Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C1C=CC(C[N:10]2[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[CH:11]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28])[CH:21]=2)=CC=1)(C)C.[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([OH:45])([CH3:44])[CH3:43])=[CH:38][CH:37]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C>CN(C)C=O.O>[OH:45][C:42]([C:39]1[CH:40]=[CH:41][C:36]([CH2:35][NH:34][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[N:10][C:11]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([OH:31])[C:27]([F:29])([F:28])[F:30])[CH:21]=2)=[CH:37][CH:38]=1)([CH3:44])[CH3:43]
Reactant: CC(C)(O)c1ccc(CN)cc1
Reactant: CC(C)(O)c1ccc(CN2C=CC=C(C(=O)O)C2Oc2cccc(C(O)C(F)(F)F)c2)cc1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2cccc(C(O)C(F)(F)F)c2)cc1

Procedure:
To a stirred solution of N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-[3-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenoxy]-nicotinic acid (0.400 grams, 1.28 mmole), 2-(4-Aminomethyl-phenyl)-propan-2-ol (0.232 grams, 1.40 mmole), and 1-hydroxybenzotriazole hydrate (0.189 grams, 1.40 mmole) in dry dimethylformamide (5 ml) was added 1-(3-dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (0.294 grams, 1.54 mmole) and stirred over night. The mixture poured into 100 ml water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to give an oil that was purified by chromatography on silica gel eluting with 2.5% methanol/methylene chloride (0.550 g). 1H NMR (CDCl3) d 1.54 (6H, s), 3.53 (1H, d), 4.66 (2H, d), 4.92 (1H, m), 7.46-7.15 (9H, m), 8.12 (1H, m), 8.16 (1H, dd) 8.62 (1H, dd). MW 313.25 MS (m/e) 313 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:21]3[C:22]4[N:13]([CH2:14][C:15](=O)[NH:16][C:17]=4[CH:18]=[CH:19][CH:20]=3)[C:12]2=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:21]3[C:22]4[N:13]([CH2:14][CH2:15][N:16]([CH3:25])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(=O)n3c4c(cccc42)NC(=O)C3)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CN3CCN(C)c4cccc2c43)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-[(4-methylphenyl)sulfonyl]-4H-imidazo[1,5,4-de]quinoxaline-2,5(1H,6H)-dione from Step D (1.16 g, 3.38 mmol) in DMF (40 mL) was added potassium carbonate (467 mg, 3.38 mmol) and the resulting mixture was stirred at ambient temperature for 10 min. Iodomethane (480 mg, 3.38 mmol) was added dropwise and the reaction mixture was stirred for 18 h, then poured into H2O (50 mL). The resulting precipitate was isolated by filtration, washed with H2O, and dried in vacuo to give the title compound. MS: m/z=358 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:6][C@@H:5]([CH2:7][CH2:8][C:9]2[NH:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=2)[CH2:4][O:3]1.C(=O)([O-])[O-].[Br:25]Br>C(Cl)Cl>[Br:25][C:10]1[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][NH:13][C:9]=1[CH2:8][CH2:7][C@H:5]1[CH2:4][O:3][C:2]([CH3:20])([CH3:1])[O:6]1
Reactant: CC1(C)OC[C@H](CCc2cc(-c3ccccc3)n[nH]2)O1
Reactant: BrBr
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC1(C)OC[C@H](CCc2[nH]nc(-c3ccccc3)c2Br)O1
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To a solution of (S)-5-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazole (1.1 g, 4.04 mmol) and MP-carbonate in CH2Cl2 (50 mL) was added bromine (0.645 g, 4.04 mmol) dropwise at 0° C. After stirring for 1 h, MP-carbonate (12.4 g, 40.4 mmol) was filtered off and washed with CH2Cl2. The combined filtrate was poured into water, extracted with CH2Cl2, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as an oil (1.129 g). LCMS m/z=351.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]3[CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=[CH:13][C:7]=3[C:6]=2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:26][N:27]([CH2:29][CH2:30]Cl)[CH3:28]>CN(C)C=O>[ClH:1].[CH3:26][N:27]([CH3:28])[CH2:29][CH2:30][O:16][C:15](=[O:17])[CH2:14][C:11]1[CH:12]=[CH:13][C:7]2[C:6]3[CH:18]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[S:9][C:8]=2[CH:10]=1
Reactant: O=C(O)Cc1ccc2c(c1)sc1ccc(Cl)cc12
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCOC(=O)Cc1ccc2c(c1)sc1ccc(Cl)cc12

Procedure:
A mixture of 2.76 g. of 8-chlorodibenzothiophene-3-acetic acid, 3.04 g. of potassium carbonate, 1.73 g. of dimethylaminoethyl chloride hydrochloride, and 250 ml. of dimethylformamide was stirred and heated at 120° for 4 hours. The solvent was removed in vacuo on the steam bath, and 75 ml. of water added to the residue. The oil was extracted with ethyl acetate and the crude product precipitated as the hydrochloride by the addition of hydrogen chloride. On crystallization from acetone, 1.5 g. of 8-chlorodibenzothiophene-3-acetic acid 2-dimethylaminoethyl ester hydrochloride, m.p. 179°-181°, was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:18]=2[CH3:24])=[O:16])=[C:11]([Cl:25])[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]([Si:47]([CH3:50])([CH3:49])[CH3:48])#[CH:46]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[C:21]([C:46]#[C:45][Si:47]([CH3:50])([CH3:49])[CH3:48])[CH:20]=[CH:19][C:18]=2[CH3:24])=[O:16])=[C:11]([Cl:25])[CH:10]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(Br)cc1C(=O)c1ccc(Nc2ccccc2N)cc1Cl
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(C#C[Si](C)(C)C)cc1C(=O)c1ccc(Nc2ccccc2N)cc1Cl
Temperature: 90 °C
Reaction time: 20 h

Procedure:
In a screw-capped vial (8 mL) was placed dry degassed triethylamine (3.0 mL) and a magnetic stirrer under argon. Compound 543 (200 mg, 0.48 mmol), Pd2(dba)3 (9.0 mg, 0.01 mmol), triphenyl phosphine (13 mg, 0.048 mmol), CuI (2 mg) and ethynyl-trimethyl-silane (66 μL, 0.48 mmol) were added to the vial and the reaction mixture was heated under vigorously stirring at 90° C. for 20 h. The cooled reaction mixture was filtered through Decalite and concentrated in vacuo. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v:v=5:95 to 30:70) as the eluent to afford the title compound as yellow foam.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:7]2=1.[H-].[Na+].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:7]2[C:6]3[C:11](=[C:2]([NH:1][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[N:3]=[CH:4][CH:5]=3)[C:10](=[O:12])[N:9]([CH3:13])[C:8]=2[CH:14]=1
Reactant: Cn1c(=O)c2c(N)nccc2c2ccc(Cl)cc21
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nccc3c2c(=O)n(C)c2cc(Cl)ccc32)cc1
Reaction time: 0.08 h
Yield: 74.6 %

Procedure:
To a stirred solution of 4-amino-8-chloro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (30 mg, 0.059 mmol) in DMF (10 mL) at 0° C. was added NaH (7.09 mg, 0.295 mmol) and the reaction was stirred for 5 min. To this mixture, 1-(chloromethyl)-4-methoxybenzene (0.026 mL, 0.191 mmol) was added and stirred at rt for 16 h. The reaction was quenched by addition of ice and the reaction mixture extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water (25 mL), dried over sodium sulfate, and concentrated under reduced pressure to yield 8-chloro-4-((4-methoxybenzyl)amino)-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (29 mg, 0.044 mmol, 75% yield). LC/MS (ESI) m/e 380.27 [(M+H)+, calcd for C21H19ClN3O2380.11]; LC/MS retention time (Method D): tR=0.86 min.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10]2>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10]2)(=[O:4])=[O:3]
Reactant: Cc1ccc2cc(N)ccc2n1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1ccc2cc(NS(C)(=O)=O)ccc2n1
Reaction time: 17 h

Procedure:
Methanesulphonyl chloride (6.2 ml) was added dropwise to a stirred solution of 6-amino-2-methylquinoline (12.5 g) in pyridine (100 ml) cooled to 5°. Stirring was continued for 17 hours at room temperature. The pyridine was then removed by evaporation in vacuo, the residue diluted with aqueous sodium bicarbonate, and extracted three times with methylene chloride. The combined organic extracts were combined, dried (MgSO4) and evaporated in vacuo to give the title compound, yield 13.0 g, m.p. 151°-153°.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:7]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:6]1.[OH-].[Li+].O>CO>[Cl:24][C:21]1[S:20][C:19]([C:7]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:9](=[O:10])[N:5]([CH2:4][C:3]([OH:25])=[O:2])[N:6]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.90 g (7.60 mmol) of the ester from Example 153A are dissolved in 77 ml methanol and treated with a 1 N solution of lithium hydroxide in water (30.3 ml, 30.4 mmol). The mixture is stirred overnight at RT, then freed of methanol on the rotary evaporator and diluted with 200 ml water. After addition of 1 N hydrochloric acid to a pH value of 2, the product precipitates out as a white solid, which is isolated by filtration and drying in high vacuum. 2.45 g (88% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:38])=[C:11]([N:14]4[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:37])[CH:21]([NH:29]C(OC(C)(C)C)=O)[CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:15]4)[N:12]=3)[C:7](=[O:39])[C:6]([C:40]([OH:42])=[O:41])=[CH:5]2)[CH2:3][CH2:2]1.Cl>C(O)C>[NH2:29][CH:21]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:20]([NH:19][CH:16]1[CH2:17][CH2:18][N:14]([C:11]2[N:12]=[C:13]3[C:8]([C:7](=[O:39])[C:6]([C:40]([OH:42])=[O:41])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:38])[CH2:15]1)=[O:37]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)NC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Agent: Cl
Solvent: CCO
Product: NC(Cc1ccccc1)C(=O)NC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1

Procedure:
A solution of 14.5 g (25 mmol) of [R-(R*,S*)]-1-cyclopropyl-7-[3-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxo-3-phenylpropyl]amino]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-napthyridine-3-carboxylic acid, 100 ml of 1.0M hydrochloric acid and 100 ml of ethanol was heated at reflux for three hours. The solution was filtered through a fiber glass pad to clarify and the solvent removed in vacuo. The residue was triturated with 100 ml of ethanol/ether (1:1) and the solid was removed by filtration. After washing with ethanol/ether (2×50 ml-1:1) and ether, the solid was dried in vacuo to give 10.2 g of the title compound, mp 216°-219°.
Reaction SMILES: Cl.[N:2]1([CH2:7][C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([C:24]([OH:26])=O)=[CH:18]3)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:49][C:50]1([F:56])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:49][C:50]1([F:56])[CH2:55][CH2:54][N:53]([C:24]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:8]2[CH2:7][N:2]2[CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:14])=[CH:23][CH:22]=3)=[O:26])[CH2:52][CH2:51]1
Reactant: FC1(F)CCNCC1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCC[C@@H]3CN3CCCC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc2cc(C(=O)N3CCC[C@@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Yield: 74 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4,4-difluoropiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a colorless solid (74%).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.[N:14]1C=CC=C[CH:15]=1.N>CN(C)P(N(C)C)(N(C)C)=O>[CH3:13][O:12][C:5]1([C:15]#[N:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:2]=[CH:3][CH2:4]1
Reactant: COc1ccc(Br)c2c1CCCC2
Reactant: c1ccncc1
Agent: N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC1(C#N)CC=CC2=C1CCCC2

Procedure:
4-Bromo-1-methoxy-5,6,7,8-tetrahydronaphthalene (1) (2.5 g, 10.4 mM) cuprous cyanide (1.07 g, 5.4 mM), pyridine (1.5 ml) and hexamethylphosphoramide (0.3 ml) were stirred at 192° C. for 16 hours. The mixture was poured into aqueous ammonia and extracted with ether. The ether was washed with ammonia, water, dilute hydrochloric acid and then saturated brine. The ether solution was then dried and evaporated to give the nitrile (2) (1.90 g).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:5]=[C:6]([CH2:13][N:14]2[C:22]3[CH2:21][C@@H:20]([C:23]([OH:25])=[O:24])[NH:19][CH2:18][C:17]=3[N:16]=[CH:15]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].Cl.[CH3:27]O>COC(OC)OC>[CH3:27][O:24][C:23]([C@H:20]1[NH:19][CH2:18][C:17]2[N:16]=[CH:15][N:14]([CH2:13][C:6]3[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([CH3:3])[CH:5]=3)[C:22]=2[CH2:21]1)=[O:25]
Reactant: CO
Reactant: Cc1cc(Cn2cnc3c2C[C@@H](C(=O)O)NC3)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: COC(OC)OC
Product: COC(=O)[C@@H]1Cc2c(ncn2Cc2ccc([N+](=O)[O-])c(C)c2)CN1
Yield: 72.3 %

Procedure:
(S)-1-(3-methyl-4-nitrophenyl)methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid dihydrochloride (VII-2) (1.1538g, 0.00296 mol) was suspended in dry methanol (46 ml) and trimethylorthoformate (4.6 ml). Hydrogen chloride was blown into the suspension to saturation under ice cooling and stirring. The reaction solution was then stirred on a 90° C. oil bath for 6 hours, cooled, and concentrated. The resulting yellowish brown oily material (0.7456 g) was purified by silica gel column chromatography (Kiesegel 60, 60 g, chloroform/methanol= 15/1) to obtain the objective compound (VI-2) (0.7076 g; yield: 72.3%) as an orange oily material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][N:19]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[N:32][N:31]=[CH:30]4)=[CH:25][CH:24]=3)C(=O)C)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[OH-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH:30]=[N:31][N:32]=[CH:33]4)=[CH:27][CH:28]=3)[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CC(=O)N(CC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1)c1ccc(-n2cnnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Clc1cnc(N2CCC([C@H]3C[C@H]3CCNc3ccc(-n4cnnc4)cc3)CC2)nc1
Temperature: 80 °C

Procedure:
N-(2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl)-N-[4-(4H-1,2,4-triazol-4-yl)phenyl]acetamide from step 1 of this example was dissolved in ethanol (0.5 mL), added sodium hydroxide (60% w/w, 0.3 mL) and heated to 80° C. for 5.5 hours. The reaction was cooled to room temperature, water (10 mL) was added and extracted with ethyl acetate (20 mL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 50% acetone/hexanes to give the title compound as a white-solid.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13]O)=[O:6])#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>O1CCCC1>[Br:34][CH2:13][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
trans-N-Cyanomethyl-2-hydroxymethyl-cyclohexanecarboxamide (12.4 g, 63.2 mmol) and triphenylphosphine (19.9 g, 75.8 mmol) were weighed into a 1000 mL round bottom flask fitted with a stir bar, addition port and nitrogen inlet. A nitrogen atmosphere was established and maintained and then anhydrous tetrahydrofuran (300 mL) was added. The reaction mixture was stirred for 30 minutes at room temperature and N-bromosuccinimide (13.5 g, 75.8 mmol) was added to the flask. The reaction slowly cleared to an orange-red solution. The reaction mixture was stirred at room temperature for 18 h and then concentrated on a rotary evaporator. Product was purified from the residue by chromatography on 2360 cm3 of silica gel in a 10×30 cm column with ethyl acetate eluent. The product fractions were concentrated on a rotary evaporator and the residue dried under high vacuum to give trans-2-bromomethyl-N-cyanomethylcyclo-hexanecarboxamide as a white solid with a slight yellow tint.
Reaction SMILES: [C:1]([C:3]1[CH2:7][CH2:6][C@@H:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:4]=1)#[N:2].O1CCOCC1.Cl>ClCCl>[N:8]1([C@@H:5]2[CH2:6][CH2:7][C:3]([C:1]#[N:2])=[CH:4]2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN([C@H]2C=C(C#N)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#CC1=C[C@H](N2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-tert-butyl 4-(3-cyanocyclopent-2-en-1-yl)piperazine-1-carboxylate (13 g, 46.9 mmol) in dry dichloromethane (30 ml) was added slowly hydrochloric acid 1,4 dioxane (100 ml, 4M solution) in a drop wise manner 0° C. The reaction mixture was stirred at 25° C. for 3 h. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue was diluted with dichloromethane (100 ml) and treated with methanolic ammonia (50 ml, 7M solution) and stirred for 30 minutes. The reaction mixture was then evaporated under reduced pressure to obtain crude product which was purified by flash column chromatography over silica gel (100-200 mesh) using 10% methanol in dichloromethane as an eluent to obtain title compound ((7 g, 84%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](Br)=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>>[CH2:1]([O:8][C:9]1[C:10]([O:18][CH3:19])=[CH:11][C:12]([B:20]([OH:25])[OH:21])=[C:13]([O:15][CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OCc2ccccc2)c(OC)cc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Product: COc1cc(B(O)O)c(OC)cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 61.9 %

Procedure:
1-Benzyloxy-4-bromo-2,5-dimethoxybenzene 4 (7.48 g,23.0 mmol) was placed in a dry flask and flushed with Ar. Dry THF (75 mL) was added and the solution was cooled to −78° C. in a dry ice/acetone bath. nBuLi (11 mL, 2.5M in hexanes) was added and the mixture was stirred for 20 min at −78° C. Triisopropyl borate (10.7 mL, 0.463 mol) was added and the reaction stirred for 2 h at −78° C. then allowed to come to room temperature at which time a white precipitate began to form. After stirring for an additional 20 h the reaction was quenched with saturated NH4Cl (25 mL). After separating the organic layer the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layers were combined, dried and concentrated. The residue was triturated with hexanes and filtered to give 4.1 g (62%) of 5b as a light off-white creamy solid. 1H-NMR (400 MHz, DMSO-d6) dH 3.70 (3H, s, OCH3), 3.79 (3H, s, OCH3), 5.16 (2H, s, CH2Ph), 6.77 (1H, s, ArH), 7.18 (1H, s, ArH), 7.33-7.52 (5H, m, CH2Ph)
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].O[C:10](=[C:13]1C(=O)OC(C)(C)[O:15][C:14]1=O)[CH2:11][CH3:12].CCOCC>CCCCCC>[CH2:11]([C:10]1[NH:1][C:2]([CH3:8])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:14](=[O:15])[CH:13]=1)[CH3:12]
Reactant: COC(=O)/C=C(/C)N
Reactant: CCC(O)=C1C(=O)OC(C)(C)OC1=O
Solvent: CCOCC
Solvent: CCCCCC
Product: CCc1cc(=O)c(C(=O)OC)c(C)[nH]1
Temperature: 120 °C
Reaction time: 18 h
Yield: 11.8 %

Procedure:
A mixture of methyl 3-aminocrotonate (5 g) and 5-(1-hydroxypropylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10 g) (obtained as described in J. Org. Chem., 1978, 43, 2087) was heated at 120° C. for 1 hour. The residue was cooled to ambient temperature and treated with a mixture of ether and hexane (1:6 v/v; 35 ml) and allowed to stand for 18 hours. The solvent was removed by decanting and the insoluble residue purified by flash chromatography, eluting with methanol/dichloromethane (1:9 v/v) to give methyl 1,4-dihydro-6-ethyl-2-methyl-4-oxopyridine-3-carboxylate (1 g), as a yellow solid, m.p. 176°-180° C.; NMR (CDCl3): 1.2(t,3H); 2.45(s,3H), 2.45(q,2H), 3.8(s,3H), 6.3(s,1H); mass spectrum (chemical ionisation, ammonia): 196(M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].Cl.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([B:20]([OH:22])[OH:21])=[CH:16][CH:15]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:10])[NH:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([B:20]([OH:22])[OH:21])=[CH:18][CH:19]=1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: O=C=Nc1ccccc1F
Agent: Cl
Product: O=C(NCc1ccc(B(O)O)cc1)Nc1ccccc1F

Procedure:
4-[3-(2-Fluoro-phenyl)-ureidomethyl]-phenylboronic acid was prepared from 2-fluorophenyl isocyanate and 4-aminomethylphenylboronic acid HCL salt according to the procedure of Example 65.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([F:11])[CH:3]=1.Cl[C:13]1[N:18]=[N:17][C:16]([N:19]([CH3:30])[CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[N:18]=[N:17][C:16]([N:19]([CH3:30])[CH:20]3[CH2:25][C:24]([CH3:26])([CH3:27])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)=[CH:15][CH:14]=2)=[C:4]([F:11])[CH:3]=1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(c1ccc(-c2ccc(Cl)cc2F)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 90 °C
Yield: 95.2 %

Procedure:
(4-Chloro-2-fluorophenyl)boronic acid (4.29 g, 24.6 mmol), Intermediate 1-1 (6.63 g, 23.4 mmol) and Na2CO3 (7.45 g, 70.3 mmol) were degassed for 10 minutes with N2, then PdCl2(dppf)CH2Cl2 (0.96 g, 1.17 mmol) was added. The reaction mixture was heated at 90° C. for 2 h. The reaction mixture was concentrated in vacuo then CH2Cl2 and 1 M HCl were added. The aqueous phase was washed with CH2Cl2, then basified to pH 14 with a 6 M NaOH solution. The aqueous phase was then extracted with CH2Cl2 (3×). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 6-(4-chloro-2-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine as a brown solid (8.40 g, 95%). [M+H]: 377.2; 1H NMR (400 MHz, MeOD) δ 7.87 (t, J=8.5 Hz, 1H), 7.76 (dd, J=9.5, 2.4 Hz, 1H), 7.32-7.40 (m, 2H), 7.17 (d, J=9.5 Hz, 1H), 5.13-5.36 (m, 1H), 1.69 (dd, J=12.5, 3.5 Hz, 2H), 1.57 (t, J=12.5 Hz, 2H), 1.38 (s, 6H), 1.23 (s, 6H).