Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:17]([CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1)=[O:18].C(Cl)Cl>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]([CH:19]2[CH2:20][CH2:21][N:22]([C:25]3[N:26]=[CH:27][CH:28]=[CH:29][N:30]=3)[CH2:23][CH2:24]2)=[O:18])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CON(C)C(=O)C1CCN(c2ncccn2)CC1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)C1CCN(c2ncccn2)CC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 83.1 %

Procedure:
A solution of 1,4-dibromobenzene (2.29 g, 9.72 mmol, 1.9 eq) in THF (20 ml) under N2 was cooled to −78° C., and n-butyllithium (1.6 M in hexanes, 4.8 ml, 7.67 mmol, 1.5 eq) was added dropwise. The reaction mixture was stirred at −78° C. for 40 minutes, and a solution of N-methoxy-N-methyl-1-(pyrimidin-2-yl)piperadine-4-carboxamide (1.28 g, 5.11 mmol, 1 eq) in THF (5 ml) was added dropwise via a cannula. After 3 hours at −78° C., the reaction mixture was warmed to 0° C., stirred for 1 hour, and then quenched with 1 N aq. HCl (10 ml). The mixture was diluted with 150 ml of ethyl acetate, washed sequentially with saturated aq. NaHCO3 and brine (75 ml each), and the organic phase was dried over Na2SO4 and concentrated. Column chromatography (silica gel, CH2Cl2 3.5% ethyl acetate/CH2Cl2) afforded 1.47 g (83% yield) of the product as a pale yellow solid: HPLC: 99% pure at 3.748 min (YMC-Pack ODS-A 4.6×33 mm column, 0% 100% solvent B over 4 min, 3 ml/min, 220 nm); LCMS (M+H)+=345.90; 400 MHz 1H NMR (CDCl3) 8.31 (d, J=4.7 Hz, 2H), 7.83 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 6.48 (t, J=4.7 Hz, 1H), 4.81 (m, 2H), 3.49 (m, 1H), 3.08 (m, 2H), 1.72-1.95 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[I:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([CH3:16])[N:3]=[C:2]([N:21]3[CH:22]=[C:18]([I:17])[N:19]=[CH:20]3)[CH:7]=2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(Cl)n1
Reactant: Ic1c[nH]cn1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-dichloro-phenyl)-6-methyl-pyridine (example A.51) (3.5 g, 12.8 mmol) and commercially available 4-iodo-imidazole (2.99 g, 15.4 mmol) according to the general procedure IVa. Obtained as a light grey solid (0.90 g, 16%). MS (ISP) 430.0 [(M+H)+], 432.1 [(M+2+H)+] and 434.0 [(M+4+H)+].
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[N:22]1[CH:27]=[CH:26][C:25]([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Reactant: OB(O)c1ccncc1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2ccncc2)s1
Yield: 16 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, using 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.055 mmol) and pyridine-4-boronic acid (7 mg, 0.06 mmol). The title compound was obtained in 16% yield (3.1 mg). MS (ESI+) calcd mass for C16H12N6O2S2 384.046315, found 384.047755.
Reaction SMILES: [CH:1]([N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])=[CH:2][CH2:3][CH3:4].[C:11](OC)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1>CN(C)C=O>[CH:1]([N:5]1[CH2:9][CH2:8][CH:7]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=2)[C:6]1=[O:10])=[CH:2][CH2:3][CH3:4]
Reactant: COC(=O)c1cccnc1
Reactant: CCC=CN1CCCC1=O
Solvent: CN(C)C=O
Product: CCC=CN1CCC(C(=O)c2cccnc2)C1=O
Temperature: 90 °C
Yield: 94.5 %

Procedure:
Sodium hydride (8.63 g, 0.36 mol of 60% dispersion in a mineral oil) was washed with toluene to remove mineral oil. To this 20 ml of dimethylformamide (DMF), 1-(but-1-enyl)pyrrolidin-2-one (25 g, 0.1798 mol) and a solution of methyl nicotinate (20.94 g, 0.152 mol) in 15 ml of DMF were added. The reaction mixture was heated at 90° C. for 2 hrs. DMF was partially removed under reduced pressure, 50 ml water added, further cooled to 0-10° C. and pH adjusted to 7 using HCl. The reaction mixture was extracted with ethyl acetate and dried over Na2SO4. After removing the solvent under reduced pressure a yellow solid was obtained, which on recrystallisation with diisopropyl ether gave 1-(but-1-enyl)-3-nicotinoyl-pyrrolidin-2-one (II, 35.1 g, 94% yield), 95% HPLC, M.R: 65-66° C. 1H NMR (CDCl3): δ 9.3 (1H, d), 8.8 (1H, d), 8.41 (1H, dt), 7.4 (1H, m), 6.76 (1H, d), 5.0 (1H, m), 4.5 (1H, m), 3.57-3.67 (2H, m), 2.7 (1H, m), 2.3 (1H, m), 2.0 (2H, m), and 1.0 (3H, t). 13C-NMR (CDCl3): δ 194.4, 167.1, 153.7, 150.4, 137.0, 134.4, 131.2, 123.3, 114.9, 51.7, 44.2, 23.2, 22.3, and 14.26. IR: 2966, 2937, 2855, 2847, 1631, 1613, 1489 Cm−1.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[C:11]([N:13]=[C:14]([NH2:16])[NH2:15])#[N:12].[OH-].[K+]>COCCO.O>[NH2:12][C:11]1[N:13]=[C:14]([NH2:16])[N:15]=[C:6]([C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([S:2][CH3:1])[CH:4]=2)[N:7]=1
Reactant: CSc1cccc(C#N)c1
Reactant: N#CN=C(N)N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: CSc1cccc(-c2nc(N)nc(N)n2)c1

Procedure:
4.0 g of m-methylthiobenzonitrile, 2.7 g of dicyanodiamide and 2.0 g of caustic potash are dissolved in 20 ml of methyl cellosolve, and the mixture is refluxed for 4 hours. After cooling, the mixture is diluted with water and the separated crystals are recrystallized from dioxane. Melting point: 229°-230° C.; Yield: 3.4 g.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[H-].[Na+].Cl[CH2:7][C:8]1[C:9]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]([CH:17]([CH3:19])[CH3:18])=[N:12][C:13]=1[CH:14]([CH3:16])[CH3:15]>O1CCCC1>[CH:17]([C:11]1[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:8]([CH2:7][O:3][CH2:1][CH3:2])=[C:13]([CH:14]([CH3:15])[CH3:16])[N:12]=1)([CH3:18])[CH3:19]
Reactant: CCO
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CCl)c1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
4.4 ml (76 mmol) of absolution ethanol are added dropwise at room temperature to a suspension of 2.29 g (76 mmol) of sodium hydride (80% strength) in 30 ml of absolute tetrahydrofuran and the mixture is stirred for 30 minutes. A solution of 2.7 g (7.6 mmol) of the compound from Example 86 are then added dropwise in 20 ml of absolute tetrahydrofuran and the mixture is heated overnight under reflux. The reaction batch is subsequently poured onto ice water and, after the pH has been adjusted to 8, extracted several times using ether. The organic phase is washed with sodium chloride solution, dried over sodium sulphate, concentrated and chromatographed over silica gel (eluent ethyl acetate/petroleum ether 5195).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])=[CH:22][CH:21]=1>>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: CC(C)(O)Cc1ccc(N)cc1
Agent: Cl
Product: CC(C)(O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 72.7 %

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.105 g, 0.35 mmol) was reacted with 1-(4-aminophenyl)-2-methylpropan-2-ol (0.086 g, 0.53 mmol) to afford the title compound (0.100 g, 73%) as a white solid. MW=392.92. 1H NMR (DMSO-d6, 500 MHz) δ 8.06 (s, 1H), 7.90-7.88 (m, 1H), 7.75-7.72 (m, 1H), 7.46-7.39 (m, 2H), 7.23-7.14 (m, 5H), 4.28 (s, 1H), 2.90 (t, J=7.5 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.64 (s, 2H), 2.08 (quin, J=7.5 Hz, 2H), 1.08 (s, 6H); APCI MS m/z 393 [M+H]+.
Reaction SMILES: Cl.C([N:4]=C=NCCCN(C)C)C.[Br:13][C:14]1[C:19]2[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:22][C:18]=2[C:17]([C:27](O)=[O:28])=[CH:16][C:15]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.OC1C2N=NNC=2C=CC=1.N>CN(C)C=O>[Br:13][C:14]1[C:19]2[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:22][C:18]=2[C:17]([C:27]([NH2:4])=[O:28])=[CH:16][C:15]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)c1cc2c(Br)c(-c3ccccc3)cc(C(=O)O)c2o1
Agent: Cl
Agent: N
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2c(Br)c(-c3ccccc3)cc(C(N)=O)c2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
1-Ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (1.61 g, 8.42 mmol) was added to an N,N-dimethylformamide (80 ml) solution of 4-bromo-2-tert-butyl-5-phenyl-1-benzofuran-7-carboxylic acid (I-256) (2.62 g, 7.02 mmol) and hydroxybenzotriazole (1.14 g, 8.42 mmol), followed by stirring at room temperature for 1 hour. The reaction liquid was cooled at 0° C., then aqueous 28% ammonia (1.42 ml, 21.1 mmol) was put into it, followed by further stirring at room temperature for 1 hour. The reaction liquid was concentrated under reduced pressure, then saturated sodium bicarbonate water (200 ml) was added, the product was extracted with ethyl acetate (200 ml×2). The organic layer was washed with saturated brine (50 ml), then dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3:2) to obtain the entitled compound (2.59 g, 99%) as a yellow white solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=3)[CH:10]=[N:11][C:7]=2[CH:6]=1.[O:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1.C(=O)(O)[O-].[Na+]>O.C(COC)OC.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>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:23]4[CH:24]=[CH:25][O:21][CH:22]=4)[CH:13]=3)[CH:10]=[N:11][C:7]=2[CH:6]=1
Reactant: CON=Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Reactant: OB(O)c1ccoc1
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: COCCOC
Solvent: O
Product: CON=Cc1ccc2c(c1)ncn2-c1cccc(-c2ccoc2)c1
Temperature: 80 °C

Procedure:
A mixture of 1-(3-Bromophenyl)-5-formylbenzimidazole O-methyloxime (29a) from Example 8 (0.7 g, 2.1 mmol), 3-furanylboronic acid (0.26 g, 2.34 mmol), sodium bicarbonate (0.89 g, 10.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (50 mg) in a mixture of water (5 ml) and dimethoxyethane (10 ml) is stirred at 80° C. under nitrogen over night. After cooling water is added and the mixture is extracted with ethyl acetate. The extract is dried over sodium sulfate and concentrated under reduced pressure. The residue is eluted through silica gel with a mixture of ethyl acetate and petroleum ether (1:1). The pure fractions are evaporated to dryness. Trituration with petroleum ether affords a white, crystalline product. Yield: 0.42 g (63%). Mp 147-148° C.
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][CH2:2]1.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:9])=[O:8].C(N(C(C)C)CC)(C)C>CN(C=O)C>[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:1]2[CH2:5][C:4](=[O:6])[NH:3][CH2:2]2)=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: O=C1CNCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CN(c2ccc([N+](=O)[O-])cc2)CN1
Temperature: 25 °C

Procedure:
A solution of 4-imidazolidinone (9.5 g, 110.5 mmol), 4-nitrobenzene (1 eq) and diisopropyl ethylamine (28.6 mL, 165 mmol) in dry DMF (80 mL) was heated to 60° C. overnight under argon. The reaction mixture was allowed to cool to room temperature and ice pieces were added. The solid formed was filtered and washed with water. The solid was air dried to yield the nitro compound as yellow crystals.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[N:19][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C[N:34](C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[N:19][C:20]([N:22]5[CH2:23][CH2:24][N:25]([CH2:28][C:29]([NH2:34])=[O:30])[CH2:26][CH2:27]5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCN(CC(=O)O)CC3)cc1OCC2
Reactant: CN(C)C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCN(CC(N)=O)CC3)cc1OCC2
Temperature: 25 °C

Procedure:
2-(4-(2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)piperazin-1-yl)acetic acid from Example 331 (0.050 g, 0.11 mmol) dissolved in N,N-Dimethylformamide (1.79 mL, 0.0231 mol) and treated sequentially with N,N-Diisopropylethylamine (0.119 mL, 0.686 mmol) Ammonium chloride (0.0244 g, 0.457 mmol) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.0521 g, 0.137 mmol;). Stir at r.t. 2 h. Add sat. sodium bicarbonate, extract with ethyl acetate. Dry organics over sodium sulfate and concentrate to give 332, analyzed by rHPLC. MS: (ESI+)=466.2. 1H NMR (400 MHz, DMSO) δ 9.11 (s, 1H), 7.89 (s, 1H), 7.85 (s, 1H), 7.20 (s, 2H), 6.35 (s, 1H), 5.93 (dt, J=13.7, 7.0 Hz, 1H), 4.50 (d, J=10.4 Hz, 4H), 3.57 (s, 5H), 2.91 (s, 2H), 1.47 (d, J=6.5 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][N:5]1[CH2:29][CH2:28][C:8]2([N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:11](=[O:20])[N:10]=[C:9]2[NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:7][CH2:6]1.Br[CH2:35][CH2:36][CH2:37][C:38]#[N:39].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH:22]1([NH:21][C:9]2[C:8]3([CH2:28][CH2:29][N:5]([CH2:4][C:3]4[CH:30]=[CH:31][CH:32]=[CH:33][C:2]=4[NH:1][CH2:35][CH2:36][CH2:37][C:38]#[N:39])[CH2:6][CH2:7]3)[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:11](=[O:20])[N:10]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: Nc1ccccc1CN1CCC2(CC1)C(NC1CCCCC1)=NC(=O)N2c1cccc(F)c1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#CCCCNc1ccccc1CN1CCC2(CC1)C(NC1CCCCC1)=NC(=O)N2c1cccc(F)c1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A 2 mL CH3CN suspension of 0.05 g (0.11 mmol) 8-(2-aminobenzyl)-4-(cyclohexylamino)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one (example 80), excess 4-bromobutyronitrile and Cs2CO3 was heated to 60° C. and allowed to stir for 2 days. HPLC/MS showed a small amount of product so the reaction was filtered and concentrated. The remaining oil was purified on an Isco automated system affixed with a Biotage Flash 25(M) cartridge eluted with 0-5% MeOH+0.5M NH3 in CH2Cl2 over 30 min at 20 mL/min. The product eluted last.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13](=O)[CH3:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([F:12])[F:11].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([F:12])[F:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCC(F)F)c(Cl)c1
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC(F)F)c(Cl)c1
Yield: 85 %

Procedure:
The title compound is prepared in 85% yield (3.56 g, a white solid) from 1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanone (2.88 g, 12.2 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:54])[C@H:21]([NH:33][C:34]([N:36]3[CH2:41][CH2:40][CH:39]([N:42]4[C:46](=[O:47])[NH:45][C:44]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)=[N:43]4)[CH2:38][CH2:37]3)=[O:35])[CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=4[CH:24]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[O:54]=[C:20]([N:17]1[CH2:16][CH2:15][CH:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:19][CH2:18]1)[C@H:21]([NH:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]2[C:46](=[O:47])[NH:45][C:44]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[N:43]2)[CH2:38][CH2:37]1)=[O:35])[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:24]=1
Reactant: [H][H]
Reactant: O=C(N[C@H](Cc1ccc2c(c1)CCCC2)C(=O)N1CCC(N2CCN(Cc3ccccc3)CC2)CC1)N1CCC(n2nc(-c3ccccc3)[nH]c2=O)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(N[C@H](Cc1ccc2c(c1)CCCC2)C(=O)N1CCC(N2CCNCC2)CC1)N1CCC(n2nc(-c3ccccc3)[nH]c2=O)CC1

Procedure:
A solution of 80 mg (0.11 mmol) 4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine-1-carboxylic acid [(R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide in 10 mL MeOH was hydrogenated in the presence of 10 mg Pd/C (10%) at 50° C. and 3 bar hydrogen pressure until the calculated volume of hydrogen had been taken up. The catalyst was filtered off, the solvent eliminated under reduced pressure and the residue purified by chromatography on silica gel. The product fractions were evaporated down under reduced pressure and dried.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][C:7]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:52][C@@H:53]([CH2:56][CH:57]([CH3:59])[CH3:58])[CH2:54][OH:55]>CN(C=O)C>[OH:55][CH2:54][C@@H:53]([NH:52][C:12]([C:10]1[CH:9]=[N:8][C:7]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:56][CH:57]([CH3:59])[CH3:58]
Reactant: CC(C)C[C@H](N)CO
Reactant: O=C(O)c1cnc(N2CCCCC2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](CO)NC(=O)c1cnc(N2CCCCC2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
A mixture of 11 mg (0.04 mmol) 6-cyclopropylmethoxy-5-piperidin-1-yl-pyrazine-2-carboxylic acid, 15.3 mg (0.048 mmol) TBTU, 15.3 mg (0.119 mmol) DIPEA and 7 mg (0.059 mmol) (S)-2-amino-4-methyl-pentan-1-ol (commercially available) in 1 mL DMF was shaken at room temperature for 16 h. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The combined product fractions were evaporated to yield 10.5 mg (70%) of the title compound. m/z (ES+): 377.5 (M+H).
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+].[CH3:16][O:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1.O>CN(C=O)C>[CH3:16][O:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:25]=[CH:26][C:27]([CH2:28][N:12]3[C:5]4[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=4[C:3]([CH3:13])=[C:2]3[CH3:1])=[CH:30][CH:31]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: COc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Reactant: Cc1[nH]c2cnn(C)c(=O)c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2ccc(Cn3c(C)c(C)c4c(=O)n(C)ncc43)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
A solution of 2,3,5-trimethyl-1H-pyrrolo[2,3-d]-pyridazin-4(5H)-one (1.06 g) in DMF (90 ml) was dripped into a suspension of 60% sodium hydride-oil (288 mg) in DMF (24 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 4-(4-methoxybenzoyl)benzyl bromide (2.40 g) in DMF (30 ml) was added and the mixture was further stirred at room temperature for 2 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=1:1-1:2) to provide the title compound as light-yellow powder (1.70 g, yield 71%).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[CH3:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[O:24][CH2:25][CH2:26][NH:27][CH3:28])[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[OH:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:3][CH2:2][C:1]([N:27]([CH2:26][CH2:25][O:24][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[C:14]([NH:13][C:11]1[CH:10]=[CH:9][C:8]([OH:29])=[C:7]([CH3:6])[CH:12]=1)=[N:15][CH:16]=[N:17]2)[CH3:28])=[O:5]
Reactant: O=C(O)CO
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ncnc3cccc(OCCN(C)C(=O)CO)c23)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.1 %

Procedure:
A solution of glycolic acid (100 mg) in DMF (2 ml) was added dropwise to a solution of 2-methyl-4-({5-[2-(methylamino)ethoxy]quinazolin-4-yl}amino)phenol (400 mg) in DMF (4 ml) and the mixture held under sonication for 5 minutes. A solution of HATU (519 mg) in DMF (2 ml) was then added and the solution was stirred at ambient temperature for 16 hours, and then concentrated in vacuo. The residue was treated with water to precipitate a brown solid that was collected by filtration, and washed with water to give 2-hydroxy-N-[2-({4-[4-hydroxy-3-methylanilino]quinazolin-5-yl}oxy)ethyl]-N-methylacetamide as a brown solid (406 mg, 86%); NMR spectrum (DMSO-d6) 2.15 (s, 3H), 2.94 (s, 3H), 3.87 (m, 2H), 4.04 (s, 2H), 4.48 (m, 2H), 6.81 (d, 1H), 7.20 (dd, 1H), 7.25 (d, 1H), 7.35 (m, 2H), 7.92 (t, 1H), 8.64 (s, 1H), 9.46 (s, 1H), 10.49 (s, 1H); Mass spectrum M+ 383.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:8]2[C:9]3[CH:10]=[CH:11][C:12]([O:16][CH:17]4[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]4)=[CH:13][C:14]=3[CH:15]=[C:7]2[C:6](=[O:26])[NH:5][CH2:4]1.[CH3:27]I.[H-].[Na+]>>[OH:1][CH2:2][C@H:3]1[N:8]2[C:9]3[CH:10]=[CH:11][C:12]([O:16][CH:17]4[CH2:22][CH2:21][N:20]([CH:23]([CH3:24])[CH3:25])[CH2:19][CH2:18]4)=[CH:13][C:14]=3[CH:15]=[C:7]2[C:6](=[O:26])[N:5]([CH3:27])[CH2:4]1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](CO)CNC2=O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](CO)CN(C)C2=O)CC1
Yield: 16 %

Procedure:
The title compound was synthesized in analogy to example 17, from (S)-4-hydroxymethyl-8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 12), methyl iodide and sodium hydride, to give the desired product as a colorless oil (16%).