Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:12]([OH:14])=O)=[CH:8][N:7]=[C:6]1[C:15]1[CH:19]=[CH:18][S:17][CH:16]=1.C(Cl)(=O)C(Cl)=O.[C:26]1(=[O:33])[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[CH2:27]1.C(N(CC)CC)C.OC(C)(C)C#N>ClCCl.CN(C)C=O>[OH:33][C:26]1[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[C:27]=1[C:12]([C:9]1[C:10](=[O:11])[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)=[N:7][CH:8]=1)=[O:14]
Reactant: O=C1CCCC(=O)C1
Reactant: COCCn1c(-c2ccsc2)ncc(C(=O)O)c1=O
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCn1c(-c2ccsc2)ncc(C(=O)C2=C(O)CCCC2=O)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1,6-dihydro-1-(2-methoxyethyl)-6-oxo-2-(3-thienyl)-5-pyrimidinecarboxylic acid (i.e. the product from Example 10, Step C) (0.5 g, 1.8 mmol) in 10 mL of dichloromethane was added oxalyl chloride (0.45 g, 3.6 mmol) and one drop of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The crude oil was redissolved in 10 mL of dichloromethane and treated with 1,3-cyclohexanedione (0.22 g, 2.0 mmol) and triethylamine (0.18 g, 1.8 mmol). The reaction mixture was stirred for 30 min then treated with a catalytic amount of 2-hydroxy-2-methyl-propanenitrile (0.015 g, 0.18 mmol) and triethylamine (0.182 g, 1.8 mmol) and stirred at ambient temperature for 16 h. The reaction mixture was then concentrated under reduced pressure and purified by medium pressure liquid chromatography on silica gel eluting with 0 to 10% methanol in chloroform to provide 0.160 g of the title compound (also known as 2-[[1,6-dihydro-1-(2-methoxyethyl)-6-oxo-2-(3-thienyl)-5-pyrimidinyl]carbonyl]-1,3-cyclohexanedione), a compound of the invention, as a solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[N:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1>C(O)C>[Br-:1].[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N+:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1
Reactant: Cc1ccncc1
Reactant: OCCCCCCBr
Solvent: CCO
Product: Cc1cc[n+](CCCCCCO)cc1
Product: [Br-]
Reaction time: 36 h
Yield: 100 %

Procedure:
6-Bromo-1-hexanol (27.61 mmol), 4-picoline (30.07 mmol) and absolute ethanol (16 mL) were added to a 3-neck, round-bottomed flask, and were heated at reflux The reaction was stopped after 36 hours. The solvent was removed under vacuum and the residue was washed with diethyl ether (4×100 ml), after which any remaining solvent was removed by vacuum. The product was obtained as an orange-yellow viscous liquid in a 100% yield. 1H NMR (400 MHz, DMSO-d6): δ 9.01 (2H, d, J=6.4 Hz), 8.02 (2H, d, J=6.4 Hz), 4.57 (2H, t, J=7.2 Hz, 7.2 Hz), 4.01 (1H, br), 3.37 (2H, t, J=6.4 Hz, 6.4 Hz), 2.26 (3H, s), 1.89 (2H, p, J=7.2 Hz, 7.2 Hz, 7.2 Hz, 7.2 Hz), 1.21-1.49 (6H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:29]([C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35])#[N:30]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[C:31]([C:29]#[N:30])[CH:32]=2)[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cccc(C#N)c2)C[C@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Example 17D (1.38 g, 4.38 mmol) in anhydrous dichloromethane (25 mL) was added triethylamine (0.9 mL) followed by 3-cyanobenzoyl chloride (0.727 g, 4.38 mmol) and the mixture was stirred for 4 hours at room temperature. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (50 mL) and H2O (20 mL). The aqueous layer was extracted with ethyl acetate (2×30 mL) and the combined organic layers dried (Na2SO4), filtered, and concentrated to an oil which was chromatographed on a Biotage 40M eluting with 10% hexane/90% ethyl acetate to provide the titled compound. MS (ESI) m/e 445 (M+H)+, 443 (M−H)−; 1H NMR (300 MHz, CD3OD) δ ppm 1.39 (s, 6 H) 1.45 (s, 3 H) 1.65 (m, 1 H) 2.53 (m, 2 H) 3.05 (m, 1 H) 3.19 (m, 2 H) 3.46 (m, 2 H) 3.78 (m, 2 H) 4.61 (m, 3 H) 7.66 (t, 1 H) 7.89 (d, 1 H) 8.11 (d, 1 H) 8.17 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4]/[C:5](=[N:8]/[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])/[NH:6][CH:7]=1.CCN(C(C)C)C(C)C.Br[CH2:29][C:30]([NH2:32])=[O:31].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4]/[C:5](=[N:8]/[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])/[N:6]([CH2:29][C:30]([NH2:32])=[O:31])[CH:7]=1
Reactant: NC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)/N=c2/ccc(Br)c[nH]2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(S(=O)(=O)/N=c2/ccc(Br)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-[5-Bromo-1H-pyridin-(2Z)-ylidene]-4-methyl-benzenesulfonamide (80 g, 244.5 mmol) is suspended in anhydrous DMF (350 ml). Hunigs base (46.8 ml, 268.9 mmol) is added followed by 2-bromoacetamide (37.12 g, 268.9 mmol) and the mixture is stirred at room temperature for 72 hours. The reaction is poured into water (1000 ml) and the mixture is stirred for 1 hour. The product is collected by filtration, washed with more water (300 ml) and dried in a vacuum oven at 50° C. to give the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[C:7]([CH3:26])[N:6]=1)[CH:2]([CH3:4])[CH3:3].[NH2:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30]>>[OH:30][CH2:29][CH:28]([NH:27][C:23](=[O:25])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[N:12]=[C:11]([C:9]3[CH:8]=[C:7]([CH3:26])[N:6]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[CH:10]=3)[O:15][N:14]=2)=[CH:17][CH:18]=1)[CH2:31][OH:32]
Reactant: NC(CO)CO
Reactant: Cc1cc(-c2nc(-c3ccc(CC(=O)O)cc3)no2)cc(CC(C)C)n1
Product: Cc1cc(-c2nc(-c3ccc(CC(=O)NC(CO)CO)cc3)no2)cc(CC(C)C)n1

Procedure:
N-(2-Hydroxy-1-hydroxymethyl-ethyl)-2-{4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-acetamide is prepared from {4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-acetic acid and 2-amino-propane-1,3-diol in analogy to Example 65; LC-MS: tR=0.73, [M+1-1]+=425.06.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC=CC=3C(F)(F)F)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[C:26]([F:25])([F:35])[F:36])[N:13]=2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccccc3C(F)(F)F)c(-c3ccc(Cl)cc3)c2CC1
Product: FC(F)(F)c1ccccc1Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 49.3 %

Procedure:
The title compound (0.04 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 2-trifluoromethylbenzyl bromide (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(2-trifluoromethyl-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H19ClF3N3, 405.12. found, m/z 406.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.45 (d, J=7.7 Hz, 2H), 7.25-7.24 (br m, 3H), 7.18-7.16 (br m, 3H), 6.46-6.44 (br m, 1H), 5.43-5.41 (s, 2H), 3.14-3.11 (br m, 4H), 2.89-2.87 (br m, 4H).
Reaction SMILES: O=[C:2]([CH2:7][C:8](=O)[CH3:9])[C:3]([O:5][CH3:6])=[O:4].O1CCCC1.[Cl:16][C:17]1[C:18]([NH:24][NH2:25])=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1>C(O)(=O)C>[Cl:16][C:17]1[C:18]([N:24]2[C:2]([C:3]([O:5][CH3:6])=[O:4])=[CH:7][C:8]([CH3:9])=[N:25]2)=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: COC(=O)C(=O)CC(C)=O
Reactant: NNc1ncc(Cl)cc1Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)nn1-c1ncc(Cl)cc1Cl
Yield: 50.7 %

Procedure:
To a 100 mL flask, methyl 2,4-dioxopentanoate (2.88 g, 0.020 mol), tetrahydrofuran (15 mL), acetic acid (30 mL), and 3,5-dichloro-2-hydrazinylpyridine (3.56 g, 0.020 mol) were added sequentially. The reaction mixture was heated to reflux for 2 hours and then the mixture was concentrated by rotary evaporator. Then ethyl acetate (150 mL) and water (100 mL) was added, the organic layer was washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate and concentrated by rotary evaporator. The residue was purified by silica gel column chromatography (Fluent: ethyl acetate/petroleum ether=1/5) to give the product (2.9 g) as a white solid in 50% yield. Melting point: 97-98° C. 1H NMR (300 MHz, CDCl3): 8.432 (d, 1H), 7.888 (d, 1H), 6.802 (s, 1H), 3.760 (s, 3H), 2.370 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[N:35]O)[NH2:34])=[CH:29][CH:28]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:35]=[C:33]([C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)[N:34]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(=NO)c1ccc(F)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccc(F)cc4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 34 mg (0.22 mmol, 1.1 eq.) of 4-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 56 mg (60% of theory)
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1.CC([O-])=O.[K+].CC(O)=O>CO.O>[C:22]([O:21][CH2:20][C@H:18]1[O:19][C@@H:7]([N:6]2[C:5]3[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=3[N:3]=[C:2]2[Br:1])[C@H:8]([OH:9])[C@@H:13]1[OH:14])(=[O:24])[CH3:23]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 52a (1.048 g, 2.0 mmol) and KOAc (0.98 g, 10.0 mmol) in MeOH/H2O (40 mL/4 mL) was stirred at room temperature for 24 hr. AcOH (0.572 mL 10.0 mmol) was added and stirring was continued at room temperature for 15 min. The reaction mixture was evaporated and the residue was partitioned between. EtOAc/H2O (75 mL/75 mL). The EtOAc layer was washed with sat. NaCl solution (75 mL), dried (Na2SO4), and evaporated. The residue was chromatographed on a silica column (1.9×24 cm, eluted with CHCl3, 2%, 3%, 4% MeOH/CHCl3). Evaporation of fractions 15-27 (15 mL per fraction) and recrystallization from MeOH gave 0.50 g (2 crops, 57%) of 52b as white crystals. MP: 85°-95° C. (melted slowly over a large range) MS: (El) m/e 437.9398 (15%, M+ =437.9385). 1H NMR (DMSO-d6): d 8.00, 7.95 (2×s, 2, 7-H and 4-H), 5.90 (d, 1, 1'-H, J1'-2' =7.5 Hz), 5.58 (d, 1, 2'-OH, J2'-2'OH =6.5 Hz), 5.46 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 4.44 (dd, 1, 5=-H, J5'-4' =4.5 Hz, J5'-5 =12.5 Hz), 4.43 (m, 1,2'-H, J2'-3' =6.0 Hz), 4.24 (dd, 1,5"-H, J5"-4' =2.0 Hz), 4.16 (m, 1, 4'-H, J3'-4' =3.0 Hz), 4.11 (m, 1, 3'-H), 2.15 (s, 3, 5'-OAc). 13C NMR (DMSO-d6): d 169.96 (COCH3), 142.57 (C3a), 132.49, 132.42 (C2 and C7a), 125.78, 125.74 (C5 and C6), 120.14 (C4), 113.28 (C7), 90.32 (C1'), 82.56 (C4"), 71.27 (C2"), 68.99 (C3'), 63.34 (C5'), 20.58 (COCH3). Anal. Calcd. for C14H13BrCl2N2O5 : C, 38.21; H, 2.98; N, 6.37. Found: C, 38.37; H, 2.86; N; 6.27.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#N)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O1CCOCC1.[OH-:21].[K+].[OH2:23]>>[N:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]([OH:23])=[O:21])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O
Reactant: [OH-]
Reactant: N#Cc1ccc(N2CCOCC2)cc1
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N2CCOCC2)cc1
Yield: 99 %

Procedure:
A solution of 4-(4-morpholinyl)benzonitrile (930 mg, 5.00 mmol) in 1:1 dioxane:water (20 mL) was treated with potassium hydroxide (1.12 g, 20 mmol). The mixture was heated at reflux for 96 h, concentrated, and the residue was dissolved in water. Upon acidification (pH ˜2-3), a white precipitate resulted which was collected by filtration yielding 1.21 g (99%) of the title compound.
Reaction SMILES: [NH2-].[Na+].Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1>O1CCCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)[NH2:12])=[CH:16][CH:17]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A flask containing tetrahydrofuran (2.0 mL) was charged with sodium amide (202 mg, 4.92 mmol; Aldrich) and chilled to 0° C. (4-Fluorophenyl)hydrazine hydrochloride (400 mg, 2.46 mmol; Aldrich) was added in portions. After 5 minutes the solid had completely dissolved and the ice bath was removed. Stirring was continued for 1 hour, then the solution was chilled again in an ice bath and 1-(bromomethyl)-4-chlorobenzene (556 mg, 2.7 mmol; Aldrich) was added dropwise. After 30 minutes, the ice bath was removed and the reaction was heated to 50° C. overnight. The mixture was diluted with water (5 mL) and extracted with dichloromethane (2×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product which was carried on without further purification: LC/MS (DCI/NH3) m/z 234 (M+H−NH3)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[C:21]([O:23][CH3:24])=[O:22]>ClCCl>[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[O:23][CH3:24])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(N)c1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Nc1cccc(C(C)=O)c1

Procedure:
A mixture of m-aminoacetophenone, diisopropylethylamine, methyl chloroformate and dichloromethane was reacted as described in Example 1, giving 33.4 g of (3-acetylphenyl)carbamic acid, methyl ester.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]2[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=2)[CH2:15][CH2:14]1)=O.C([BH3-])#N.[Na+].C(Cl)Cl>CO>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=3)[CH2:15][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(CCCN2CCC(C=O)CC2)cc1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1ccc(CCCN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 1899.1 %

Procedure:
A solution of (1R,2S)-2-phenylcyclopropanamine (1.051 g, 7.89 mmol) and ethyl 4-(3-(4-formylpiperidin-1-yl)propyl)benzoate (1.9 g, 6.26 mmol) in methanol (50 mL) was heated to reflux for 5 minutes. The reaction was cooled to room temperature and sodium cyanoborohydride (0.590 g, 9.39 mmol) was added. The reaction was stirred at room temperature for 16 hours. After concentrating, dichloromethane was added and the solution was washed with water followed by brine and dried over MgSO4, filtered and concentrated. The residue was purified via Biotage (0% to 100% EtOAc:Hex; to get off impurity then 0% to 20% MeOH:DCM to get off product 50 g-HP-silica gel column) to yield 1.18 g 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90-1.18 (m, 2H), 1.20-1.36 (m, 2H), 1.40 (t, J=7.07 Hz, 4H), 1.66-1.80 (m, 2H), 1.81-2.02 (m, 5H), 2.24-2.45 (m, 3H), 2.56-2.79 (m, 4H), 2.95 (d, J=10.86 Hz, 2H), 4.38 (q, J=7.24 Hz, 2H), 6.99-7.10 (m, 2H), 7.10-7.20 (m, 1H), 7.21-7.38 (m, 5H), 7.97 (d, 2H) MS (ES); [M+H]+ 421.3
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[C:29]([NH:31][CH2:32][CH2:33]O)=[O:30])=[O:8].CCN(CC)CC.CS(Cl)(=O)=O>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[C:29]1[O:30][CH2:33][CH2:32][N:31]=1)=[O:8]
Reactant: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(=O)NCCO)n(Cc3ccccn3)c2c1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C3=NCCO3)n(Cc3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N3-(3,4-difluorobenzyl)-N2-(2-hydroxyethyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-2,3-dicarboxamide (Compound 103, 36 mg, 0.069 mmol) in CH2Cl2 (3 ml) at 0° C was added Et3N (58 μl, 0.41 mmol) and methanesulfonyl chloride (11 μl, 0.14 mmol). The reaction was stirred at room temperature for 0.5 h, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a yellow film.
Reaction SMILES: [F:1][C:2]1[C:11]2[NH:10][CH:9]=[C:8]3[C:12](=[O:24])[N:13]([C:15]4[CH:23]=[CH:22][C:18]([C:19]([Cl:21])=[O:20])=[CH:17][CH:16]=4)[N:14]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30]>O1CCCC1>[ClH:21].[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH:30][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([N:13]2[C:12](=[O:24])[C:8]3=[CH:9][NH:10][C:11]4[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=4[C:7]3=[N:14]2)=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1ccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)cc1
Reactant: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1ccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.6 %

Procedure:
To a partial solution of 4-(6-Fluoro-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl]-benzoyl chloride (0.1 g, 0.3 mmol) in tetrahydrofurane (5 ml) under nitrogen was added a solution of 3-dimethylamino-propyl amine (0.03 g, 0.3 mmol) in tetrahydrofurane. The mixture was stirred at rt for 90 minutes. The solvent was removed under reduced pressure and the yellow solid was purified via FCC silica gel (gradient elution, MeOH:H2O, Fluka C18 reverse phase) to yield N-(3-Dimethylamino propyl)-4-(6-fluoro-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl]-benzamide hydrochloride (70 mg, 53%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[CH3:29][NH2:30]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13]([NH:30][CH3:29])[C:12]=2[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Reactant: CN
Solvent: O
Product: CNc1nc2c(OCC(F)(F)F)cccc2c2c1CCN2c1ccccc1OC
Temperature: 180 °C

Procedure:
1-(2-Methoxyphenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(598 mg, 1.5 mmol) was dissolved in aqueous solution of methylamine(40%, 5.0 ml) in the pressure tube, and the resultant was refluxed at 180° C. for 15 hours. The reaction mixture was dissolved in water, extracted with dichloromethane, and the organic layer was washed with water for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 312 mg of desired compound as solid in 53% of yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.ClC[C:11]([NH:13]C(C)(C)CC(C)(C)C)=[O:12].C(N(C(C)C)CC)(C)C.C(COC)[O:32]C>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=[O:12])[C:3]=1[C:2]([NH2:1])=[O:32]
Reactant: NCc1ccccn1
Reactant: COCCOC
Reactant: CC(C)(C)CC(C)(C)NC(=O)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cccnc1C(N)=O

Procedure:
Pyridine diamide 4 was prepared according to the general procedure described in Example 8 using 2-(aminomethyl)pyridine (0.011 mol), 2-chloro-N-(1,1,3,3-tetramethylbutyl)acetamide (0.033 mol), diisopropylethylamine (0.025 mol) and dimethoxyethane (25 mL). The product was isolated from the methylene chloride extraction of the acidic aqueous layer. The product was made basic by extraction of the methylene chloride solution with aqueous NaOH. The methylene chloride solution was concentrated, and the residue was distilled (150° C., 0.03 mm) to afford 3.7 g of pure product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[C:11]3[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCc1cc2c(NCc3ccc(OC)c(OC)c3)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: CCc1cc2c(NCc3ccc(OC)c(OC)c3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-ethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-ethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Br:13][C:14]1[CH:15]=[C:16]([F:22])[C:17]([F:21])=[C:18]([F:20])[CH:19]=1.[C:23](=[O:25])=[O:24].Cl>C1COCC1>[Br:13][C:14]1[C:19]([C:23]([OH:25])=[O:24])=[C:18]([F:20])[C:17]([F:21])=[C:16]([F:22])[CH:15]=1
Reactant: O=C=O
Reactant: Fc1cc(Br)cc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1c(Br)cc(F)c(F)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a solution of i-Pr2NH (3.65 mL, 25.8 mmol) in THF (50 mL) was added n-BuLi (10.3 mL, 25.8 mmol, 2.50 M solution in hexanes) at 0° C. After stirring for 15 minutes, the reaction mixture was cooled to −78° C. A solution of 5-bromo-1,2,3-trifluorobenzene (5.00 g, 23.7 mmol) in THF (5 mL) was added. The resulting mixture was stirred for 2 hours at −78° C., poured into an excess of freshly crushed dry ice, and stirred for 30 minutes To this mixture was added 10% aqueous HCl to adjust its pH to 1. The resulting mixture was extracted with ether (3×). The combined organic layers were washed with 5% aqueous NaOH (2×). The combined basic aqueous layers were acidified to pH 1 with concentrated HCl, and extracted with ether (2×). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give the desired product (5.06 g, 84%) that was used directly without further purification.