Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:6]=1[C:7]#[N:8]>N1C=CC=CC=1>[C:13]1([C:10]2[CH:9]=[C:6]3[C:7]([NH2:8])=[N:3][NH:2][C:5]3=[N:12][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#Cc1cc(-c2ccccc2)cnc1Cl
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: Nc1n[nH]c2ncc(-c3ccccc3)cc12

Procedure:
Hydrazine hydrate (1.42 g, 28 mmol) was added to a stirred solution of 2-chloro-5-phenylnicotinonitrile (2.45 g, 11.4 mmol) in pyridine (25 ml). The reaction mixture was stirred at reflux for 6 hours, cooled and the resulting solid was filtered and dried in vacuo, affording the title compound as a solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 60 °C

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (20.4 mmol), piperazine-1-carboxylic acid tert-butyl ester (20.4 mmol), potassium carbonate (40.8 mmol), and N′N-dimethylformamide (80 mL) is heated at 60° C. for 3 hrs. The mixture is cooled to room temperature, treated with water (100 mL), extracted with ethyl acetate (3×80 mL). The extracts are washed with water (3×60 mL) and brine (1×75 ml), dried over magnesium sulfate, and concentrated in vacuo to give 4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (11) as a yellow solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:26][N:27]1[C:31]2[CH:32]=[C:33]([C:36]([OH:38])=O)[CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1.CCN(C(C)C)C(C)C.[CH2:48]([O:50][C:51](=[O:65])[C@H:52]([OH:64])[CH2:53][C@H:54]([NH2:63])[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([Br:62])=[CH:58][CH:57]=1)[CH3:49]>>[CH2:48]([O:50][C:51](=[O:65])[C@H:52]([OH:64])[CH2:53][C@H:54]([NH:63][C:36]([C:33]1[CH:34]=[CH:35][C:30]2[N:29]=[N:28][N:27]([OH:26])[C:31]=2[CH:32]=1)=[O:38])[CH2:55][C:56]1[CH:57]=[CH:58][C:59]([Br:62])=[CH:60][CH:61]=1)[CH3:49]
Reactant: O=C(O)c1ccc2nnn(O)c2c1
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)c1ccc2nnn(O)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.5 %

Procedure:
HCTU (837 mg, 2.0 mmol) was added to a solution of 1-hydroxy-1H-1,2,3-benzotriazole-6-carboxylic acid (362 mg, 2.0 mmol) and the mixture was stirred at room temperature for 10 minutes. DIPEA (529 μL, 3.0 mmol) and (2R,4R)-4-amino-5-(4-bromophenyl)-2-hydroxy-pentanoic acid ethyl ester (320 mg, 1.0 mmol) were then added and the resulting mixture was stirred at room temperature for 15 minutes. The mixture was concentrated in vacuo and the resulting residue was purified (C18 column, 55 g, 20-70% MeCN in water with 5% TFA) to yield the title compound as a white solid 365 mg).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:10]=[C:9]([C:11]2([OH:34])[CH2:17][CH:16]3[N:18]([CH:19]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH:8]=[CH:7][CH:6]=1)=[N+]=[N-].N>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCOC(C)=O.CO>[NH2:1][CH2:4][C:5]1[N:10]=[C:9]([C:11]2([OH:34])[CH2:17][CH:16]3[N:18]([CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])[CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH:8]=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1cccc(C2(O)CC3CCC(C2)N3C(c2ccccc2Cl)c2ccccc2Cl)n1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: NCc1cccc(C2(O)CC3CCC(C2)N3C(c2ccccc2Cl)c2ccccc2Cl)n1
Reaction time: 1.5 h

Procedure:
Add Lindlar catalyst (44 mg) to a suspension of the product from Step 5 (279 mg) in a mixture of EtOAc and CH3OH in the presence of 7N NH3 in CH3OH (1 ml). Hydrogenate the mixture at 1 atm for 1.5 h, filter through celite, wash with NH3/CH3OH (3.5 N) and concentrate to give the desired compound.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:11]=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:14]=2)[O:4]1.[C:22](Cl)(=[O:24])[CH3:23].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:2][C:3]1([CH3:21])[C:7]([CH3:8])([CH3:9])[O:6][B:5]([C:10]2[CH:11]=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][N:18]([C:22](=[O:24])[CH3:23])[CH2:17][CH2:16]3)[CH:14]=2)[O:4]1
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A solution of 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine hydrochloride (3.66 g, 11.7 mmol) in DMF (109.8 mL) was charged with acetyl chloride (0.91 mL, 12.84 mmol) and DIPEA (5.08 mL, 29.17 mmol) at 0° C. and left to warm up to RT in an ice bath overnight. The crude product was concentrated in vacuo to a solid and purified by flash chromatography (0 to 5% MeOH:EtOAc) to afford 3.71 g (99%) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 7.97 (s, 1H), 7.59 (s, 1H), 4.38-4.48 (m, 2H), 3.85-3.94 (m, 1H), 3.13-3.22 (m, 1H), 2.69 (td, J=12.8, 2.7 Hz, 1H), 2.03 (s, 3H), 1.81-2.02 (m, 3H), 1.72 (qd, J=12.1, 4.6 Hz, 1H), 1.24 (s, 12H).
Reaction SMILES: CS(OC[C@@H:7]1[C:12]([CH3:14])([CH3:13])[O:11][C:10]2[CH:15]=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:9]=2[C@H:8]1[N:21]1[CH:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][C:22]1=[O:32])(=O)=O.CC(C)([O-])C.[K+]>O1CCCC1>[C:19]([C:17]1[CH:16]=[CH:15][C:10]2[O:11][C:12]([CH3:13])([CH3:14])[CH:7]=[C:8]([N:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][C:22]3=[O:32])[C:9]=2[CH:18]=1)#[N:20]
Reactant: CCOC(=O)c1ccn([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2COS(C)(=O)=O)c(=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccn(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1
Yield: 57.3 %

Procedure:
In 8 ml of anhydrous tetrahydrofuran, is dissolved 250 mg of trans-3-methanesulfonyloxy-6-cyano-3,4-dihydro-2,2-dimethyl-4-(4-ethoxycarbonyl-1,2-dihydro-2-oxo-1-pyridinyl)-2H-benzo[b]pyran obtained in Example 20. Then, 112 mg of potassium t-butoxide is added at room temperature, and the resulting mixture is reacted at that temperature for 40 minutes. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in methylene chloride, washed with saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 1/2 mixture of ethyl acetate/n-hexane as a developing solvent. Thus, 109 mg of 6-cyano-2,2-dimethyl-4-(4-ethoxycarbonyl-1,2-dihydro-2-oxo-1-pyridinyl)-2H-benzo[b]pyran is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[C:13](=[O:14])[CH2:12][CH2:11][CH:10]1[C:15]#[N:16].[CH2:17](O)[CH2:18][OH:19]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[C:15]([CH:10]1[CH2:11][CH2:12][C:13]2([O:19][CH2:18][CH2:17][O:14]2)[CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])#[N:16]
Reactant: N#CC1CCC(=O)C1CCCCCCCO
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: N#CC1CCC2(OCCO2)C1CCCCCCCO
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A mixture of 2-(7-hydroxyheptyl)-3-oxocyclopentanecarbonitrile (20 g.), ethylene glycol (5.6 g.), p-toluenesulphonic acid (1 g.) and benzene (160 ml.) was heated to reflux for 31/2 hours with continuous removal of water. The mixture was cooled to ambient temperature, anhydrous sodium carbonate was added, and after filtration through a bed of sodium carbonate, the solvent was removed under reduced pressure. The residue was distilled under reduced pressure to give 7-cyano-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (19.3 g.), b.p. 166°-182° C./0.1 mm.Hg. This material was used as a starting material in the next stage, an aliquot being redistilled to b.p. 177°-179° C./0.1 mm.Hg for elemental analysis:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][CH2:10][O:11][CH3:12])=[C:4]([CH3:13])[N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:6]1[C:5]([CH2:9][CH2:10][O:11][CH3:12])=[C:4]([CH3:13])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: COCCc1c(C)nc(N)nc1O
Reactant: O=P(Cl)(Cl)Cl
Product: COCCc1c(C)nc(N)nc1Cl
Reaction time: 5.5 h
Yield: 30.3 %

Procedure:
A mixture of 2-amino-5-(2-methoxyethyl)-6-methylpyrimidine-4-ol (600 mg, 3.27 mmol) and phosphorus oxychloride (6 ml) was kept at 90° C. for 5.5 hours. The reaction mixture was concentrated in vacuo. Was added to the residue and an aqueous ammonia solution was cautiously added. The mixture was extracted with chloroform and the organic layer was washed with saturated brine, dried over sodium sulfate and the solvent was concentrated. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate=8:2) to give the object compound (200 mg, 30.3%).
Reaction SMILES: [N:1]1([C:6]2[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.O=[C:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1.O.CC1C=CC(S(O)(=O)=O)=CC=1.ClC(Cl)C>>[N:7]1[C:6]2[N:1]3[CH:2]=[CH:3][CH:4]=[C:5]3[C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Oc1cccnc1-n1cccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(Cl)Cl
Product: c1cnc2c(c1)OC1(CCNCC1)c1cccn1-2
Temperature: 130 °C
Yield: 93 %

Procedure:
A mixture of 2-pyrrol-1-ylpyridin-3-ol (1.00 g, 6.24 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (1.24 g, 6.24 mmol), 4-methylbenzenesulfonic acid hydrate (119 mg, 0.625 mmol), molecular sieves (442 mg) and dichloroethane (8.9 mL) was heated at 130° C. for 162 hours. The reaction was filtered and washed with dichloroethane. The solid was dissolved in MeOH and filtered through a plug of Celite. The solvent was evaporated under reduced pressure to yield spiro[piperidine-4,6′-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine] (1.4 g, 38%). ESI-MS m/z calc. 241.1. found 242.5 (M+1)+; Retention time: 1.10 minutes (4 min run).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1>[Pd]>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:10]2[NH:11][C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=2)=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Agent: [Pd]
Product: Nc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Reaction time: 4 h

Procedure:
A mixture containing 4-(4-fluorophenyl)-2-(4-nitrophenyl)-5-(4-pyridyl)-1H-imidazole (2.0 g, 5.6 mmol) [See Ex. 26 above] and 10% palladium on activated carbon (0.4 g) was stirred under an atmosphere of H2 for 4 h, then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography, eluting with a solvent gradient of 1-10% MeOH/CHCl3. The title compound was obtained as a light orange solid (0.50 g, 27%): 1H NMR (DMSO-d6): d 8.40 (d, 2H); 7.73 (d, 2H); 7.57 (m, 2H); 7.35 (m, 4H); 6.62 (t, 2H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:27]=[C:26]4[C:22]([C:23](C)=[N:24][N:25]4C)=[CH:21][CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CC1[N:42]=NN2C=CC(B(O)O)=CC=12>>[C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:27]=[CH:26][N:25]4[N:24]=[N:42][C:22]([CH3:23])=[C:21]4[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1nnn2ccc(B(O)O)cc12
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(C)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccn4nnc(C)c4c3)sc2c1-c1ccc(Cl)cc1

Procedure:
Prepared in a manner similar to (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,3-dimethyl-1H-indazol-6-yl)-5-methylbenzo[d]thiazol-6-yl)acetate, but using 3-methyl-[1,2,3]triazolo[1,5-a]pyridin-5-ylboronic acid instead of 1,3-dimethyl-1H-indazol-6-ylboronic acid. 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J=7.4 Hz, 1H), 8.21 (s, 1H), 7.91 (s, 1H), 7.66 (dd, J=7.4, 1.6 Hz, 1H), 7.61-7.50 (m, 3H), 7.50-7.43 (m, 1H), 5.17 (s, 1H), 4.27-4.17 (m, 2H), 2.67 (s, 3H), 2.62 (s, 3H), 1.30-1.22 (m, 3H), 0.99 (s, 9H).
Reaction SMILES: OCC(CO)O.C[C@@H]1O[C@@H](O[C@H:14]2[C@H:19](O)[C@@H:18](O)[C@H:17]([NH:22]C(N)=N)[C@@H:16]([OH:26])[C@@H:15]2[NH:27]C(N)=N)[C@H](O[C@@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2NC)[C@@]1(O)C=O.[OH-:47].[K+]>O>[NH2:22][C@H:17]([C:16]([OH:26])=[O:47])[CH2:18][CH2:19][CH2:14][CH2:15][NH2:27]
Reactant: [OH-]
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: [K+]
Solvent: OCC(O)CO
Solvent: O
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 20 h

Procedure:
The glycerol stocks of the Escherichia coli WC196ΔcadAΔldcC/pCABD2 strain were thawed, 100 μL of each was uniformly applied to an L-plate containing 25 mg/L of streptomycin, and culture was performed at 37° C. for 20 hours. The cells in an amount of about ⅛ of the cells obtained on one plate were inoculated in 20 mL of the fermentation medium described below containing 25 mg/L of streptomycin in a Sakaguchi flask, and cultured at 37° C. for 16 hours or 20 hours on a reciprocally shaking culture apparatus. Each of the samples derived from the alga obtained in of Example 7 (2) was suspended in distilled water, Tween 80 was added to the suspension at a concentration of 1%, and the mixture was adjusted to pH 7.0 with 3 N KOH, autoclaved at 120° C. for 20 minutes, and used as the carbon source solution. The medium composition used for the culture is shown below. The hydrolysate of the fat-and-oil fraction derived from the alga, or the water-soluble fraction derived from the alga was used as the carbon source. The totals of the measured aliphatic acid concentration and glycerol concentration of the carbon sources are indicated.
Reaction SMILES: [CH3:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:13].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:18]=1[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)=[O:20].O>CN(C=O)C>[Cl:16][C:17]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:12]2[C:5]3[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=3[C:3]([CH3:13])=[C:2]2[CH3:1])=[CH:27][CH:28]=1)=[O:20]
Reactant: Cc1[nH]c2cnn(C)c(=O)c2c1C
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C)n(Cc2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)c2cnn(C)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
A solution of 2,3,5-trimethyl-1H-pyrrolo[2,3-d]-pyridazin-4(5H)-one (354 mg) in DMF (30 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (8 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 4-(2,4-dichlorobenzoyl)benzyl bromide (757 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 1.5 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer: n-hexane-ethyl acetate 1:1) to provide the title compound as light-yellow powder (612 mg, yield 70%).
Reaction SMILES: COC1C=CC(C2CCN(C3C=CC=C(OC)C=3)C2)=C(N)C=1.Cl.[N:24]1([CH2:31][CH2:32][O:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=O)=[CH:36][CH:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.N1(CCOC2C=C[C:56]([CH2:57][NH:58][C:59]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=3[CH:67]3[CH2:71][CH2:70][N:69]([C:72]4[CH:77]=[CH:76][CH:75]=[C:74]([O:78][CH3:79])[CH:73]=4)[CH2:68]3)=CC=2)CCCCCC1>>[N:24]1([CH2:31][CH2:32][O:33][C:34]2[CH:42]=[CH:41][C:37]([CH2:38][N:58]([CH2:57][CH3:56])[C:59]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=3[CH:67]3[CH2:71][CH2:70][N:69]([C:72]4[CH:77]=[CH:76][CH:75]=[C:74]([O:78][CH3:79])[CH:73]=4)[CH2:68]3)=[CH:36][CH:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Reactant: COc1cccc(N2CCC(c3ccc(OC)cc3NCc3ccc(OCCN4CCCCCC4)cc3)C2)c1
Agent: COc1cccc(N2CCC(c3ccc(OC)cc3N)C2)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1cc(OC)ccc1C1CCN(c2cccc(OC)c2)C1

Procedure:
Synthesized from 5-methoxy-2-[1-(3-methoxyphenyl)pyrrolidin-3-yl]phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl]{5-methoxy-2-[1-(3-methoxyphenyl)pyrrolidin-3-yl]phenyl}amine (202 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl{5-methoxy-2-[1-(3-methoxyphenyl) pyrrolidin-3-yl]phenyl}amine (188 mg). The total amount of this compound was used according to an analogous synthetic method to Example 111 to provide the title compound (153 mg).
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:44]([OH:46])=[O:45])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH:31]([P:38]([CH2:42][CH3:43])([CH2:40][CH3:41])=[O:39])[P:32]([CH2:36][CH3:37])([CH2:34][CH3:35])=[O:33])=[CH:23][CH:22]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.Cl>N1CCCCC1.CN(C=O)C.O>[CH2:36]([P:32]([CH:31]([P:38]([CH2:40][CH3:41])([CH2:42][CH3:43])=[O:39])[CH2:30][CH2:29][CH2:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C@@H:19]([C:44]([OH:46])=[O:45])[NH2:18])=[CH:26][CH:25]=1)([CH2:34][CH3:35])=[O:33])[CH3:37]
Reactant: CCP(=O)(CC)C(CCCOc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1)P(=O)(CC)CC
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: O
Product: CCP(=O)(CC)C(CCCOc1ccc(C[C@H](N)C(=O)O)cc1)P(=O)(CC)CC
Yield: 97.8 %

Procedure:
A solution of 84 (490 mg, 0.622 mmol) in piperidine/DMF (1:1, 4 mL) was stirred at room temperature for 45 min. After diluting with water and adjusting the pH to ˜3 by the addition of 1N HCl the aqueous layer was washed with diethyl ether (2×) then the pH was readjusted to ˜10 by the addition of 1N NaOH. The product was extracted with ethyl acetate (3×) washed with saturated aqueous NaCl and dried over Na2SO4. The crude material was purified by silica gel chromatography (0 to 10% methanol in CH2Cl2 over 10 column volumes then 10 to 20% over 5 column volumes) using a Biotage Horizon™ apparatus resulting in the colourless liquid 85 (271 mg, 77%): 1H NMR (400 MHz, CDCl3) δ 1.33 (t, J=7.1, 6H), 1.34 (t, J=7.1, 6H), 1.43 (s, 9H), 2.04-2.17 (m, 4H), 2.37 (tt, J=5.8, 24.1, 1H), 2.77 (dd, J=7.6, 13.7, 1H), 2.97 (dd, J=5.5, 13.7, 1H), 3.55 (dd, J=5.5, 7.6, 1H), 3.94 (t, J=5.8, 2H), 4.14-4.23 (m, 8H), 6.78 (d, J=8.6, 2H), 7.10 (d, J=8.6, 2H): 31P (162 MHz, CDCl3) δ 24.76 (s, 2P).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].CN(C)CC[N:11]1[C:19]2[CH:18]=[CH:17][C:16](Cl)=[C:15]3[C:21](=[O:28])[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][C:27]=4[C:13]([C:14]=23)=[N:12]1>N1C=CC=CC=1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:16]1[CH:17]=[CH:18][C:19]2[NH:11][N:12]=[C:13]3[C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[C:21](=[O:28])[C:15]=1[C:14]=23
Reactant: CN(C)CCn1nc2c3c(c(Cl)ccc31)C(=O)c1cnccc1-2
Reactant: CN(C)CCN
Solvent: c1ccncc1
Product: CN(C)CCNc1ccc2[nH]nc3c2c1C(=O)c1cnccc1-3
Temperature: 80 °C

Procedure:
Under a nitrogen atmosphere N,N-dimethylethylenediamine (1.79 mL) is added to a stirred solution of 2-[2-(dimethylamino)ethyl]-5-chloroisoquino[5,6,7-cd]indazole-6(2H)-one of Example 8 (0.539 g) in pyridine (6.80 mL) and the resulting solution is heated at 80° C. for 12 hours. The pyridine and excess N,N-dimethylethylenediamine are removed by roto-evaporation and the obtained residue is purified by silica gel column chromatography eluting first with methylene chloride, then with methylene chloride/methanol 95/5 and finally with methylene chloride/methanol/concd. ammonia from 95/5/0.5 to 95/5/1 v/v/v. The fractions containing the yellow desired product are pooled and the solvents roto-evaporated. The obtained residue (0.529 g) is crystallized from diisopropylether to give 2-[2-(dimethylamino)ethyl)]-5-[[2-(dimethylamino)ethyl]amino]isoquino[5,6,7-cd]indazole-6(2H)-one as a yellow powder (0.291 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[N:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[S:11][C:12]=1[C:13](O)=[O:14]>C1COCC1>[CH3:7][C:8]1[N:9]=[C:10]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=2)[S:11][C:12]=1[CH2:13][OH:14]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Temperature: 5 °C
Reaction time: 3.5 h

Procedure:
Cool (0° C.) a solution of lithium aluminum hydride (10 mL, 1M in THF) and add a solution of 4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid (Commercially available, 2.87 g, 10 mmol) in THF (20 mL). On complete addition, remove the cold bath and stir for 3.5 hrs. Cool this solution to 5° C., and then add water (0.25 mL), dropwise, followed by NaOH solution (0.25 mL, 5M in water) and water (0.5 mL). Dilute the resulting mixture with ethyl acetate and then filter through a pad of celite. Wash the solids with dichloromethane and then concentrate the combined filtrates under reduced pressure to give the title compound as a yellow solid (2.59 g).
Reaction SMILES: C([O:8][C:9](=[O:47])[C@H:10]([N:16]1[CH2:20][C@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[C@@H:18]([CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][C:37]([F:46])([F:45])[C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:31][CH2:30]2)[CH2:17]1)[CH2:11][CH:12]1[CH2:15][CH2:14][CH2:13]1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[F:46][C:37]([F:45])([C:38]1[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=1)[CH2:36][CH2:35][CH:32]1[CH2:33][CH2:34][N:29]([CH2:28][C@@H:18]2[C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH2:20][N:16]([C@H:10]([CH2:11][CH:12]3[CH2:15][CH2:14][CH2:13]3)[C:9]([OH:47])=[O:8])[CH2:17]2)[CH2:30][CH2:31]1
Reactant: O=C(OCc1ccccc1)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCC(F)(F)c3ccc(F)cc3)CC2)[C@@H](c2cccc(F)c2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCC(F)(F)c3ccc(F)cc3)CC2)[C@@H](c2cccc(F)c2)C1
Reaction time: 1 h

Procedure:
2-(R)-(3-(S)-((4-(3,3-Difluoro-3-(4fluorophenyl)propyl) piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid benzyl ester (170 mg, 0.261 mmol, from EXAMPLE 155, Step I) dissolved in 95% ethanol (15 mL) was hydrogenated at atmospheric pressure using 20% Pd(OH)2/C (35 mg). After 1 h, the mixture was filtered, the catalyst was washed with 95% ethanol, and the filtrate was evaporated. The crude product was purified by flash column chromatography on silica gel eluting with 95:5:1 v/v/v CH2Cl2/CH3OH/NH4OH followed by 90:10:1 v/v/v CH2Cl2/CH3OH/NH4OH to give the title compound as 137 mg of amorphous glass which could be recrystallized from CH3OH: 1H NMR (500 MHz, CD3OD) δ 7.49 (dd, J=9, 5, 2H), 7.39-7.33 (m, 1H), 7.19-7.11 (m, 4H), 7.01 (td, J=8, 2, 1H), 3.63 (dd, J=11, 8, 1H), 3.57 (bt, J=10, 1H), 3.42 (dd, J=9,4, 1H), 3.39-3.26 (m, 2H), 3.15 (bq, J=10, 1H), 2.89 (d, J=11, 1H), 2.77-2.66 (m, 2H), 2.54-2.44 (m, 2H), 2.35 (dd, J=13, 4, 1H), 2.22-2.06 (m, 4H), 2.03-1.54 (m, 10H), 1.31-1.00 (m, 5H); ESI-MS 561 (M+H); HPLC A: 2.72 min.