (2.26 g, 19.2 mmol), and tetrakis(triphenylphosphine)palladium (1.6 g, 1.4 mmol) in DMF (50 mL) was stirred at 120° C. for 15 hr. The cooled reaction mixture was poured into 200 mL 1 N NH4Cl solution and extracted with ethyl acetate (3×350 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, evaporation of the solvent, and purification on a silica column (10% ethyl acetate—hexanes) yielded 1.28 g (51%) of the title compound as a white solid: mp 62-66° C.; 1H NMR (DMSO-d6): δ 4.00 (3H, s), 7.25 (1H, dd, J=2.48 Hz, J=8.96 Hz), 7.36-7.47 (1H, m), 7.47 (1H, d, J=2.39 Hz), 7.81 (1H, d, J=9.00 Hz), 7.88 (1H, dd, J=0.81 Hz, J=7.23 Hz), 8.00 (1H, d, J=8.21 Hz); MS (EI) m/z 183 (M)+;
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:26])=[C:16]([CH:25]=1)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O.[OH-].[Na+]>CCOCC.O>[CH2:17]([C:16]1[CH:25]=[C:12]([CH:13]=[CH:14][C:15]=1[Cl:26])[NH2:11])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(Cl)c(C(=O)c2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: Nc1ccc(Cl)c(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
6.8 g of lithium aluminium hydride, followed by 44.4 g of aluminium chloride and then 22 g of 5-amino-2-chlorobenzophenone dissolved in anhydrous ether are added in small amounts, under a nitrogen atmosphere, into 1000 ml of anhydrous ether which is cooled to 0° C. After stirring for 2 hours and under reflux, the excessive reagents are decomposed by very slowly adding 7 ml of 15% caustic soda and, finally, 21 ml of water. After filtering and washing the precipitate with 2×200 ml of ether, the organic phase is washed, dried over Na2SO4 and then evaporated to dryness under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.C1(S([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)=[CH:20]2)(=O)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:30]2[N:29]=[C:28]([C:21]3[C:22]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[NH:19][CH:20]=3)[CH:33]=[CH:32][N:31]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)c1
Yield: 29.2 %

Procedure:
Using the procedure of example 1, m-anisidine (100 mg) was reacted with compound 1f (100 mg) to provide compound 6 (25 mg, 29%). 1H NMR (400 MHz, CD3OD) δ 8.84 (d, J=8.0 Hz, 1H), 8.33 (d, J=5.2 Hz, 1H), 8.31 (d, J=4.8 Hz, 1H), 8.12 (s, 1H), 7.48 (m, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.23 (m, 2H), 7.13 (d, J=5.2 Hz, 1H), 6.68 (d, J=8.0 Hz, 1H), 3.86 (s, 3H). MS (ESI) m/z: 318 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24]([OH:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31].[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37]>CN(C)C=O.C(C(C)=O)C>[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37].[C:29]([O:26][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24](=[O:25])[N:16]1[CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)(=[O:33])[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)C(=O)Cl
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CC(C)C(=O)OC1c2ccccc2C(=O)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 2 h
Yield: 35.4 %

Procedure:
15 A solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1pyridyl)propyl]-3-hydroxy-1-isoindolinone (7 g) in anhydrous dimethylformamide (75 cc) is added to a suspension of sodium hydride (as a 50% suspension in oil) (1 g) in anhydrous dimethylformamide (25 cc) at a temperature close to 20° C. in the course of 10 minutes and agitation is continued for 2 hours. Then, 2.3 g of isobutyryl chloride is added in the course of 5 minutes, and agitation is continued for a further 20 hours. The suspension obtained is poured into distilled water (100 cc) and extracted with methylene chloride (4×50 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methyl ethyl ketone (45 cc). A solution of oxalic acid (1.5 g) in methyl ethyl ketone (35 cc) is added and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration and recrystallized from boiling methanol (200 cc). 3 g of 3-isobutyryloxy-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 164° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.C(N(CC)CC)C.O>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:14][C@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)C1
Temperature: 90 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (166 mg, 0.774 mmol), tert-butyl (3S)-3-aminopiperidine-1-carboxylate (from Aldrich, 186 mg, 0.929 mmol) and triethylamine (0.32 mL, 2.3 mmol) in isopropyl alcohol (1.8 mL) was stirred at 90° C. for 2 h. After cooling to room temperature, solids were observed. Water was added which caused more solids to form. The yellow solids were filtered, washed with water, and dried to give 0.26 g of the desired product. LCMS calculated for C17H23N4O4S (M+H)+: m/z=379.1. Found: 379.0. 1H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 9.29 (s, 1H), 7.84 (d, J=5.5 Hz, 1H), 7.49 (d, J=5.5 Hz, 1H), 4.42 (m, 1H), 3.83 (m, 1H), 3.46 (m, 3H), 2.12 (m, 1H), 1.83 (m, 3H), 1.41 (s, 9H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]2[C:8]([C:16]#[C:17][Si](C)(C)C)=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1COCC1>[C:16]([C:8]1[C:7]2[CH:22]=[CH:23][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[S:10][C:9]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[CH:17]
Reactant: CCOC(=O)c1sc2cc([N+](=O)[O-])ccc2c1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: C#Cc1c(C(=O)OCC)sc2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 6-nitro-3-[(trimethylsilyl)ethynyl]-1-benzothiophene-2-carboxylate obtained in Example (183c) (110 mg, 0.32 mmol) was dissolved in ethanol (8 mL) and THF (8 ml). Potassium carbonate (13 mg, 0.1 mmol) was added, and the mixture was stirred at room temperature for four hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:19]=[C:18]([Cl:20])[C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH:15]([CH3:17])[CH3:16])[CH:9]=2)=[C:5]([Cl:21])[CH:4]=1.[O:22]1[C:26](=[O:27])[NH:25][C:24](=[O:28])[NH:23]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.Cl>[Cl:21][C:5]1[CH:4]=[C:3]([CH:19]=[C:18]([Cl:20])[C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH:15]([CH3:17])[CH3:16])[CH:9]=1)[CH2:2][N:23]1[C:24](=[O:28])[NH:25][C:26](=[O:27])[O:22]1
Reactant: O=c1[nH]oc(=O)[nH]1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(CBr)cc2Cl)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1cc(Oc2c(Cl)cc(Cn3oc(=O)[nH]c3=O)cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To a solution of the title compound of Step B (59 mg, 0.15 mmol) and [1,2,4]oxadiazolidine-3,5-dione (16 mg, 0.15 mmol) in DMF (1.5 ml) at room temperature was added sodium carbonate (32 mg, 0.30 mmol). After stirring at room temperature for about two hours, the solution was diluted with 0.5N HCl (10 ml) and extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (3×15 ml), brine (15 ml), dried, filtered, and concentrated. The crude product was purified by preparative TLC (22% methanol/3.5% water/74.5% chloroform) to afford the title compound (61 mg). MS (APCI−) Calc: 410.0, found: 409.1 (M−1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=3)[C:10]2=O)=[CH:5][CH:4]=1)#[N:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:36]2)=CC=1>C1(C)C(C)=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=3)[C:10]2=[S:36])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)CCc1ccc(N2CCN(c3ccc(C#N)cc3)C2=O)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Product: COC(=O)CCc1ccc(N2CCN(c3ccc(C#N)cc3)C2=S)cc1

Procedure:
Prepared by heating 1-(4-cyano-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one with 2,4-bis-(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetan-2,4-disulphide in xylene.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]5[S:25][CH:26]=[CH:27][CH:28]=5)[CH:22]=4)[NH:17][C:16]=3[OH:29])=[N+:12]([O-])[CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.P(Cl)(Cl)[Cl:31].Cl>C(Cl)(Cl)Cl.CO.C(OCC)C>[ClH:31].[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]5[S:25][CH:26]=[CH:27][CH:28]=5)[CH:22]=4)[NH:17][C:16]=3[OH:29])=[N:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1cc(CN2CCOCC2)ccc1-c1c(O)[nH]c2ccc(-c3cccs3)cc12
Reactant: ClP(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOCC
Product: Oc1[nH]c2ccc(-c3cccs3)cc2c1-c1ccc(CN2CCOCC2)cn1
Yield: 9 %

Procedure:
The title compound was prepared as described for Example 86 using 3-[5-(morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-5-thien-2-yl-1H-indol-2-ol and phosphorus trichloride. The base was dissolved in chloroform/methanol, (3:1), and a solution of HCl in diethyl ether (1 M) was added until acidic pH. The formed precipitation was filtered, washed with diethyl ether and dried. Yield: 9% of the title compound as an yellow solid: 1H NMR (DMSO-d6, 400 MHz) δ 11.10 (br s, 1 H), 10.55 (s, 1 H), 8.21 (s, 1 H), 8.02-7.90 (m, 1 H), 7.85-7.62 (m, 2 H), 7.54-7.46 (m, 1 H), 7.46-7.37 (m, 1 H), 7.18 (d, J=8 Hz, 1 H), 7.15-7.06 (m, 1 H), 6.92 (d, J=8 Hz, 1 H), 4.24 (s, 2 H), 4.03-3.89 (m, 2 H), 3.84-3.51 (m, 2 H), 3.39-3.28 (m, 2 H) 3.16-3.05 (m, 2 H); MS (ES) m/s 392 (M++1).