Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]3([C:35]4=[CH:36][C:37]5[O:41][CH2:40][O:39][C:38]=5[CH:42]=[C:34]4[O:33][CH2:32]3)[C:24]2=[O:43])[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:1]1([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]4([C:35]5=[CH:36][C:37]6[O:41][CH2:40][O:39][C:38]=6[CH:42]=[C:34]5[O:33][CH2:32]4)[C:24]3=[O:43])[CH2:17][CH2:16]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCC1
Reactant: O=C1N(CCC2CCNCC2)c2ccccc2C12COc1cc3c(cc12)OCO3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1N(CCC2CCN(C3CCCC3)CC2)c2ccccc2C12COc1cc3c(cc12)OCO3
Reaction time: 16 h

Procedure:
To a solution of cyclopentanone (0.04 mL, 0.45 mmol) and triethyl amine (0.12 mL, 0.84 mmol) in dichloroethane (5.00 mL) was added 1′-(2-piperidin-4-ylethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one hydrochloride (0.12 g, 0.28 mmol) and sodium triacetoxyborohydride (0.10 g, 0.45 mmol). The reaction mixture was stirred for 16 hrs and concentrated in vacuo to dryness. The residue was subjected to flash chromatography eluting with ethyl acetate/methanol/ammonium hydroxide (15/1/0.1) to give 1′-[2-(1-cyclopentylpiperidin-4-yl)ethyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one as a white solid, which was treated with 4.0 M HCl in dioxane to give the title compound (0.05 g, 32% yield): mp 153-155° C.; 1H NMR (300 MHz, CD3OD) δ 7.37 (td, 1H), 7.21-7.08 (m, 3H), 6.53 (s, 1H), 6.11 (s, 1H), 5.88 (s, 1H), 5.87 (s, 1H), 4.83 (d, 1H), 4.69 (d, 1H), 3.98-3.75 (m, 2H), 3.68-3.38 (m, 3H), 3.01-2.83 (m, 2H), 2.25-2.08 (m, 4H), 1.92-1.37 (m, 11H); 13C NMR (75 MHz, CD3OD) δ 179.8, 157.6, 150.4, 143.8, 143.4, 133.6, 130.3, 124.9, 124.8, 120.8, 110.3, 103.7, 103.0, 94.3, 81.4, 69.1, 59.8, 53.2, 38.6, 34.3, 32.5, 30.6, 30.5, 29.4, 24.7; MS (ES+) m/z 461 (M+1).
Reaction SMILES: Cl.Cl.[CH:3]1([CH2:9][C@H:10]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[O:13])[NH2:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=2)[CH:29]=[CH:28]1>>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]([NH:11][C@@H:10]([C:12]([N:14]3[CH2:15][CH2:16][CH:17]([CH:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)[CH2:18][CH2:19]3)=[O:13])[CH2:9][CH:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)=[O:37])[CH:34]=2)[CH:29]=[CH:28]1
Reactant: CN1CCC(C2CCN(C(=O)[C@H](N)CC3CCCCC3)CC2)CC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: Cl
Product: CN1CCC(C2CCN(C(=O)[C@@H](CC3CCCCC3)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Using methods substantially equivalent to that described in Method D-1, the titled compound was prepared from 1-(β-cyclohexyl-D-alanyl)-4-(1-methylpiperidin-4-yl)piperidine dihydrochloride and indole-6-carboxylic acid (65%).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:4]=1[NH:5][C:6]2=O.O(Cl)[Cl:21]>CN(C)C=O>[Cl:21][C:6]1[C:7]2[C:2](=[CH:1][CH:10]=[CH:9][CH:8]=2)[C:3]2[C:18]3[C:13]([C:12](=[O:19])[C:4]=2[N:5]=1)=[CH:14][CH:15]=[CH:16][CH:17]=3
Reactant: O=C1c2ccccc2-c2c1[nH]c(=O)c1ccccc21
Reactant: ClOCl
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-c2c1nc(Cl)c1ccccc21
Yield: 78.7 %

Procedure:
A mixture of 6H-indeno[2,1-c]isoquinoline-5,7-dion obtained in reference example 16 (26.6 g, 108 mmol) and phophorous oxychloride (300 ml) was refluxed with heat in the presence of 1 ml of N,N-dimethylformamide for 2 hours. The reaction mixture was distilled to dryness. To the residue was added ice water to obtain a crystal precipitated by filtration. The crystal obtained was washed with water and recrystallized from toluene to give 22.5 g (yield 78.7%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:18]([NH:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:25]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:15]([CH:13]1[CH2:12][CH2:11][C:10]2[C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[S:8][C:9]=2[CH2:14]1)=[O:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)C1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: CN(C)CCNCc1ccccc1
Product: CN(C)CCN(Cc1ccccc1)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1

Procedure:
300 mg (1.12 mmol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 31b) were transformed in analogy to example 3 using N′-benzyl-N,N-dimethylethane-1,2-diamine to give after working up and purification 152 mg (32%) of the title compound.
Reaction SMILES: CC([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])CO.C(C(CCCCCCCCCCCCCC)[CH2:23][OH:24])C>>[CH2:12]([CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH3:5])[CH2:23][OH:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCC(C)CO
Reactant: CCCCCCCCCCCCCCC(CC)CO
Product: CCCCCCCCC(CO)CCCCCC

Procedure:
2-methyl-1-heptadecanol; 2-ethyl-1-hexadecanol;
Reaction SMILES: C=O.[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH2:19][CH:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[C:27](OCC)(=O)C>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[CH2:27][N:22]([C:23](=[O:25])[CH3:24])[CH:20]([CH3:21])[CH2:19]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(CC(C)NC(C)=O)cc1OCc1ccccc1
Agent: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OCc1ccccc1)CC(C)N(C(C)=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Paraformaldehyde (6.32 g) was added portionwise to a solution of 211 (2.21 g, 7.04 mmol) in toluene (55 ml) with pTSA (60 mg). The reaction mixture was heated under reflux for 2 h. Further paraformaldehyde (632 mg) was added and heating under reflux was continued overnight. Additional pTSA (60 mg) and paraformaldehyde (1.9 g) was added to the reaction mixture portionwise over 2 h. The solution was cooled to rt, water (50 ml) and ethyl acetate (60 ml) were added. The layers were separated and the organic layer was washed with water (2×50 ml) and brine (50 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound (2.15 g, 94%) as a colourless oil. 1H NMR indicated a mixture of conformers, signals for both conformers are listed 1.04, 1.12 (3H, d, J=6.7 Hz, CH3CH), 2.14, 2.17 (3H, s, CH3CO), 2.38-2.51 (1H, m, CHH for both conformers), 2.89-3.06 (1H, m, CHH for both conformers), 3.84, 3.85 (3H, s, OCH3), 4.06-4.6 (2H, m, CH2 for both conformers), 5.01-5.02 (3H, m, CHCH3 and CH2Ph for both conformers), 6.6-6.64 (2H, m, 2×CH for both conformers), 7.28-7.44 (5H, m, 5×CH, phenyl for both conformers). LC/MS (ES+) tr=1.02 min, m/z 348.19 (M++Na).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[CH3:16][S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:19])=[O:18].N1C=CC=CC=1.[NH:32]1[C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([CH:41]=O)[C:35]=2[CH:34]=[CH:33]1>O1CCCC1>[CH3:16][S:17]([N:20]1[CH2:25][CH2:24][N:23]([CH2:41][C:36]2[CH:37]=[CH:38][CH:39]=[C:40]3[C:35]=2[CH2:34][CH2:33][NH:32]3)[CH2:22][CH2:21]1)(=[O:19])=[O:18]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCN(Cc2cccc3c2CCN3)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2.92 g of sodium triacetoxyborohydride, 2.26 of 1-methanesulfonylpiperazine hydrochloride and 545 mg of pyridine are successively added to a solution of 1 g of indole-4-carboxaldehyde in 40 ml of tetrahydrofuran under argon. The reaction mixture is stirred at ambient temperature for 15 hours, and then concentrated under reduced pressure. The residue is taken up in 40 ml of acetic acid cooled to 15° C., and then 1.30 g of sodium cyanoborohydride are added in portions. The reaction medium is stirred for 2 hours while allowing it to rise to ambient temperature, poured into a water/ice mixture, treated with 28% aqueous ammonia until the pH is neutral, and extracted with dichloromethane (4×30 ml). The organic phases are combined, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified on a silica column (eluent: heptane/ethyl acetate, from 0 to 100% of ethyl acetate), so as to give 890 mg of 4-(4-methanesulfonylpiperazin-1-ylmethyl)-2,3-dihydro-1H-indole in the form of a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:24])[N:9]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:25](I)[CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:24])[N:9]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[C:10](=[O:14])[N:11]2[CH2:25][CH2:26][CH3:27])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc(Cn2c(=O)[nH]c3cc([N+](=O)[O-])ccc3c2=O)cc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCn1c(=O)n(Cc2ccc(C#N)cc2)c(=O)c2ccc([N+](=O)[O-])cc21

Procedure:
Prepared analogously to Example 1c from 4-[(7-nitro-1,4-dihydro-2H-quinazolin-2,4-dion-3-yl)-methyl]-benzonitrile, propyl iodide and potassium carbonate in dimethyl sulphoxide.
Reaction SMILES: O[CH:2]([C:4]1[O:5][C:6](=[O:20])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].CS([Cl:25])(=O)=O>C(Cl)Cl>[Cl:25][CH:2]([C:4]1[O:5][C:6](=[O:20])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(Cl)c1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 49.8 %

Procedure:
3-(1-Hydroxyethyl)-4-phenyl-1H-isochromen-1-one (intermediate B1, 300 mg, 1.27 mmol), Methane sulfonyl chloride (516 mg, 4.51 mmol), TEA (0.62 mmol, 4.5 ml) were reacted in DCM (10 ml) at RT. Solvent was then removed under reduced pressure to give the title compound (180 mg). This was used in next step without any further purification.
Reaction SMILES: [F:1][C@H:2]1[C@H:5]([CH2:6][O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C:3]1=O.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:16]([NH:23][CH:3]1[CH2:4][CH:5]([CH2:6][O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:2]1[F:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: O=C1C[C@@H](COCc2ccccc2)[C@@H]1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: FC1C(COCc2ccccc2)CC1NCc1ccccc1
Reaction time: 0.08 h

Procedure:
In a 25 mL flask with trans-2-fluoro-3-(benzyloxymethyl)cyclobutanone (0.20 g, 0.96 mmol) inside, dry 1,2-DCE 3.4 mL was added under argon to give a colorless solution. To this, benzylamine (0.11 mL, 1.01 mmol) was added to give still a colorless solution. After stirring for 5 min, sodium triacetoxyborohydride (0.29 g, 1.37 mmol) was added all at once to give a white emulsion. Then AcOH (0.06 mL, 1.05 mmol) was added drop by drop. After 5 min, it gave a yellow solution and this was left stirring for 2 hr and then the reaction was quenched by sat. NaHCO3. The organic phase was separated and the aqueous phase was extracted with EtOAc twice. The combined organic phase was dried over MgSO4 and the crude product was purified by silica gel flash chromatography (Hexane: EtOAc=3:1) to give 0.19 g (65%, Rf=0.18) of the product. 1H NMR (CDCl3, 600 MHz): δ 1.81-1.95 (m, 3H), 2.80-2.89 (m, 1H), 3.46-3.56 (m, 3H), 3.76-3.84 (m, 3H), 4.51-4.55 (m, 2H), 4.89-5.00 (td, 1H, J=54.6, 4.8), 7.25-7.37 (m, 10H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].CCCCCC.[Li]CCCC.[CH:33]1([CH:39]=[C:40]2[CH:44]=[CH:43][CH:42]=[CH:41]2)[CH2:38][CH2:37][CH2:36][CH2:35]C1>C1COCC1>[CH:40]1([C:39]2([C:11]3[C:10]4[CH2:9][C:8]5[C:16](=[CH:17][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=5)[C:15]=4[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=3)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:33]2)[CH:41]=[CH:42][CH:43]=[CH:44]1
Reactant: C1=CC(=CC2CCCCC2)C=C1
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C3(C4C=CC=C4)CCCCC3)c1C2
Yield: 43.8 %

Procedure:
In a 200 ml two-necked flask purged with nitrogen, 1.96 g (7.04 mmol, 1 eq) of 3,6-di-tert-butylfluorene was placed at room temperature. Then, 40 ml of dehydrated THF was added, and the mixture was stirred by a magnetic stirrer to give a solution. The solution was cooled with an ice bath (colorless transparent solution). To the solution, 5.0 ml (8.15 mmol, 1.16 eq) of a hexane solution of n-BuLi was dropwise added over a period of 5 minutes. Then, the ice bath was removed, and the solution was stirred at room temperature for 21 hours (red solution). After the solution was cooled with an ice bath, a solution of 1.37 g (9.37 mmol, 1.33 eq) of 6-cyclohexylfulvene in 5 ml of dehydrated THF was dropwise added over a period of 10 minutes. The ice bath was removed, and the solution was stirred at room temperature for 42 hours. The resulting brownish red solution was poured into 50 ml of a diluted hydrochloric acid solution to perform quenching. The soluble component was extracted from the aqueous layer with 100 ml of diethyl ether, and the organic phase was washed with 80 ml of a saturated saline solution. The dispensed organic phase was dried over MgSO4, then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator to obtain a brownish yellow solid. The solid was purified by silica gel column chromatography (developing solvent: hexane) to obtain 1.31 g of a white solid (yield: 44%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:16]1([CH:12]2[O:13][CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[C:23]([F:34])([F:33])[F:22])=[CH:3][CH:4]=3)=[O:9])[CH2:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(c1ccc(Br)cc1)N1CCOC(c2ccccc2)C1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(c1ccc(-c2ccccc2C(F)(F)F)cc1)N1CCOC(c2ccccc2)C1
Temperature: 120 °C
Yield: 97 %

Procedure:
100 mg of (4-Bromo-phenyl)-(2-phenyl-morpholin-4-yl)-methanone was combined with 82 mg of 2-(Trifluoromethyl)phenyl boronic acid, 33 mg of tetrakis(triphenylphosphine)palladium(0), 0.968 mL of 2M sodium carbonate solution, 2.6 mL toluene and 1.3 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by reverse phase HPLC. ES MS (+) m/z 412, 97% yield.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][C@@H:48]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:49]1[CH:50]=[C:51]([P:55]([CH3:60])(=[O:59])[O:56][CH2:57][CH3:58])[CH:52]=[CH:53][CH:54]=1>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:47][C@@H:48]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:49]2[CH:50]=[C:51]([P:55]([CH3:60])(=[O:59])[O:56][CH2:57][CH3:58])[CH:52]=[CH:53][CH:54]=2)=[O:10])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1
Reactant: CCOP(C)(=O)c1cccc([C@@H](N)c2ccccc2)c1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1cccc([C@@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (12.3 g, 40 mmol) and Et3N (11 g, 109 mmol) in MeCN (200 ml) was added HATU (16.6 g, 43.8 mmol). The mixture was stirred for 10 min at room temperature and then ethyl 3-((S)-amino(phenyl)methyl)phenyl(methyl)phosphinate, 25-d, (10.55 g, 36.5 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with saturated NH4Cl. The organic layer was dried over sodium sulfate and concentrated under vacuum to provide the crude product, 25-e, (33 g) as red oil. The crude product was used for the next step directly.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([N+:19]([O-])=O)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:4]>CO.[H][H].[Ni]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH2:19])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:4]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OCCN1CCCC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1cc(N)ccc1OCCN1CCCC1

Procedure:
1.65 g (5.61 mmol) of 3-methoxycarbonyl-4-(2-pyrrolidin-1-ylethoxy)nitrobenzene (V.1.a) is dissolved in 100 mL of methanol and hydrogenated with hydrogen and 200 mg of Raney nickel as catalyst until the reaction is complete. Then the catalyst is filtered off and the solvent is eliminated. Yield: 1.43 g (97% of theory); Rf value: 0.15 (silica gel, methylene chloride/methanol/ammonia=9:1:0.1); C14H20N2O3; EII mass spectrum: m/z=265 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)=[N:4][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl.[C:20]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5](=[N:4][C:3]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:33]1[CH2:32][CH2:31][N:30]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH2:35][CH2:34]1)[NH:6][C:7](=[O:12])[CH2:8][CH2:9]2
Reactant: O=CCCCOc1nc2c(cc1Cl)CCC(=O)N2
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(Cl)c(OCCCCN3CCN(c4cccc5ccccc45)CC3)nc2N1
Reaction time: 0.25 h
Yield: 46.8 %

Procedure:
To a solution of 4-(3-chloro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (400 mg, approx. 1.49 mmol, crude from previous reaction) in DCE (7 mL) was added 1-naphthalen-1-yl-piperazine hydrochloride (370 mg, 1.49 mmol) followed by Et3N (0.42 mL, 2.98 mmol). The solution was stirred for 15 min and NaBH(OAc)3 (410 mg, 1.94 mmol) was added as a powder. The reaction was stirred at room temperature for 2 h and quenched with saturated NaHCO3 and H2O. The mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography (0–3% MeOH/CH2Cl2) afforded the title compound as an off-white foam (324 mg, 0.697 mmol, 47%). Et2O was added and the foam turned into a white solid after 5 minutes of stirring. The solid was collected by filtration, washed with Et2O and dried to give a white solid. MS: APCI: M+1: 465.2 (Exact Mass: 464.20).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].C(N(C(C)C)C(C)C)C.[CH3:20][O:21][CH2:22][CH2:23][OH:24]>CCOC(C)=O>[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: N#Cc1cccc(CBr)c1
Reactant: COCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCCOCc1cccc(C#N)c1
Yield: 81 %

Procedure:
A solution of 3-(bromomethyl)benzonitrile (1 g, 5.1 mmol) in 2-methoxyethanol (10 mL) and n-ethyldiisopropylamine (0.89 mL, 5.1 mmol) was heated under microwave irradiations for 2 hours at 150° C. After this time, reaction mixture was diluted with EtOAc (200 mL), washed with water and brine to give the title compound as a colorless oil (800 mg, 81%). 1H NMR (DMSO-d6, 300 MHz) δ 7.76-7.74 (m, 2H), 7.68-7.65 (m, 1H), 7.59-7.54 (m, 1H), 4.54 (s, 2H), 3.59-3.56 (m, 2H), 3.51-3.47 (m, 2H), 3.25 (s, 3H). HPLC (Method A) Rt 3.09 min (Purity: 82.9%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])C(O)=O.[NH2:7][CH2:8][CH2:9][C@@H:10]([O:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18])[CH2:11][O:12]C.[BH4-].[Li+].CO>O1CCCC1>[Cl:23][C:21]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([CH:22]=1)[O:14][C@@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][NH:7][C:1](=[O:5])[O:6][C:16]([CH3:19])([CH3:17])[CH3:15]
Reactant: O=C(O)C(=O)O
Reactant: COC[C@@H](CCN)Oc1cc(Cl)ccc1C#N
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC[C@H](CO)Oc1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 148.6 %

Procedure:
The product from step (c) (881 mg, 2.39 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml) and lithium borohydride (2M solution in tetrahydrofuran, 2.6 ml, 5.26 mmol) added dropwise. The mixture was stirred at room temperature for 18 h. Methanol (5 ml) was added and the reaction stirred for 15 minutes. The solvent was removed in vacuo and the residue chromatographed on flash silica, eluting with hexane:ethyl acetate (3:2, then 1:1) to give the title compound as a colourless oil (605 mg, 74%).
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19](=[O:23])[N:18]([NH2:24])[C:17]=2[CH3:25])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[CH:26](=O)[CH2:27][CH3:28].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19](=[O:23])[N:18]([NH:24][CH2:26][CH2:27][CH3:28])[C:17]=2[CH3:25])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCC=O
Reactant: Cc1cc(=O)n(N)c(C)c1C(=O)N[C@H](c1cccc(F)c1)C1CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCNn1c(C)c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c(C)cc1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 34 %

Procedure:
To a mixture of 1-amino-2,4-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (415 mg, 1.21 mmol), propionaldehyde (0.52 mL, 7.3 mmol) and acetic acid (0.5 mL, 9 mmol) in methanol (10 mL) was added sodium cyanoborohydride (0.27 g, 4.2 mmol) and the mixture was stirred under argon atmosphere for 3 days at room temperature. The crude reaction mixture was concentrated in vacuo, diluted with H2O (30 mL) and extracted with dichloromethane (3×30 mL). The combined organic phases were washed with brine, dried over MgSO4 and evaporated. The crude mixture was purified by flash chromatography, yield 34%. LC-MS (m/z) 386.5 (MH+); tR=1.63 (method C).