Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)C)=O)=NC([O:5][CH:6](C)[CH3:7])=O.[OH:15][C@H:16]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:43]=[N:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=2)=[CH:38][CH:37]=1)[C@H:17]([CH2:21][CH2:22][N:23]1[C:28](=[O:29])[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]=[N:24]1)[C:18]([OH:20])=[O:19].C(P(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1>[C:6]([O:15][C@H:16]([CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[CH:43]=[N:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=2)=[CH:40][CH:41]=1)[C@H:17]([CH2:21][CH2:22][N:23]1[C:28](=[O:29])[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]=[N:24]1)[C:18]([OH:20])=[O:19])(=[O:5])[CH3:7]
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: COc1ccc(-c2ccc(CC[C@@H](O)[C@H](CCn3nnc4ccccc4c3=O)C(=O)O)cc2)cn1
Agent: CCCCP(CCCC)CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(CC[C@@H](OC(C)=O)[C@H](CCn3nnc4ccccc4c3=O)C(=O)O)cc2)cn1
Reaction time: 1 h
Yield: 73.5 %

Procedure:
Diisopropyl azodicarboxylate (63 mg) was added to a solution of compound (100 mg) obtained from Example 1A above, tri-n-butylphosphine (93 mg) and acetic acid (1 ml) in dry tetrahydrofuran (3 ml) at 0° C. Reaction mixture was stirred for 1 hour and concentrated. Residue was taken in ethyl acetate and washed with water and brine. Organic layer was concentrated to get oily residue which was purified on preparative thin layer chromatography (2 mm thickness) using 10% methanol in dichloromethane to get the title compound (80 mg) (formed probably by esterfication of acetic acid (used in large excess) and not due to Mitsunobu reaction). Mass (m/z): 517.06 (M++1); 1HNMR: δ 8.37 (m, 2H), 8.15 (d, 1H, J=8 Hz), 7.97-7.93 (m, 1H), 7.82-7.80 (m, 1H), 7.41 (d, 2H, J=8 Hz), 7.20 (d, 2H, J=8 Hz), 6.83 (d, 1H, J=8 Hz), 5.28-5.27 (m, 1H), 4.56-4.58 (m, 2H), 4.01 (s, 3H), 2.85-2.80 (m, 1H), 2.55-2.75 (m, 2H), 2.31-2.29 (m, 2H), 2.25-2.10 (m, 2H), 2.063 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].O.NN>C(O)C.[Pd]>[CH3:3][CH:2]([C:4]1[CH:5]=[C:6]([O:10][C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(C)c1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)c1cccc(Oc2ccc(N)cn2)c1
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
2-{[3-(1-methylethyl)phenyl]oxy}-5-nitropyridine (Intermediate 23, 1.39 g) was dissolved in ethanol (25 mL). Hydrazine monohydrate (0.524 mL, 1076 mmol) and palladium on carbon (401 mg, 0.377 mmol) were added. The reaction mixture was heated at reflux under argon for 1 hour. The reaction was cooled down and then filtered on celite. The organic phase was evaporated under vacuum. The residue was purified by flash chromatography on silica (Companion instrument, 120 g silica cartridge, gradient cyclohexane/ethylacetate from 100/0 to 30/70 in 15 min then 30/70 during 30 min). Evaporation afforded the title compound as a yellow oil (821 mg).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:10]=[C:9]([N:11]2[CH:15]([CH3:16])[C:14](=[O:17])[C:13]([CH3:19])([CH3:18])[C:12]2=[O:20])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C1COCC1.O>C1COCC1>[OH:17][C@H:14]1[C@@H:15]([CH3:16])[N:11]([C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:10]=2)[C:12](=[O:20])[C:13]1([CH3:18])[CH3:19]
Reactant: CC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](O)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A solution of 2-(trifluoromethyl)-4-(3,3,5-trimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (50 mg) in THF (5 mL) was cooled to −78° C., lithium tri(sec-butyl)borohydride-THF solution (0.242 mL, 1 mol/L) was added, and the mixture was stirred at −78° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the obtained solid was recrystallized from hexane-ethyl acetate to give the title compound as a colorless solid (yield: 32.2 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=2)/[C:24](=[CH:32]/[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)/[C:23]1=[O:40])=[O:21])[CH3:18].CO>C1(C)C=CC=CC=1>[CH2:17]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=2)[C:24]2([CH:32]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[CH2:12][C:10](=[O:11])[NH:9][CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:23]1=[O:40])=[O:21])[CH3:18]
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Reactant: CCOC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1cccc(Cl)c1
Temperature: 135 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1b in toluene (20 mL) was added E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester prepared in example 6b (0.3 g, 0.83 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 135° C. for 1 h. After the solution was cooled to room temperature, methanol (50 mL) was added, and then the mixture was concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:3) to give racemic (2′R,3R,4′S)-6-chloro-2′,4′-bis(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow oil (Yield 0.45 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:5]2Cl.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:5]2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: C1COCCN1
Reactant: Cc1nc2ccc(Br)cc2c(Cl)c1S(C)(=O)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccc(Br)cc2c(N2CCOCC2)c1S(C)(=O)=O
Temperature: 80 °C
Yield: 81.5 %

Procedure:
6-Bromo-4-chloro-3-methanesulfonyl-2-methyl-quinoline (compound of example D.1) (11.5 g, 34.4 mmol), morpholine (3.3 mL, 37.8 mmol) and N,N-diisopropyl ethyl amine (6.5 mL, 37.8 mmol) were heated at 100° C. in dry N,N-dimethylformamide (10 mL) for 30 min. The reaction mixture was evaporated to dryness, and the residue extracted with dichloromethane, 10% Na2CO3 and sat. NaCl. The crude product was stirred and heated at 80° C. in ethyl acetate (80 mL) for 10 min, the resulting suspension was cooled in ice, the crystals were filtered off and washed with little cold ethyl acetate. One obtained 10.8 g (81%) of white crystals. MS: m/z=385/387 (M+H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[N:17]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:27]([O:26][C:24]([N:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:2]2[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=2)[CH2:19][CH2:18]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CN(c1cc(F)ccc1[N+](=O)[O-])S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])S(C)(=O)=O

Procedure:
N-(5-Fluoro-2-nitrophenyl)-N-methyhnethanesulfonamide (3.1 g, 12.5 mmol), tert-butyl 1-homopiperazinecarboxylate (2.5 g) and potassium carbonate (2 g) were heated together in DMSO (50 mL) at 80° C. overnight. The solution was allowed to cool and poured into 500 mL of water. The solid product was collected by filtration, washed with water and dried. Yield 4.6 g (86%); 1H NMR (400 MHz, CDCl3) δ 1.41 (s, 9 H), 2.0 (br s, 2 H), 3.01 (s, 3 H), 3.28 (s, 3 H), 3.3-3.8 (br, 8 H), 6.64 (d, J=8.1 Hz, 1 H), 6.74 (d, J=4.8 Hz, 1 H), 8.09 (d, J=8.1 Hz, 1 H); MS (ESI+) for C18H28N4O6S m/z 428.1709 (M+) (calc. 428.1730).
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1.CC(C)([O-])C.[K+].[Cl:23][C:24]1[N:25]=[N:26][C:27](Cl)=[CH:28][CH:29]=1>O>[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:27]2[N:26]=[N:25][C:24]([Cl:23])=[CH:29][CH:28]=2)[CH:10]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: Clc1ccc(Cl)nn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(Oc2ccc(Cl)nn2)c1
Yield: 58.8 %

Procedure:
To a dimethylformamide (8.0 mL) solution of 3-hydroxy-benzoic acid methyl ester (928 mg, 6.1 mmol) was added potassium t-butoxide (750 mg, 6.7 mmol). Upon stirring the reaction at room temperature for 15 min, 3,6-dichloro-pyridazine (1.0 g, 6.7 mmol) was added. The reaction was stirred at room temperature for 15 h. Crude reaction mass was added to water, aqueous layer was acidified to pH 4.0 and product was extracted with ethyl acetate to give 3-(6-chloro-pyridazin-3-yloxy)-benzoic acid methyl ester (950 mg).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[S:25][C:24]([C:26]5[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=5)=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.Cl>>[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[S:25][C:24]([C:26]5[CH:33]=[CH:32][C:29]([CH2:30][NH:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4])=[CH:28][CH:27]=5)=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: NC(CO)CO
Agent: Cl
Product: OCC(CO)NCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from serinol and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. The product was converted to the mesylate salt analogous to example 17 being converted to the HCl salt. 1H NMR (400 MHz, MeOH) d 8.37 (s, 1H), 7.67 (s, 1H), 7.59 (d, 2H), 7.49 (s, 1H), 7.41 (m, 5H), 7.30 (d, 1H)7.19 (dd, 1H), 6.48 (d, 1H), 3.85s, 2H), 3.59 (m, 4H), 2.72 (m, 1H); LC-MS: 446 (MH+); HPLC RT: 3.2 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](O)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[C:25]([CH2:26][CH2:27][OH:28])=[CH:24][CH:23]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[N:21]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:28][CH2:27][CH2:26][C:25]3[C:20]([CH3:19])=[N:21][C:22]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=4)=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCOc1ccc2c(ccn2CC(=O)OC(C)(C)C)c1

Procedure:
In analogy to the procedure described in example 5 f], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 5 b]) was reacted with 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol in the presence of di-tert-butyl azodicarboxylate and triphenylphosphine in tetrahydrofuran to yield (5-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as colorless liquid.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21]1([CH3:30])[C:22]([C:27](Cl)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>>[C:21]1([CH3:30])[C:22]([C:27]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: Cc1ccccc1C(=O)Cl
Product: CCOC(=NC(=O)c1ccccc1C)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and o-toluoyl chloride, there is obtained ethyl N-(o-toluoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum: m/e: M+ 384 (5), 355 (10), 194 (100), 119 (31);
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[C:2]=[S:3].[I:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[I:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2](=[S:3])[NH:1][C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=2)=[CH:17][CH:16]=1
Reactant: Nc1ccc(I)cc1
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Product: NS(=O)(=O)c1ccc(NC(=S)Nc2ccc(I)cc2)cc1

Procedure:
The subject compound was prepared utilizing the procedure described above from 4-isothiocyanatobenzenesulfonamide and 4-iodoaniline. 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 10.08 (s, 1H), 7.76-7.65 (m, 6H), 7.32 (d, J=8.8 Hz, 2H), 7.29 (bs, 2H); (M+H)+ (434).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:23])[F:24])=[CH:19][CH:18]=1)=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1ccc([N+](=O)[O-])cc1O
Yield: 32.5 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(4-trifluoromethylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 4-trifluoromethyl phenyl isocyanate (1.0 mmol) according to the procedure in General Method B. The producft was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (111 mg, 32%). EI-MS m/z 340 (M−H)−
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:13]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C:27](=[O:31])[CH2:26][CH2:25]4)[CH:12]=2)=[CH:7][N:6]=1)(=O)=O.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36]>>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH:36][C:5]1[N:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)=[C:13]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C:27](=[O:31])[CH2:26][CH2:25]4)[CH:12]=2)=[CH:7][N:6]=1
Reactant: CN(C)CCN
Reactant: CS(=O)(=O)c1ncc(-c2cc(-c3ccc4c(c3)CCC4=O)c(-c3ccncc3)o2)cn1
Product: CN(C)CCNc1ncc(-c2cc(-c3ccc4c(c3)CCC4=O)c(-c3ccncc3)o2)cn1
Yield: 20 %

Procedure:
The title compound (0.03 g, 20%) was prepared from the product of Example 7 Step 6 and N,N-dimethylethylenediamine using the method of Example 7 Step 7; 1H NMR (CDCl3) 8.68 (2H, s), 8.52 (2H, d, J 8 Hz), 7.82 (1H, d, J 10 Hz), 7.57 (H, s), 7.46 (1H, d, J 10 Hz), 7.39 (2H, J 8 Hz), 6.67 (1H, s), 5.90 (1H, m), 3.53 (2H, m), 3.18 (2H, t, J 5 Hz), 2.77 (2H, t, J 8 Hz,), 2.56 (2H, t, J 5 Hz) 2.29 (6H, s).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12.C([O-])([O-])=O.[K+].[K+].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].C(OCC)(=O)C>CN1CCCC1=O>[C:19]1([CH3:24])[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12
Reactant: O=C1CN2C(=O)CCC2N1
Reactant: Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccccc1N1C(=O)CN2C(=O)CCC21
Yield: 15.4 %

Procedure:
To a solution of tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione (1.3 g, 9.28 mmol, prepared as described in J. Med. Chem. 36, 4214, 1994) in N-methylpyrrolidone (NMP, 12 cc), Cul (0.5 g, 2.62 mmol), K2CO3 (1.3 g, 9.28 mmol) and 2-bromotoluene (6 g, 35 mmol) were added under stirring. The suspension was heated in a microwave apparatus (250 Watt) for 1 h. Ethyl acetate was added to the suspension and the solid was filtered. The organic phase was washed with water and the aqueous phase was re-extracted with CH2Cl2. The organic phases were gathered and dried over Ma2SO4, filtered and concentrated to dryness. The residue was triturated with Et2O. The solid was filtered, and crystallized the first time with IPrOH and then with AcOEt to yield 0.33 g of the title compound, mp=138-139° C.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:16]2[C:10]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[N:9]1.[OH-].[Na+]>C1COCC1.CO>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:25])=[O:2])[N:9]=[C:10]3[C:16]=2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:19][CH:20]=1
Reactant: COC(=O)CCCCn1nc2c(c1-c1ccc(Cl)cc1)CCNCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCCCn1nc2c(c1-c1ccc(Cl)cc1)CCNCC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.1 %

Procedure:
5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentanoic acid methyl ester (Example 82, 0.009 g) was dissolved in 1 mL of 9:1 THF/MeOH and treated with 2 mL of 1 M NaOH. After stirring at RT for 5 h, the solvent was removed in vacuo. The aqueous residue was acidified with 1 mL of 1 N HCl and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, concentrated, and dried on a vacuum line. The residue was then dissolved in 1 mL of 9:1 CH2Cl2/MeOH and treated with 3 mL of 1 N HCl in Et2O. After 4 h, the volatiles were removed in vacuo. The crude oil was purified by preparative TLC (9:1 CH2Cl2/2 M NH3 in MeOH) to afford 0.002 g of the title compound. MS (ESI): exact mass calculated for C18H22ClN3O2, 347.14. found, m/z 348.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.55-7.53 (m, 4H), 7.35-7.32 (m, 2H), 3.98 (t, J=7.0 Hz, 2H), 3.38-3.35 (m, 2H), 3.28-3.26 (m, 2H), 3.13-3.10 (m, 2H), 2.77-2.74 (m, 2H), 2.09-2.06 (m, 2H), 1.71-1.66 (m, 2H), 1.41-1.37 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]1[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1)[N:20]=[CH:19]2.[ClH:40].C(Cl)[Cl:42]>CO.CCOCC>[ClH:42].[ClH:40].[CH2:8]([C:6]1[CH:5]=[CH:4][N:3]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:20]=[CH:19]3)[C:2](=[O:1])[CH:7]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2ncc3cc(-n4ccc(CCc5ccccc5)cc4=O)ccc32)CC1
Reactant: ClCCl
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=c1cc(CCc2ccccc2)ccn1-c1ccc2c(cnn2CCN2CCNCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution of tert-butyl 4-(2-(5-(2-oxo-4-phenethylpyridin-1(2H)-yl)-1H-indazol-1-yl)ethyl)piperazine-1-carboxylate (247 mg, 0.468 mmol) in MeOH (2 mL) was treated with 2N HCl in ether (7 mL) under a nitrogen atmosphere. The solution was stirred at room temperature for 2 h and then treated with CH2Cl2 (20 mL) to precipitate product. The liquid was decanted off, and the solids were triturated with ether (3×100 mL) and concentrated to yield the title compound (161.7 mg, 69%) as yellow solid: mp 280-290° C.; 1H NMR (500 MHz, CD3OD) δ 8.23 (s, 1H), 7.83 (s, 2H), 7.62 (d, J=6.95 Hz, 1H), 7.46 (d, J=1.4 Hz, 1H), 7.30-7.17 (m, 5H), 6.51 (dd, J=7.0, 1.1 Hz, 1H), 6.48 (s, 1H), 4.95 (t, J=5.85, 2H), 3.57 (m, 2H), 3.61-3.56 (m, 8H), 3.01-2.98 (m, 2H), 2.94-2.91 (m, 2H); ESI MS m/z 428 [M+H]+. HPLC (Method D) 95.4% (AUC), tR=12.9 min.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:5][CH:4]([C:6](O)=[O:7])[CH2:3]1.C(Cl)(=O)C([Cl:13])=O>ClCCl>[F:1][C:2]1([F:9])[CH2:5][CH:4]([C:6]([Cl:13])=[O:7])[CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CC(F)(F)C1
Solvent: ClCCl
Product: O=C(Cl)C1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
3,3-Difluorocyclobutanecarboxylic acid (Parkway Scientific, New York, N.Y., USA) (531 mg, 3.90 mmol) was dissolved in dichloromethane (3.00 mL) and oxalyl chloride (1.02 mL, 11.7 mmol) was added. The solution was stirred at room temperature for 4 h before concentrating in vacuo to provide 3,3-difluorocyclobutanecarbonyl chloride (ca. 50% pure), which was carried on without purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](O)([C:18]1[C:19]([OH:29])=[CH:20][C:21]3[O:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]=3[CH:28]=1)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:18]1[C:19]([OH:29])=[CH:20][C:21]3[O:25][C:24]([CH3:26])([CH3:27])[CH2:23][C:22]=3[CH:28]=1)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)OC(C)(C)C3)c2c(Br)cccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)OC(C)(C)C3)c2c(Br)cccc21
Temperature: 35 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
A mixture of ethyl [4-bromo-3-hydroxy-3-(6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate (1.32 g, 2.80 mmol), triethylsilane (2.00 mL, 12.2 mmol) and trifluoroacetic acid (0.94 mL, 12.2 mmol) in dichloromethane (50.0 mL) was stirred at 35° C. for 3 hours. The mixture was diluted with dichloromethane (100 mL), washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/3) to give the title compound (1.04 g, 81%): 1H NMR (300 MHz, CDCl3) δ 7.32-7.15 (m, 2H), 6.74 (d, 1H), 6.50-6.36 (br, 2H), 5.04 (s, 1H), 4.51-4.34 (m, 2H), 4.25-4.14 (m, 2H), 2.92-2.69 (m, 2H), 1.43 (s, 3H), 1.37 (s, 3H), 1.23 (t, 3H); MS (ES+) m/z 460.5 (M+1), 462.5 (M+1).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.CON(C)[C:9]([C:11]1[C:16]([NH2:17])=[N:15][CH:14]=[C:13]([C:18]2[CH:23]=[C:22]([S:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=2[CH3:33])[N:12]=1)=[O:10].Cl>C1COCC1>[NH2:17][C:16]1[C:11]([C:9]([CH:1]2[CH2:3][CH2:2]2)=[O:10])=[N:12][C:13]([C:18]2[CH:23]=[C:22]([S:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=2[CH3:33])=[CH:14][N:15]=1
Reactant: CON(C)C(=O)c1nc(-c2cc(S(=O)(=O)N3CCOCC3)ccc2C)cnc1N
Reactant: Br[Mg]C1CC1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCOCC2)cc1-c1cnc(N)c(C(=O)C2CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1M solution of cyclopropyl magnesium bromide in THF (0.21 ml, 0.21 mmol) is added to a solution of 3-amino-6-[2-methyl-5-(morpholine-4-sulfonyl)-phenyl]-pyrazine-2-carboxylic acid methoxy-methyl amide (Intermediate C) (0.058 mg, 0.14 mmol) in anhydrous THF (3 ml) under N2. The orange solution is stirred at room temperature for 2 hours after which time a 1M solution of cyclopropyl magnesium bromide in THF (0.21 ml, 0.21 mmol) is added. The orange solution is stirred at room temperature for 1 hour. 1M HCl (15 ml) is added, and the product extracted into EtOAc (30 ml), dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (SiO2, 33-50% EtOAc in iso hexane) yields the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-6) δ 8.63 (1H, s), 7.92 (2H, bs), 7.79 (1H, s), 7.70-7.63 (2H, m), 3.64-3.62 (4H, m), 3.49-3.43 (1H, m), 2.90 (4H, bs) 2.54 (3H, s), 1.09-1.01 (4H, m); MS m/z 403 [M+H]+