Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][C@H:32]([OH:37])[C:33]([F:36])([F:35])[F:34])[C:10](=[O:30])[N:11]([CH2:13][C:14]3[CH:15]=[C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[Cl:29])[CH:17]=[CH:18][C:19]=3[CH2:20][OH:21])[N:12]=2)=[CH:4][CH:3]=1.ClS([N:42]=[C:43]=[O:44])(=O)=O.O.C(=O)(O)[O-].[Na+]>ClCCl>[C:43](=[O:44])([O:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[Cl:29])=[CH:15][C:14]=1[CH2:13][N:11]1[C:10](=[O:30])[N:9]([CH2:31][C@H:32]([OH:37])[C:33]([F:34])([F:36])[F:35])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:12]1)[NH2:42]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=c1n(Cc2cc(-c3cccc(Cl)c3Cl)ccc2CO)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: NC(=O)OCc1ccc(-c2cccc(Cl)c2Cl)cc1Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
65 mg (0.11 mmol) of the compound from Example 137 were dissolved in 3 ml of dichloromethane, and the mixture was cooled to 0° C. 14 μl (0.16 mmol) of chlorosulfonyl isocyanate were added, and the mixture was stirred at RT for 18 h. 1.5 ml of water were then added, and the mixture was stirred at 60° C. for a further 18 h. For work-up, 3 ml of saturated aqueous sodium bicarbonate solution were added, and the mixture was extracted twice with in each case 10 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 30 mg (43% of theory) of the target compound.
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[C:6]([C:9]1C(I)=C(NC(=O)CN2CCNCCNCCNCC2)C(I)=CC=1I)([OH:8])=[O:7].[C:34]([CH:37]([CH2:64][CH3:65])[CH2:38][C:39]1[C:40]([I:63])=[C:41]([NH:47][C:48](=[O:62])[CH2:49][N:50]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57][NH:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[C:42]([I:46])=[CH:43][C:44]=1[I:45])([OH:36])=[O:35]>O>[C:34]([CH:37]([CH2:64][CH3:65])[CH2:38][C:39]1[C:40]([I:63])=[C:41]([NH:47][C:48](=[O:62])[CH2:49][N:50]2[CH2:51][CH2:52][N:53]([CH2:2][C:3]([OH:5])=[O:4])[CH2:54][CH2:55][N:56]([CH2:2][C:3]([OH:5])=[O:4])[CH2:57][CH2:58][N:59]([CH2:9][C:6]([OH:8])=[O:7])[CH2:60][CH2:61]2)[C:42]([I:46])=[CH:43][C:44]=1[I:45])([OH:36])=[O:35]
Reactant: CCC(Cc1c(I)cc(I)c(NC(=O)CN2CCNCCNCCNCC2)c1I)C(=O)O
Reactant: O=C(CN1CCNCCNCCNCC1)Nc1c(I)cc(I)c(C(=O)O)c1I
Reactant: O=C(O)CBr
Solvent: O
Product: CCC(Cc1c(I)cc(I)c(NC(=O)CN2CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC2)c1I)C(=O)O
Yield: 13.4 %

Procedure:
According to the procedure described in Example 3, 17.74 g of bromoacetic acid (0.127 mol) in 20 ml of H2O are reacted with 25 g of compound (B) N-[3-(2-carboxybutyl)-2,4,6-triiodophenyl]-1,4,7,10-tetraazacyclododecane-1-acetamide (0.032 mol) in 20 ml of H2O. 4.1 g of 10-[2-[[3-(2-carboxybutyl)-2,4,6-triiodophenyl]amino]-2-oxoethyl ] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (0.0043 mol) are obtained.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH:5]([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[O:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH2:7]([O:6][CH:5]([O:9][CH2:10][CH3:11])[CH2:4][O:12][C@@H:13]([C@@H:13]1[CH2:14][CH2:15][CH2:16][O:12]1)[CH2:14][CH:15]=[CH2:16])[CH3:8].[CH2:7]([O:6][CH:5]([O:9][CH2:10][CH3:11])[CH2:4][O:12][C@H:13]([C@@H:13]1[CH2:14][CH2:15][CH2:16][O:12]1)[CH2:14][CH:15]=[CH2:16])[CH3:8]
Reactant: C1CCOC1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Product: C=CC[C@@H](OCC(OCC)OCC)[C@@H]1CCCO1
Product: C=CC[C@H](OCC(OCC)OCC)[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of crude (C94) (16.0 g, ≦1.112 mol) in tetrahydrofuran (600 mL) at 0° C. was added sodium hydride (60% in mineral oil, 13.5 g, 0.33 mol) portion-wise. After addition was complete, the reaction was allowed to warm to room temperature and stir at that temperature for 30 minutes. 2-Bromo-1,1-diethoxyethane (83 g, 0.33 mol) was added and the reaction was refluxed for 16 hours. The reaction mixture was cooled to room temperature and poured into ice-water (100 mL). The aqueous layer was washed with ethyl acetate (3×200 mL), and the organic phases were combined and washed with saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (Gradient: 1% to 10% ethyl acetate in petroleum ether) provided (2S)-2-[(1R)-1-(2,2-diethoxyethoxyl)but-3-en-1-yl]tetrahydrofuran as the first eluting isomer and (2S)-2-[(1S)-1-(2,2-diethoxyethoxyl)but-3-en-1-yl]tetrahydrofuran as the second eluting isomer, both as yellow oils.
Reaction SMILES: [N:1]([C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([OH:15])[CH2:7][CH2:6][C@H:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23])=[N+:2]=[N-:3].[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[N:26]1[CH:34]1[CH2:39][CH2:38][N:37]([C:40](OC2C=CC([N+]([O-])=O)=CC=2)=[O:41])[CH2:36][CH2:35]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C)C=O>[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[N:26]1[CH:34]1[CH2:35][CH2:36][N:37]([C:40]([O:15][C@H:8]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:14]3[C@@H:4]([N:1]=[N+:2]=[N-:3])[C@H:5]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=3[F:23])[CH2:6][CH2:7]2)=[O:41])[CH2:38][CH2:39]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: [N-]=[N+]=N[C@@H]1c2cccnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1c2cccnc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
In a 100 mL round-bottom flask was dissolved (5S,6S,9R)-5-azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (0.490 g, 1.549 mmol) (azeotroped with dry benzene) and 4-nitrophenyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (0.713 g, 1.859 mmol) in dimethylformamide (8 mL) to give a light yellow suspension under nitrogen. After cooling to −15° C. (ice-methanol bath), NaHMDS (4.18 mL, 4.18 mmol) was added dropwise. The resulting tan solution was stirred under nitrogen at −10° C.˜0° C. for 2 h and at room temperature for 2 h. LCMS showed complete conversion. The reaction was quenched with sodium bicarbonate solution. The mixture was diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried with sodium sulfate, and concentrated to give a tan oil. Purification by FCC up to 8% methanol/methylene chloride afforded the desired product (major peak, 632 mg, 73% for 3 steps) as a light yellow foam.
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.C(P(CCCC)CCCC)CCC.[CH2:30]([O:37][C:38]1[CH:39]=[C:40]([C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:45]=2[NH:51][C:52](=[O:58])[CH2:53][NH:54][CH2:55][CH2:56]O)[CH:41]=[CH:42][CH:43]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[ClH:50].[CH2:30]([O:37][C:38]1[CH:39]=[C:40]([C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:45]=2[N:51]2[CH2:56][CH2:55][NH:54][CH2:53][C:52]2=[O:58])[CH:41]=[CH:42][CH:43]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(CNCCO)Nc1cc(Cl)ccc1-c1cccc(OCc2ccccc2)c1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: Cl
Product: O=C1CNCCN1c1cc(Cl)ccc1-c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of di-tert-butylazodicarboxylate (733 mg, 3.2 mmol) in 5 mL of THF at 0° C. was added tributylphosphine (0.797 mL, 3.2 mmol) dropwise. After 10 minutes, a solution of the product from Step D (895 mg, 2.10 mmol) in 5 mL of THF was added dropwise over 15 minutes, and the reaction was allowed to warm to room temperature. After 16 hours, the solution was concentrated in vacuo. The crude product mixture was purified by silica gel chromatography (50% EtOAc/CH2Cl2, then 5% MeOH/CH2Cl2). The resulting product was taken up in ether, excess 1N HCl/Ether was added, and the solution was concentrated in vacuo. The titled product, containing tributylphosphine oxide impurity, was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23].Cl.C(N1CCCCC1)C>C(Cl)Cl>[CH3:19][O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH:23][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CCN1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
11.0 grams of N,N-dicyclohexylbodiimide was added to a solution of 12.45 grams of benzyloxycarbonyl proline and alanine methyl ester released from 7.0 grams of the corresponding hydrochloride using 7 ml of N-ethyl piperidine in 40 ml of methylene chloride cooled to -5 degrees C. The resultant reaction suspension was stirred for 1 hour at 0 degree C. N,N-dicyclohexylurea separated from the suspension and was filtered off after it was allowed to stand for 12 hours at 3 degrees C. Then, the filtrate was successively washed with 1M hydrochloric acid, water, 5% sodium hydrogen carbonate, with water, dried with anhydrous sodium sulfate and evaporated. A solid evaporation residue was crystallized from 100 ml of ethyl acetate and 500 ml of petroleum ether. 12.2 g of a product having a melting point of 45 to 49 degrees C. was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:12])[C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCOCC1>[CH3:12][N:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:11]=[C:3]1[CH2:2][O:1][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CO)nc2ncccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ncccc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 2.5 g of 2-hydroxymethyl-1-methylimidazo[4,5-b]pyridine (prepared as described in Preparation 30), 6.5 g of 5-(4-hydroxybenzyl)-3-tri-phenylmethylthiazolidine-2,4-dione, 3.47 ml of tributylphosphine, 3.52 g of 1,1'-(azodicarbonyl)dipiperidine and 250 ml of 1,4-dioxane were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:1 to 0:1 by volume and subsequently mixtures of ethyl acetate and methanol in ratios ranging from 20:1 to 10:1 by volume as the eluent, to give 4.1 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=3)[CH:9]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:3]=1.[H][H]>C1COCC1.CO.[Pd]>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][CH:24]=2)[CH:3]=1
Reactant: [H][H]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc([N+](=O)[O-])c3)c2)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(N)c3)c2)n1
Yield: 97.7 %

Procedure:
A mixture of 6-methyl-2′-(3-nitro-phenyl)-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example 306) (6.6 g, 15.15 mmol) in THF-MeOH 1:1 (300 mL) and 10% palladium on carbon (10 mol %) was hydrogenated (1 bar hydrogen) at 23° C. for 2 h. The catalyst was filtered off, washed with MeOH and the filtrate was completely evaporated totally to leave a crude product, which was triturated with diethyl ether and dried in HV to give the title compound as a light brown solid (6.0 g, 97%). MS (ISP) 406.3 [(M+H)+]; mp 162° C. (dec.).
Reaction SMILES: [OH-:1].[Na+].CS([C:7]1[N:12]=[CH:11][C:10]2=[CH:13][CH:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:9]2[N:8]=1)(=O)=O.Cl>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]1[N:9]2[C:10]([CH:11]=[N:12][C:7]([OH:1])=[N:8]2)=[CH:13][CH:14]=1
Reactant: [OH-]
Reactant: CS(=O)(=O)c1ncc2ccc(-c3ccccn3)n2n1
Agent: Cl
Agent: [Na+]
Product: Oc1ncc2ccc(-c3ccccn3)n2n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
5M NaOH (2 mL, 10 mmol) was added to 2-Methanesulfonyl-7-pyridin-2-yl-pyrrolo[2,1-f][1,2,4]triazine and the reaction was stirred and heated at 80° C. overnight. The reaction was let cool to room temperature and HCl was then added dropwise to the reaction mixture to precipitate the product (pH 1), which was filtered immediately and washed with water and left on vacuum overnight to give 7-Pyridin-2-yl-pyrrolo[2,1-f][1,2,4]triazin-2-ol (100 mg, 66% over two steps). 1H-NMR (DMSO-d6): 11.89 (s, 1H), 9.05 (s, 1H), 8.83 (d, 1H, J=7.91 Hz), 8.69 (d, 1H, J=4.74 Hz), 7.96 (t, 1H, J=7.69 Hz), 7.53 (d, 1H, J=4.86 Hz), 7.35 (t, 1H, J=4.86 Hz), 7.04 (d, 1H, J=4.86 Hz).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[CH:25]5[CH2:26][CH2:27][CH:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1.C(N(CC)CC)C.[OH:45][C:46]([CH3:51])([CH3:50])[C:47](O)=[O:48].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[C@H:25]5[CH2:26][CH2:27][C@@H:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:13][CH2:14][N:15]([C:47](=[O:48])[C:46]([CH3:51])([OH:45])[CH3:50])[CH2:16][CH2:17]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccc3c(c2)OCO3)CCNCC1
Reactant: CC(C)(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccc3c(c2)OCO3)CCN(C(=O)C(C)(C)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
A mixture of 1-(8-{2-[4-(1,3-benzodioxol-5-yl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.20 g, 0.39 mmol), triethylamine (0.17 mL, 1.25 mmol) and 2-hydroxyisobutyric acid (41 mg, 0.39 mmol) in dimethylformamide (1.25 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (163 mg, 0.43 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting precipitate was collected, washed with saturated sodium bicarbonate solution, with water, dried and purified by chromatography on silica gel eluting with a dichloromethane to methanol-dichloromethane 1:19 gradient to give 1-(4-(1,3-benzodioxol-5-yl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)-2-methyl-1-oxopropan-2-ol as a solid (0.10 g, 44%). HRMS C33H42N4O4 m/z 559.3284 (M+H)Cal. 559.3276 (M+H)Obs..
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:3][C:4]([O:6]CC)=O.C(O)(=O)C(O)=O.C1(NN)CC1.C1(C2[N:33]([CH:34]([CH3:36])[CH3:35])[N:32]=[CH:31]C=2C=O)CC1>>[CH:34]1([N:33]2[C:2]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)=[C:3]([CH:4]=[O:6])[CH:31]=[N:32]2)[CH2:36][CH2:35]1
Reactant: CCOC(=O)CC(=O)c1ccccn1
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Agent: NNC1CC1
Agent: O=C(O)C(=O)O
Product: O=Cc1cnn(C2CC2)c1-c1ccccn1

Procedure:
1-Cyclopropyl-5-pyridin-2-yl-1H-pyrazole-4-carbaldehyde was prepared from ethyl 3-oxo-3-pyridin-2-yl-propionate and cyclopropyl hydrazine oxalate in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([CH:35]=O)=[CH:29]3)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.N1CCCCC1>C(O)C>[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([CH:35]=[C:11]2[C:10]4[C:14](=[CH:15][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:8][CH:9]=4)[NH:13][C:12]2=[O:16])=[CH:29]3)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(-c3ccccc3)ccc2C1=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 71.6 %

Procedure:
A mixture of 6-phenyl-2-oxindole (44 mg, 0.21 mmol), 5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde (58 mg, 0.21 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 70 mg (71%) of the title compound as an orange solid.
Reaction SMILES: [NH2:1][C:2]1([C:9]([OH:11])=[O:10])[CH2:7][CH:6]2[O:8][CH:3]1[CH2:4][CH2:5]2.S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:10][C:9]([C:2]1([NH2:1])[CH2:7][CH:6]2[O:8][CH:3]1[CH2:4][CH2:5]2)=[O:11]
Reactant: CO
Reactant: NC1(C(=O)O)CC2CCC1O2
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(N)CC2CCC1O2
Reaction time: 24 h

Procedure:
3.0 g of 2-amino-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid were suspended in 100 ml of methanol and 11.4 g of thionyl chloride were added at room temperature. The mixture was left at room temperature for 24 h. Then the volatiles were evaporated in vacuo to yield 3.9 g of the title compound as a racemic mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][C:6]([CH3:14])([CH3:13])[CH2:5][C:4]=2[N:3]=1.[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[ClH:1].[CH2:15]([O:22][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][C:6]([CH3:14])([CH3:13])[CH2:5][C:4]=2[N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: CC1(C)CC(=O)c2ccc(Cl)nc2C1
Product: CC1(C)CC(=O)c2ccc(OCc3ccccc3)nc2C1
Product: Cl
Yield: 33 %

Procedure:
In analogy to the procedure described in Example 9, 2-chloro-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one was treated with benzyl alcohol to give the title compound in 33% yield.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]([F:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+]([O-])([O-])=O.[Na+].[ClH:18]>O.O1CCOCC1.[Cu](Cl)Cl>[Br:12][C:8]1[C:9]([F:11])=[CH:10][C:2]([Cl:18])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Cl
Reactant: Nc1cc(F)c(Br)cc1C(=O)O
Agent: Cl[Cu]Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(Br)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 2-amino-5-bromo-4-fluorobenzoic acid (14.5 g, 62.2 mmol) in concentrated hydrochloric acid (30 mL) at 0° C. was added dropwise a solution of sodium nitrate (4.72 g, 68.4 mmol) in water (15 mL). The mixture was stirred at 0° C. for 2 hours, then diluted with 1,4-dioxane (40 mL) and added dropwise to a solution of copper chloride (7.4 g, 74.4 mmol) in concentrated hydrochloric acid (25 mL) under mechanical stirring while the reaction temperature was kept below 7° C. (ice-salt bath). After the addition was complete, the mixture was stirred at 0° C. for another 1 hour. Water was added, and the precipitate was filtered. The filter cake was washed with water and dissolved in ethyl acetate. The filtrate was extracted with ethyl acetate once and washed with water and then with brine. The combined organic layers were dried over sodium sulfate and concentrated to give the crude product 28 (14.5 g, 92%), which was used for the next step without further purification. MS ESI (m/z): 251 (M−H)−.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([N:11]2[C:17](=[O:18])[CH2:16][C:15](=[O:19])[NH:14][C:13]3[C:20]4[C:25]([CH:26]=[CH:27][C:12]2=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:8]=[CH:9][CH:10]=1)=[NH:4].C1CCN2C(=NCCC2)CC1.[C:39](N1C=CN=C1)(N1C=CN=C1)=[S:40].Cl>C(#N)C>[S:40]=[C:39]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[C:7]([N:11]3[C:17](=[O:18])[CH2:16][C:15](=[O:19])[NH:14][C:13]4[C:20]5[C:25]([CH:26]=[CH:27][C:12]3=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:8]=[CH:9][CH:10]=2)[NH:4]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: N=C(NO)c1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CC(=O)N(c2cccc(-c3noc(=S)[nH]3)c2)c2ccc3ccccc3c2N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.6 %

Procedure:
To an ice-cold solution of 5-[3-(N-hydroxyamidino)phenyl]-1H-naphtho[1,2-b][1,4]diazepin-2,4(3H,5H)-dione (310 mg, 0.94 mmol) and 1,8-diazabicyclo[5,4,0]-7-undecene (561 □L, 3.75 mmol) in acetonitrile (5.7 mL) was added dropwise, a solution of thiocarbonyldiimidazole (251 mg, 1.41 mmol) in acetonitrile (6 mL). The mixture was stirred at room temperature for 1.5 hours, to which was added 1M hydrochloric acid, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1-0/1), to give the titled compound (161 mg, yield 41%).
Reaction SMILES: [H-].[Na+].[OH:3][C@:4]1([C:22]2[CH:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]=[CH2:35])[CH:29]=3)[CH:25]=[CH:26][CH:27]=2)[CH2:8][N:7]([C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[C@H:6]([C:18]([O:20][CH3:21])=[O:19])[CH2:5]1.[CH3:36]I>CN(C=O)C>[CH3:36][O:3][C@:4]1([C:22]2[CH:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]=[CH2:35])[CH:29]=3)[CH:25]=[CH:26][CH:27]=2)[CH2:8][N:7]([C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[C@H:6]([C:18]([O:20][CH3:21])=[O:19])[CH2:5]1
Reactant: CI
Reactant: C=Cc1cccc(-c2cccc([C@]3(O)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C3)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1cccc(-c2cccc([C@]3(OC)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C3)c2)c1
Reaction time: 3 h
Yield: 77.1 %

Procedure:
NaH (60% in oil) (0.446 g, 11.16 mmol) was added to a solution of (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-hydroxy-4-(3′-vinylbiphenyl-3-yl)pyrrolidine-1,2-dicarboxylate (2.9 g, 6.20 mmol) and methyl iodide (0.698 mL, 11.16 mmol) at 0° C. in DMF and stirred at this temperature for 3 hrs. The reaction was then quenched with saturated NH4Cl solution and ether. The ether layer was washed with brine, dried, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (5-45% EtOAc in hexanes) to give (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-methoxy-4-(3′-vinylbiphenyl-3-yl)pyrrolidine-1,2-dicarboxylate (2.3 g, 4.78 mmol, 77% yield) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.04-0.11 (m, 9H) 0.89-1.12 (m, 2H) 2.56 (dd, J=13.18, 8.91 Hz, 1H) 2.86 (t, J=12.67 Hz, 1H) 2.99 (d, J=3.01 Hz, 3H) 3.66-3.92 (m, 1H) 3.79 (d, J=7.03 Hz, 3H) 3.99-4.12 (m, 1H) 4.18-4.29 (m, 2H) 4.44-4.70 (m, 1H) 5.33 (d, J=10.79 Hz, 1H) 5.84 (d, J=16.82 Hz, 1H) 6.80 (dd, J=17.57, 11.04 Hz, 1H) 7.34 (d, J=7.53 Hz, 1H) 7.39-7.52 (m, 4H) 7.53-7.59 (m, 3H). LCMS: rt=2.49 min. [M+H]+=482; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.