Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19](O)=[O:20])=[O:5].Cl.[F:31][C:32]([F:37])([F:36])[CH2:33][CH2:34][NH2:35]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:16])([CH3:17])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([NH:35][CH2:34][CH2:33][C:32]([F:37])([F:36])[F:31])=[O:20])=[O:5]
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Reactant: NCCC(F)(F)F
Agent: Cl
Product: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)NCCC(F)(F)F

Procedure:
The title compound was prepared from the product of Example 45A and commercially available 3,3,3-trifluoropropylamine hydrochloride by the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz), 1.43 (s, 6H), 1.48 (s, 6H), 2.39-3.50 (m, 2H), 3.35-3.42 (m, 2H), 7.68-7.81 (m, 3H), 8.31 (t, J=5.4 Hz, 1H), 11.53 (br s, 1H). MS (ESI+) m/z 527 (M+H)+. Anal. calcd. for C22H21F7N2O3S: C, 50.19; H, 4.02; N, 5.32. Found: C, 50.30; H, 4.13; N, 5.00.
Reaction SMILES: [NH:1]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:16][C:17]([CH3:23])([CH2:21][CH3:22])[C:18](Cl)=[O:19]>>[CH3:16][C:17]([CH3:23])([CH2:21][CH3:22])[C:18]([N:1]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:19]
Reactant: CCC(C)(C)C(=O)Cl
Reactant: C1COCCOCCOCCOCCN1
Product: CCC(C)(C)C(=O)N1CCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13-tetraoxacyclopentadecane and 2,2-dimethylbutyryl chloride.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].[CH:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)=O.Cl>C(O)C.O>[C:18]([C:17]1[CH:21]=[CH:22][C:14]([CH:12]=[CH:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])=[CH:15][CH:16]=1)([OH:20])=[O:19]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(C=CC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.9 %

Procedure:
Acetophenone (44b, 0.50 ml, 4.3 mmol) and sodium hydroxide (0.50 g, 12.5 mmol) were combined in ethanol (2 ml) and water (2 ml) and stirred for 30 min at room temperature. 4-Formylbenzoic acid (1ad, 0.71 g, 4.7 mmol) was added and the mixture stirred for 48 hr at room temperature. Water (25 ml) was added, the mixture acidified with hydrochloric acid (1 N) and the resulting precipitate was filtered and recrystallized from ethyl acetate to give 0.65 g (60%) of a white solid: mp 222-224° C. [expected mp 227-229° C.]; 1H NMR: (DMSO) δ 7.67 (m, 4H), 7.99 (m, 4H), 8.18 (m, 3H), 13.14 (s, 1H); 13C NMR: (DMSO) δ 124.2, 128.5, 128.7, 128.8, 129.6, 132.1, 133.2, 137.3, 138.7, 142.4, 166.7, 189.0.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[CH:6][CH:7]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:15][C:14]1[O:13][N:12]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]=1[CH2:9][O:8][C:5]1[N:4]=[N:3][C:2]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:7][CH:6]=1
Reactant: C1CCNC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(Cl)nn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(N2CCCC2)nn1
Temperature: 110 °C
Yield: 23.8 %

Procedure:
To a solution of 3-chloro-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine (300 mg, 1.0 mmol) in toluene (5 mL) was added pyrrolidine (0.10 mL, 1.2 mmol), sodium tert-butoxide (115 mg, 1.2 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1-binaphtalene (19 mg, 0.03 mmol) and tris(dibenzylideneacetone)dipalladium chloroform complex (10 mg, 0.01 mmol). The resulting mixture was heated at 110° C. for 55 min with microwave heating. Then the reaction mixture was concentrated and extracted (ethyl acetate/brine). The organic phase was dried over sodium sulfate, concentrated and chromatographed (SiO2, dichloromethane:methanol=100:0 to 99:1) to afford the title compound as a light yellow oil (80 mg, 24%). MS: m/e=337.5 [M+H]−.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[OH:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[O:29][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Reactant: Cc1cccc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1Oc1cc(-c2cccc3[nH]ncc23)nc2c1cnn2C
Temperature: 155 °C
Yield: 19.2 %

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (0.040 g, 0.141 mmol) was dissolved in 2 mL DMF. 2,6-Dimethylphenol 8b (0.034 g, 0.281 mmol) was added followed by the addition of potassium carbonate (0.2 g, 1.41 mmol) and the resultant reaction mixture was heated in a microwave at 155° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate and filtered and the organic portions were washed with saturated sodium bicarbonate solution followed by brine, dried over anhydrous sodium sulfate and solvent removed and purified to obtain 106 as a white solid (10 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.77 (s, 1H), 7.58 (t, J=7.2, 2H), 7.48 (dd, J=11.8, 19.0, 2H), 7.18 (s, 3H), 6.97 (d, J=23.8, 1H), 4.22 (s, 3H), 2.19 (s, 6H)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:21]=[C:22]4[C:28]([C:29](=[O:35])[C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:27][NH:26][C:23]4=[N:24][CH:25]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)C(F)(F)F>[CH3:31][C:30]([CH3:32])([C:29](=[O:35])[C:28]1[C:22]2[C:23](=[N:24][CH:25]=[C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:15]=3)[N:21]=2)[NH:26][CH:27]=1)[C:33]#[N:34]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3cnc4[nH]cc(C(=O)C(C)(C)C#N)c4n3)c2)CC1
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: CC(C)(C#N)C(=O)c1c[nH]c2ncc(-c3cccc(N4CCNCC4)c3)nc12
Temperature: 25 °C

Procedure:
A solution of 4-{3-[7-(2-Cyano-2,2-dimethyl-acetyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester from step 1 in hexafluoroisopropanol was heated at 150° C. in a microwave oven for 45 min. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with a mixture of 28% aqueous ammonium hydroxide:methanol:DCM (1:10:60) in DCM (20% to 80% gradient over 30 min) to give 39 mg of the desired product as a yellow powder. 1H NMR (CDCl3, 400 MHz): δ 8.81 (s, 1H), 8.50 (s, 1H), 7.91 (s, 1H), 7.60-7.54 (m, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.08-7.04 (m, 1H), 3.35 (t, J=4 Hz, 2H), 3.14 (t, J=4 Hz, 2H), 1.92 (s, 6H); MS [M+H]+: 375.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:32])[CH2:15][CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=1[O:30][CH3:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2].C([O:35]CC)C.CCCCCC>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:35])=[O:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:32])[CH2:15][CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=1[O:30][CH3:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOCC
Reactant: CCCCCC(CC(=O)Nc1cc(C=O)ccc1C(C)(C)C)c1cccc(OC)c1OC
Solvent: CCCCCC
Product: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1cccc(OC)c1OC

Procedure:
Following a procedure similar to that described in Preparation 21, but using N-(2-t-butyl-5-formylphenyl)-3-(2,3-dimethoxyphenyl)octanamide (prepared as described in Preparation 24) as a starting material, the title compound was obtained as crystals, melting at 146°-147° C. (from diethyl ether-hexane).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[B:12](OC(C)C)([O:17]C(C)C)[O:13]C(C)C.Cl>CCCCCC.O1CCCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([B:12]([OH:17])[OH:13])=[CH:3][C:4]=1[CH2:10][CH3:11])#[N:7]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCc1cc(Br)ccc1C#N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1cc(B(O)O)ccc1C#N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3.66 ml of n-butylithium solution (1.6M in hexane) are added dropwise to a solution of 1.14 g of 4-bromo-2-ethylbenzonitrile in 20 ml of dry tetrahydrofuran at −78° C. After stirring at this temperature for 20 minute, 1.51 ml of triisopropyl borate are added. After 45 minutes, 12 ml of 1N HCl are added to the reaction mixture, which is warmed to room temperature. The phases are separated and the aqueous phase is extracted three more times with 100 ml of diethyl ether/tetrahydrofuran (1.1) each time. The combinred organic phases are dried with sodium sulphate, filtered and concentrated to 4 ml in vacuo. The remainig oil is mixed with 40 ml of pentane, and the precipitate which has separated out is filtered off with suction and washed twice with pentane. Drying under high vacuum results in the title compound as a yellow solid. Rt=3.27.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Br:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:28]([C:27]2[CH:31]=[CH:32][C:24]([Br:23])=[CH:25][CH:26]=2)=[O:29])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccc(Br)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 51.1 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) and commercially available 4-bromobenzoic acid (78 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (102 mg) was added, and the admixture was stirred at room temperature for 17 hours. The reaction mixture was then purified in the same manner as described in Example 51 to obtain 43 mg of the title compound (yield: 52%).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:27]3[O:26][CH2:25][CH2:24][O:23][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[O:23]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([C:16]([NH:15][C:6]3([C:4]([OH:5])=[O:3])[CH2:7][C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:14]3)=[O:17])[C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2OCCO3)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
The mixture of 2-[(2,3-dihydro-benzo[1,4]dioxine-5-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (59) (495 mg, 1.35 mmol) and KOH (1 g, 17.9 mmol) is dissolved in EtOH (10 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (60) as white solid (440 mg, 96%).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]1[N:20]2[N:21]=[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[C:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[C:19]2[N:18]=[C:17]([CH3:38])[N:16]=1)=O)(C)(C)C.Cl.C(OCC)C>C(Cl)Cl.CO>[ClH:30].[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:22]1[C:23]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[C:19]2[N:18]=[C:17]([CH3:38])[N:16]=[C:15]([N:11]3[CH2:10][C@@H:9]4[CH2:14][C@H:12]3[CH2:13][NH:8]4)[N:20]2[N:21]=1
Reactant: Cc1nc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: Cc1nc(N2C[C@@H]3C[C@H]2CN3)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reaction time: 8 h

Procedure:
To a solution of (1S,4S)-5-[7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (8A-1; 200 mg, 0.36 mmol) in methylene chloride (3 ml) and methanol (3 ml) was added 1M HCl in diethyl ether (1.8 ml, 1.8 mmol). After stirring overnight, the reaction was concentrated, in vacuo, and then triturated from diethyl ether to afford 9A-1 (180 mg, 96%) as a solid: +ESI MS (M+1) 451.3; 1H NMR (400 MHz, CD3OD) δ 7.48-7.36 (m, 4H), 7.32 (d, J=8.7 Hz, 2H), 7.26 (d, J=8.7 Hz, 2H), 4.64 (s, 1H), 3.68 (d, J=10.8 Hz, 1H), 3.55 (dd, J=10.8, 1.6 Hz, 1H), 2.58 (s, 3H), 2.41 br d, J=11.2 Hz, 1H), 2.18 (d, J=11.2 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([S:12](=[O:33])(=[O:32])[NH:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([S:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=3[F:31])[N:15]=2)[CH2:8][CH2:7]1)C.[BH4-].[Li+]>C1COCC1>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][S:22][C:16]1[N:15]=[C:14]([NH:13][S:12]([N:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][OH:3])[CH2:7][CH2:8]2)(=[O:33])=[O:32])[CH:19]=[C:18]([O:20][CH3:21])[N:17]=1
Reactant: CCOC(=O)CN1CCN(S(=O)(=O)Nc2cc(OC)nc(SCc3cccc(F)c3F)n2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(NS(=O)(=O)N2CCN(CCO)CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 24 using a mixture of {4-[2-(2,3-Difluoro-benzylsulfanyl)-6-methoxy-pyrimidin-4-ylsulfamoyl]-piperazin-1-yl}-acetic acid ethyl ester (the product from example 86 step i) (0.31 g) lithium borohydride (1M solution in THF) (1.2 mL) in THF (5 mL). Purification was by reverse phase HPLC (symmetry as the stationary phase and NH4OAc/acetonitrile as the mobile phase) then titurated with Toluene, MeOH followed by DCM to give the title compound as a white solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]=[C:21]1[C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][N:22]1[CH2:39][C:40](O)=[O:41].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:40](=[O:41])[CH2:39][N:22]2[CH2:23][CH2:24][CH2:25][C:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzhydrylpiperazine (1.63 g, 6.46 mmol) in dichloromethane (75 mL) under nitrogen was added the product of Example 68E (2.00 g, 6.46 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (2.48 g, 12.93 mmol) and N,N-dimethylpyridin-4-amine (0.079 g, 0.65 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:3) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.38-7.42 (m, 4H), 7.25-7.31 (m, 12H), 7.16-7.24 (m, 4H), 4.23 (s, 1H), 4.20 (s, 2H), 3.64 (t, J=4.7 Hz, 2H), 3.47 (t, J=6.5 Hz, 2H), 3.41-3.45 (m, 2H), 2.60-2.65 (m, 2H), 2.34-2.42 (m, 4H), 1.78-1.87 (m, 2H); MS (DCI+) m/z 544 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][C@H:14]2[CH3:27])=[O:12])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CN1CCOCC1.[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1>ClCCl>[Cl:8][C:6]1[CH:7]=[C:2]([NH:1][C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])[C:3]([O:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][C@H:14]2[CH3:27])=[O:12])=[N:4][CH:5]=1
Reactant: O=C1CCC(=O)O1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ncc(Cl)cc1N
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ncc(Cl)cc1NC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 31.2 %

Procedure:
To a solution of 2-(3-amino-5-chloro-pyridin-2-yloxy)-1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-ethanone (0.10 g, 0.26 mmol) in dichloromethane (3 mL) was added N-methylmorpholine (0.028 mL, 0.26 mmol) and succinic anhydride (0.026 g, 0.26 mmol). The reaction was stirred at ambient temperature for 3 days. The reaction was diluted with dichlormethane and washed with 1N hydrochloric acid solution. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.040 g, LRMS: 493.2).
Reaction SMILES: C(S)CS.[BH4-].[Na+].[C:7]([C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH:23]([CH3:29])[C:24](OCC)=[O:25])[C:11]=2[CH:10]=1)#[N:8].[OH-].[Na+]>O1CCCC1.C(Cl)Cl>[OH:25][CH2:24][CH:23]([N:12]1[C:11]2[CH:10]=[C:9]([C:7]#[N:8])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:29]
Reactant: CCOC(=O)C(C)N1c2ccccc2Sc2ccc(C#N)cc21
Agent: SCCS
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(CO)N1c2ccccc2Sc2ccc(C#N)cc21
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
1,2-ethanedithiol (113 cc) is poured into a suspension of sodium borohydride (52 g) in tetrahydrofuran (1.4 liters), with stirring, in 15 minutes and at a temperature of about 20° C., and then a solution of ethyl (2RS)-2-(2-cyano-10-phenothiazinyl)propionate (296 g) in tetrahydrofuran (1.4 liters) is poured in 15 minutes under the same conditions. At the end of the addition, the reaction mixture is heated for 20 hours at a temperature of about 60° C. After cooling to a temperature of 5° C., a 4N aqueous solution of sodium hydroxide (1 liter) is poured in over 1 hour: a strong evolution of gas is observed. The reaction mixture is then poured into a mixture of a 4N aqueous solution of sodium hydroxide (1 liter) and methylene chloride (3 liters), while stirring. The organic phase is isolated and the aqueous phase is again extracted with methylene chloride (1 liter). The pooled organic phases are washed with a saturated aqueous solution of sodium chloride (2×1 liter), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The viscous orange oil (290 g) is purified on a column (height: 50 cm; diameter: 8.5 cm) of silica gel (0.2-0.063 mm), eluting successively with methylene chloride (3 liters), then a mixture of methylene chloride and methanol (97.5-2.5 by volume) (4 liters) and with a mixture of methylene chloride and methanol (95-5 by volume) (10 liters) and collecting fractions of 1 liter. Fractions 3 to 15 are pooled and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. 10-[(2RS)1-hydroxy-2-propyl]- 2-phenothiazinecarbonitrile (169.7 g) is thus obtained in the form of a yellow solid which melts at 123° C.
Reaction SMILES: [C:1]([CH:4]([CH:6]1[C:18]2[N:17]3[CH:19]=[CH:20][N:21]=[C:16]3[C:15](=[O:22])[NH:14][C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2)O)([OH:3])=[O:2].C(OC(=O)C)(=O)C>[Cl-].[Zn+2].[Cl-].O>[C:1]([CH:4]=[C:6]1[C:18]2[N:17]3[CH:19]=[CH:20][N:21]=[C:16]3[C:15](=[O:22])[NH:14][C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2)([OH:3])=[O:2]
Reactant: O=C(O)C(O)C1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C(O)C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Yield: 23.1 %

Procedure:
2.4 g of 10-(1-carboxy-1-hydroxymethyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 20 ml of acetic anhydride and 20 mg of zinc chloride are heated to reflux for 4 hours, under cover of argon. The reaction mixture is treated with 25 ml of water and the precipitate formed is filtered off, washed with 25 ml of water and then with 2×25 ml of acetone and dried at 80° C. under vacuum (1 mmHg; 0.13 kPa) to give 0.52 g of 10-(carboxymethylene)-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one in the form of an orange-yellow solid, which product is converted into the sodium salt of formula C15H8N3O3Na (Analysis, % calculated C: 59.81, H: 2.68, N: 13.95, O: 15.93, Na : 7.63, % found C 59.5, H: 2.1, N: 13.6).
Reaction SMILES: COC1N=C2C(=CC=1)N[C@@H](C)C[C@H]2NC(=O)C.[CH2:18]([CH:20]1[CH:29]([CH3:30])[CH:28]([NH:31][C:32]2[CH:33]=[N:34][C:35]3[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=3[CH:41]=2)[C:27]2[N:26]=[C:25]3[CH2:42][CH2:43][CH2:44][CH2:45][C:24]3=[CH:23][C:22]=2[NH:21]1)[CH3:19].Cl[C:47]([O:49][CH:50]([CH3:52])[CH3:51])=[O:48].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH:50]([O:49][C:47]([N:21]1[CH:20]([CH2:18][CH3:19])[CH:29]([CH3:30])[CH:28]([NH:31][C:32]2[CH:33]=[N:34][C:35]3[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=3[CH:41]=2)[C:27]2[N:26]=[C:25]3[CH2:42][CH2:43][CH2:44][CH2:45][C:24]3=[CH:23][C:22]1=2)=[O:48])([CH3:52])[CH3:51]
Reactant: CCC1Nc2cc3c(nc2C(Nc2cnc4c(c2)CCCC4)C1C)CCCC3
Reactant: CC(C)OC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: COc1ccc2c(n1)[C@H](NC(C)=O)C[C@H](C)N2
Solvent: c1ccncc1
Product: CCC1C(C)C(Nc2cnc3c(c2)CCCC3)c2nc3c(cc2N1C(=O)OC(C)C)CCCC3
Yield: 31 %

Procedure:
Prepare the title compound by essentially following the procedure described in Example 46, Step 2, by replacing (+/−)-cis-N-(6-methoxy-2-methyl-1,2,3,4-tetrahydro-[1,5]naphthyridin-4-yl)acetamide, with (2-ethyl-3-methyl-1,2,3,4,6,7,8,9-octahydro benzo [b][1,5]napthyridin-4yl)-(5,6,7,8-tetrahydro-quinolin-3-yl)-amine (0.575 g, 1.52 mmol), and using isopropyl chloroformate, pyridine, and dimethylaminopyridine. Purify using silica gel column chromatography (gradient eluent, neat ethyl acetate) to provide the title compound (0.218 g, 31%). MS (ES+): 463 (M+H).
Reaction SMILES: [I-:1].[I-].[I-].[C:4]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[C:15]([CH3:28])[C:16]3[C:25]([CH:26]=2)=[S+:24][C:23]2[C:18](=[C:19]([CH3:27])[CH:20]=[CH:21][CH:22]=2)[N:17]=3)[CH2:9][CH2:8]1)(=[O:6])[CH3:5].[C:29]([N:32]1[CH2:37][CH2:36][N:35](C2C=C(C)C3C(C=2)=[S+]C2C(=C(C)C=CC=2)N=3)[CH2:34][CH2:33]1)(=[O:31])[CH3:30].C(N1CCN(C2C=C(C)C3C(C=2)=[S+]C2C(=C(C)C=CC=2)N=3)CC1)(=O)C.C(N1CCNCC1)(=O)C>CO>[I-:1].[C:29]([N:32]1[CH2:37][CH2:36][N:35]([C:21]2[CH:20]=[C:19]([CH3:27])[C:18]3[C:23]([CH:22]=2)=[S+:24][C:25]2[C:16](=[C:15]([CH3:28])[CH:14]=[C:13]([N:10]4[CH2:9][CH2:8][N:7]([C:4](=[O:6])[CH3:5])[CH2:12][CH2:11]4)[CH:26]=2)[N:17]=3)[CH2:34][CH2:33]1)(=[O:31])[CH3:30]
Reactant: CC(=O)N1CCN(c2cc(C)c3nc4c(C)cccc4[s+]c3c2)CC1
Agent: CC(=O)N1CCNCC1
Agent: [I-]
Solvent: CO
Product: CC(=O)N1CCN(c2cc(C)c3nc4c(C)cc(N5CCN(C(C)=O)CC5)cc4[s+]c3c2)CC1

Procedure:
A solution of 3-(4-acetylpiperazin-1-yl)-1,9-dimethylphenothiazin-5-ium triiodide (73 mg, 0.1 mmol) in methanol (5 mL) and 1-acetylpiperazine (38.5 mg, 0.3 mmol) was stirred for 24 h at room temperature. The resulting mixture was concentrated to dryness and purified by flash chromatography using the methanol-chloroform gradient to provide the title compound.