Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.Cl.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([NH2:24])[CH2:20][CH2:19]1.CN(C)CCN(C)C>O1CCOCC1>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19]1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN1CCN(N)CC1
Agent: CN(C)CCN(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-3-nitrobenzenesulfonamide (1 g), 4-methylpiperazin-1-amine dihydrochloride (1 g) and N1,N1,N2,N2-tetramethylethane-1,2-diamine (3 mL) in dioxane (10 mL) was refluxed for 12 hours, cooled to ambient temperature and filtered. The filtrate was added to a silica gel column (Analogix, SF65-200 g) and purified by eluting with 1-5% methanol/dichloromethane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19](Cl)=[O:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:19](=[O:20])[C:18]3[C:17]([Cl:16])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:26])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1c(Cl)cccc1Cl

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-dichlorobenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 2,6-dichlorobenzoyl chloride in a similar manner as described above to give a white solid (25% yield). 1H-NMR (DMSO-d6): δ 10.80 (s, 1H), 9.18 (d, 1H), 7.61 (d, 1H), 7.52 (d, 1H), 7.49 (d, 1H), 7.43 (dd, 1H), 7.36 (d, 1H), 7.19 (dd, 1H), 5.27 (m, 1H), 2.69 (m, 2H), 2.08-1.82 (m, 4H); MS m/z 437 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([NH:17][C@@:18]2([C:23](O)=[O:24])[CH2:22][CH2:21][O:20][CH2:19]2)=[O:16])[CH:12]=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][CH2:27][C:28]1[N:33]=[CH:32][C:31]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=2[C:43]([F:46])([F:45])[F:44])=[CH:30][CH:29]=1>>[CH3:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([NH:34][C:31]2[CH:30]=[CH:29][C:28]([CH2:27][NH:26][C:23]([C@:18]3([NH:17][C:15]([C:11]4[CH:10]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:14]=[N:13][CH:12]=4)=[O:16])[CH2:22][CH2:21][O:20][CH2:19]3)=[O:24])=[N:33][CH:32]=2)=[C:36]([C:43]([F:46])([F:44])[F:45])[CH:37]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(C(=O)N[C@@]2(C(=O)O)CCOC2)c1
Reactant: COc1ccc(Nc2ccc(CN)nc2)c(C(F)(F)F)c1
Product: COc1ccc(Nc2ccc(CNC(=O)[C@]3(NC(=O)c4cncc(NC(=O)OC(C)(C)C)c4)CCOC3)nc2)c(C(F)(F)F)c1

Procedure:
Analogously to Example 1e), (S)-3-[(5-tert-butoxycarbonylamino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid (product from Example 5d, 1.7 mmol) was reacted with (6-aminomethyl-pyridin-3-yl)-(4-methoxy-2-trifluoromethyl-phenyl)-amine (product from Example 5b, 1.7 mmol). The product was purified by chromatography (silica gel, dichloromethane with 0-10% methanol).
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][C:14]=3[C:6]=2[C:5]([OH:19])=[N:4][CH:3]=1.[C:20]([Cu])#[N:21]>CN1C(=O)CCC1>[OH:19][C:5]1[C:6]2[C:14]3[CH:13]=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=3[NH:8][C:7]=2[C:2]([C:20]#[N:21])=[CH:3][N:4]=1
Reactant: N#C[Cu]
Reactant: Oc1ncc(Br)c2[nH]c3cc(C(F)(F)F)ccc3c12
Solvent: CN1CCCC1=O
Product: N#Cc1cnc(O)c2c1[nH]c1cc(C(F)(F)F)ccc12
Temperature: 225 °C

Procedure:
A mixture of 4-bromo-7-(trifluoromethyl)-5H-pyrido[4,3-b]indol-1-ol, CuCN (1.4 equiv) in NMP (0.2 M) was heated in the microwave reactor at 225° C. for 40 min. The reaction mixture was then poured into EtOAc/hexanes (10/1) which was passed through a plug of silica gel and eluted with EtOAc. The EtOAc was evaporated and the resulting mixture was partitioned between EtOAc and brine. The organic phase was separated, dried over Na2SO4 and evaporated. The residue was suspended in EtOAc and hexanes, and was then filtered to provide the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([F:18])[CH:10]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>>[C:20]([C:23]1[NH:24][N:25]=[C:26]([C:28]([NH:1][C@@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:10]=[C:11]([F:18])[C:12]([C:13]#[N:14])=[C:15]([F:17])[CH:16]=3)=[N:5]2)=[O:29])[CH:27]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(F)c3)n2)n[nH]1
Yield: 27.3 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (0.7 g, 2.67 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.494 g, 3.20 mmol), HOBt (0.433 g, 3.20 mmol), DIPEA (0.558 ml, 3.20 mmol) and EDCI (0.614 g, 3.20 mmol) using the method of Example 34(d) producing 0.29 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.17 (m, 3H), 4.32 (m, 2H), 4.44 (m, 1H), 6.97 (m, 1H), 7.31 (m, 1H), 7.71 (m, 2H), 7.83 (m, 1H), 8.44 (m, 1H), 14.15 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)ccc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CBr)ccc1F

Procedure:
41.7 g (297.54 mmol) of 2-fluoro-5-methylanisole is refluxed overnight with 59.9 g (327.48 mmol) of N-bromosuccinimide and 145 mg of benzoyl peroxide in 945 ml of carbon tetrachloride. The reaction mixture is filtered through a glass-fiber filter, and after the solvent is spun off, the residue (72.85 g>100%) is incorporated in crude form into the next stage.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[N:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=[O:27].[K+].[K+].OO>CS(C)=O>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:27])[NH2:24])[N:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2cccc(C#N)n2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2cccc(C(N)=O)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 158784064 %

Procedure:
Dissolve {2-[4-(6-cyanopyridin-2-yloxy)phenyl]ethyl}carbamic acid tert-butyl ester (0.814 g, 0.240 mmol) in DMSO (4.8 mL). Add K2CO3 (0.166 g, 0.120 μmol) and then 30% H2O2 (0.071 mL 0.624 mmol). Stir at room temperature for 3 hours. Quench the reaction mixture with water (30 mL). Extract with ethyl acetate (1× 60 mL). Wash the organic layer with water (1× 30 mL), dry over MgSO4, filter and concentrate to give the title compound (68.1 g, 79.5%): MS ES+ 357.9 (M+H)+, base peak ES+ 301.9 (M+2H—C(CH3)3), MS ES− 356.1 (M−H)−; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=18.5 min, 94.5% purity.
Reaction SMILES: [OH:1][CH:2]([CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([CH2:11][CH2:12][C:13]([NH:15]C)=[O:14])=O)=[CH:7][CH:6]=1.O.[NH2:25]N>C(O)(=O)C>[OH:1][CH:2]([CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]2[CH2:11][CH2:12][C:13](=[O:14])[NH:15][N:25]=2)=[CH:7][CH:6]=1
Reactant: CNC(=O)CCC(=O)c1ccc(OCC(O)CNC(C)C)cc1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CC(C)NCC(O)COc1ccc(C2=NNC(=O)CC2)cc1
Yield: 52.4 %

Procedure:
3-[4-(2-Hydroxy-3-isopropylaminopropoxy)benzoyl]-N-methylpropionamide (5g, 0.015 mole) in 50% aqueous acetic acid (50 ml) was treated with hydrazine hydrate (2.4 ml, 0.047 mole) and heated under reflux for one hour. After evaporation under reduced pressure, the residue was dissolved in water, neutralised with aqueous sodium bicarbonate and extracted with dichloromethane. Evaporation of the dried organic solution gave 6-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (2.4 g, 50%, m.p. 108°-115° C). Crystallisation from water gave the pure pyridazinone, m.p. 116.5°-118° C.
Reaction SMILES: [OH:1][C:2]([CH3:26])([CH3:25])[CH2:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][C:8]1[CH2:12][N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14](O)=[O:15])[C:10](=[O:21])[CH:9]=1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH:39][C:14](=[O:15])[C@@H:13]([N:11]3[CH2:12][C:8]([O:7][C:6]4[CH:22]=[CH:23][CH:24]=[C:4]([CH2:3][C:2]([OH:1])([CH3:25])[CH3:26])[CH:5]=4)=[CH:9][C:10]3=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:35]2)[CH2:30][O:29]1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.1 %

Procedure:
To a solution of (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (prepared as in Example 235, 0.159 g, 0.44 mmol) in N,N-dimethylformamide (5 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.129 g, 0.65 mmol), N,N-diisopropylethylamine (0.312 g, 2.41 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.778 g, 1.76 mmol) at 0° C. The mixture was allowed to slowly warm up to room temperature and stirred for 48 h. The solvents were then concentrated in vacuo. The residue was dissolved in ethyl acetate and the mixture formed was washed with aqueous saturated ammonium chloride and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was initially purified by flash column chromatography (silica gel 10% to 100% ethyl acetate/hexanes). Then followed by reverse phase HPLC (C18, 20×150 mm column and 45-100% water/acetonitrile gradient at a flow rate of 30 mL/min) to afford (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (0.181 g, 76%) as a white solid: HR-ES-MS m/z calculated for C29H40N4O6 [M+H]+ 541.3021, observed 541.3017; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.89 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.05 (s, 6H), 1.24 (s, 3H), 1.29 (s, 3H), 1.36-1.64 (m, 2H), 1.63-1.80 (m, 1H), 2.67 (s, 2H), 3.73 (dd, J=8.4, 5.9 Hz, 1H), 4.00 (dd, J=8.4, 6.3 Hz, 1H), 4.03-4.14 (m, 2H), 4.17 (d, J=18.4 Hz, 1H), 4.28-4.37 (m, 1H), 4.36 (s, 1H), 4.55 (d, J=18.4 Hz, 1H), 4.82 (s, 1H), 4.87 (dd, J=10.7, 4.7 Hz, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.03-7.17 (m, 3H), 7.24-7.41 (m, 1H), 7.59 (d, J=2.1 Hz, 1H), 10.77 (s, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[C:11]([C:17]([CH3:21])([CH3:20])[CH:18]=[O:19])=[CH:10][C:9]2=[O:22])[CH2:2][CH2:3][CH3:4].[NH2:23][OH:24]>CO.O>[CH2:1]([O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:12]3[C:11]([C:17]([CH3:21])([CH3:20])[CH:18]([OH:19])[N+:23]=3[O-:24])=[CH:10][C:9](=[O:22])[C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCOc1ccc2c(c1)C(=O)C=C(C(C)(C)C=O)C2=O
Solvent: O
Solvent: CO
Product: CCCCOc1ccc2c(c1)C(=O)C=C1C2=[N+]([O-])C(O)C1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(6-Butoxy-1,4-dioxo-1,4-dihydro-2-naphthalenyl)-2-methylpropanal (compound 5 prepared in step (I) above) (53 mg, 0.18 mmol) in MeOH (5 mL) and water (0.5 mL), 50% NH2OH in water solution (17 μL, 0.28 mmol) was added. The mixture was stirred 3 h at room temp and the solvent was evaporated. The crude product was fairly pure and was taken into the next step without further purification. Yield: 52 mg (92%). 1H NMR (400 MHz, CDCl3) δ 0.99 (tr., 3H), 1.38 (s, 3H), 1.52 (s, 3 H), 1.55 (m, 2 H), 1.84 (quint., 2H), 4.13 (tr., 2H), 5.31 (s, 1 H), 6.43 (s, 1H), 7.24 (d, 1 H), 7.73 (d, 1 H), 9.07 (d, 1 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[OH:23][C:24]1[CH:25]=[C:26]([O:33][CH:34]([CH3:36])[CH3:35])[CH:27]=[C:28]([CH:32]=1)[C:29](O)=[O:30].[Cl-].[NH4+]>C(Cl)(Cl)Cl>[OH:23][C:24]1[CH:25]=[C:26]([O:33][CH:34]([CH3:36])[CH3:35])[CH:27]=[C:28]([CH:32]=1)[C:29]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)=[O:30]
Reactant: CC(C)Oc1cc(O)cc(C(=O)O)c1
Reactant: Nc1nccs1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)Oc1cc(O)cc(C(=O)Nc2nccs2)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 53.3 %

Procedure:
After adding 2.45 g (24.5 mmol) of 2-aminothiazole, 3.40 ml (24.5 mmol) of triethylamine and 4.14 g (24.5 mmol) of 2-chloro-1,3-dimethylimidazolinium chloride to a solution of 2.40 g (12.2 mmol) of the obtained carboxylic acid in chloroform (50 ml) while cooling on ice, the mixture was stirred at room temperature for 13 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, extraction was performed with chloroform, and the organic layer was dried and then concentrated under reduced pressure. After adding 10 ml of 4N aqueous sodium hydroxide to a solution of the obtained residue in methanol (40 ml), the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then saturated aqueous ammonium chloride was added, extraction was performed with chloroform, and the organic layer was dried and then concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=100:1) to obtain 1.81 g of 5-hydroxy-3-isopropoxy-N-thiazol-2-yl-benzamide (yield: 53%) as a white solid.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][CH2:15][CH2:16][C:17]#[N:18]>CN(C=O)C>[Si:6]([O:14][CH2:15][CH2:16][C:17]#[N:18])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#CCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.7 %

Procedure:
Imidazole (33.6 g, 495 mmol) and tert-butyldimethylsilyl chloride (27.2 g, 180 mmol) were added to a 0° C. solution of 3-hydroxypropanenitrile (10.6 g, 150 mmol) in DMF 50 mL). The mixture was allowed to warm to rt, then was stirred at rt for 12 hrs. The mixture was quenched with water (500 mL), and then extracted with EtOAc (3×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (gradient elution 0˜5% EtOAc/petroleum ether) to give 3-(tert-butyldimethylsilyloxy) propanenitrile (18 g, 75%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 3.74 (t, J=6.0 Hz, 2H), 2.43 (t, J=6.0 Hz, 2H), 0.81 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=[O:18])=[N:9]2)=[CH:4][CH:3]=1.C[Mg+].[Br-].[CH2:25](O)C>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:18])[CH3:25])[CH:19]=[CH:20][CH:21]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1

Procedure:
To 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde, MeMgBr was added (in THF at 0° C.) to give an ethanol derivative, which was oxidized to the title compound as in Example 15, Step 11. 1H NMR (CD3COCD3): δ 2.68 (3H, s), 7.55-7.68 (3H, m), 7.89-8.05 (6H, m), 8.36 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.Cl.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.NC1C=CC(C(F)(F)F)=CC=1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1cc2ncnc(Nc3ccc(C(F)(F)F)cc3)c2cn1
Temperature: 180 °C
Reaction time: 0.03 h
Yield: 63.2 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (390 mg, 2.03 mmol), 4-aminobenzotrifluoride hydrochloride (0.40 g, 2.02 mmol) and 4-aminobenzotrifluoride (1.61 g, 10.0 mmol) is stirred at 180° C. for 2 min. The resulting product is neutralized with excess NaHCO3, dissolved in MeOH/CHCl3, dried onto alumina and chromatographed over alumina (4-7% MeOH/CH2Cl2) to give 7-amino-4-(4-trifluoromethylanilino)pyrido[4,3-d]pyrimidine (390 mg, 63%) as a cream solid. Analytically pure material was obtained by further chromatography over silica gel (5% MeOH/CH2Cl2) to give pale yellow needles. 1H NMR (DMSO) δ 10.09 (1H, brs), 9.40 (1H, s), 8.48 (1H, s), 8.13 (2H, d, J=8.2 Hz), 7.74 (2H, d, J=8.7 Hz), 6.72 (2H, brs), 6.40 (1H, s)
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[CH:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:28](=[O:29])[CH2:27][C:22]3[CH:21]=[C:20]([F:19])[CH:25]=[C:24]([F:26])[CH:23]=3)[N:11]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nn1nc(C2CCCCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(C2CCCCC2)c2ccccc2c1=O

Procedure:
The product of Example 74A and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.60-11.61 (bs, 1H), 8.34 (dd, J=7.9, 1.4 Hz, 1H), 8.13 (d, J=8.2 Hz, 1H), 8.00 (ddd, J=8.1, 7.2, 1.5 Hz, 1H), 7.90 (ddd, J=8.0, 7.1, 1.0 Hz, 1H), 7.07-7.22 (m, 3H), 3.75 (s, 2H), 3.26 (d, J=10.3 Hz, 1H), 1.89-1.93 (m, 2H), 1.79-1.83 (m, 2H), 1.70-1.76 (m, 1H), 1.39-1.58 (m, 4H), 1.19-1.32 (m, 1H); MS (ESI) m/z 398 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.N1C=CC=CC=1.[C:17]1([CH:23]([N:25]2[CH2:29][CH2:28][CH:27]3[CH2:30][NH:31][CH2:32][CH:26]23)[CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCO>[CH2:8]([C:6]1[CH:7]=[C:2]([N:31]2[CH2:30][C@@H:27]3[C@@H:26]([N:25]([CH:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:24])[CH2:29][CH2:28]3)[CH2:32]2)[N:3]=[C:4]([NH2:10])[N:5]=1)[CH3:9]
Reactant: CCc1cc(Cl)nc(N)n1
Reactant: CC(c1ccccc1)N1CCC2CNCC21
Solvent: CCO
Solvent: c1ccncc1
Product: CCc1cc(N2C[C@H]3CCN(C(C)c4ccccc4)[C@H]3C2)nc(N)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
To a solution of 4-chloro-6-ethyl-pyrimidin-2-ylamine (200 mg, 1.27 mmol) in EtOH (2.4 mL) was added pyridine (210 μL, 2.54 mmol) and 1-(1-phenyl-ethyl)-octahydro-pyrrolo[3,4-b]pyrrole (360 mg, 1.65 mmol). The solution was stirred for 2 h at 90° C. The compound was purified directly with reversed-phase HPLC to yield 115 mg (28%) of the desired compound as a yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])[CH3:2].Cl.[NH2:26][CH2:27][C:28]1[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=1[CH:34]([CH3:36])[CH3:35].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH2:1]([N:3]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:12]=1)[C:7]([NH:26][CH2:27][C:28]1[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=1[CH:34]([CH3:35])[CH3:36])=[O:8])[CH3:2]
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)O)c1C)C1CCN(C)CC1
Reactant: Cc1cc(C(C)C)c(CN)c(=O)[nH]1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.5 %

Procedure:
To a stirred solution of 3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzoic acid (crude material, ˜0.313 mmol) and 3-(aminomethyl)-6-methyl-4-(propan-2-yl)-1,2-dihydropyridin-2-one HCl salt (88.0 mg, 0.407 mmol) in DMSO (2.4 mL) was added PyBOP (244 mg, 0.470 mmol) and hunig base (164 ul, 0.939 mmol). The reaction mixture was stirred at rt for 16 hours. The reaction mixture was quenched with water and diluted with ethylacetate. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (NH—SiO2 ethylacetate/MeOH=20/1+5% triethylamine). The crude compound was dissolved with DMSO, diluted with water. The precipitated solid was collected and triturated with ethylacetate/TBME/hexane to give the titled compound as a white solid (80.0 mg, 51% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.31 (s, 1H), 7.26 (s, 1H), 7.03-7.10 (m, 1H), 6.04 (s, 1H), 4.59 (d, J=6.0 Hz, 2H), 3.49-3.55 (m, 1H), 3.09 (q, J=6.8 Hz, 2H), 2.81-2.84 (m, 2H), 2.70-2.78 (m, 1H), 2.32 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H), 1.86-1.89 (m, 2H), 1.68-1.71 (m, 4H), 1.22 (d, J=6.4 Hz, 6H), 0.84 (t, J=6.8 Hz, 3H); MS (ES) [M+H] 507.2, [M+Na] 529.2; HPLC 97.7% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([NH:12][CH2:13][C@H:14]1[O:18][C@@H:17]([N:19]2[CH:26]=[C:25]([CH2:27][CH3:28])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:16][C@@H:15]1[OH:29])=[O:11].[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:30]([O:29][C@@H:15]1[C@@H:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[O:18][C@@H:17]([N:19]2[CH:26]=[C:25]([CH2:27][CH3:28])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:16]1)(=[O:34])[CH2:31][CH2:32][CH3:33]
Reactant: CCCC(=O)Cl
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3c(Cl)cccc3Cl)O2)c(=O)[nH]c1=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCC(=O)O[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1CNC(=O)Cc1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
A mixture of 400 mg of 5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine, 0.15 ml of butyryl chloride and 1 mg of 4-dimethylaminopyridine in 50 ml of pyridine was stored at room temperature overnight and then evaporated. The residue was subjected to flash chromatography on a column of silica gel using dichloromethane/methanol (24:1) for the elution, there being obtained 175 mg of 3'-O-butyryl-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine in the form of a white solid of melting point 130°-132° C.