Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N:16]3[C:20](=[O:21])[NH:19][C:18]([C:22]([CH3:27])([CH3:26])[CH2:23][O:24][CH3:25])=[N:17]3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O.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>[CH3:25][O:24][CH2:23][C:22]([C:18]1[NH:19][C:20](=[O:21])[N:16]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:32]4[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=4)[CH:7]=3)=[C:14]([CH3:15])[N:13]=2)[N:17]=1)([CH3:27])[CH3:26]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COCC(C)(C)c1nn(-c2ccc(Oc3ccnc(Cl)c3)c(C)n2)c(=O)[nH]1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COCC(C)(C)c1nn(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(=O)[nH]1
Temperature: 85 °C
Reaction time: 12 h
Yield: 75.1 %

Procedure:
1-(5-((2-Chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(1-methoxy-2-methylpropan-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.10 g, 0.26 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.07 g, 0.33 mmol), and K2CO3 (0.09 g, 0.66 mmol) were suspended in a solution of dioxane (2.0 mL) and water (0.4 mL). The suspension was sonicated and sparged with Ar for 10 min followed by the addition of Pd(PPh3)4 (0.03 g, 0.026 mmol). The reaction mixture was stirred at 85° C. for 12 h, allowed to cool to RT, diluted with water (2.0 mL), and extracted with EtOAc (5×3 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford an orange oil. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 3-(1-methoxy-2-methylpropan-2-yl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.085 g, 76%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.93 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 6.65 (dd, J=5.7, 2.5 Hz, 1H), 3.84 (s, 3H), 3.39 (s, 2H), 3.25 (s, 3H), 2.33 (s, 3H), 1.24 (s, 6H); MS (ESI) m/z: 436.2 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1.[CH2:22]([CH:24]([NH2:27])[CH2:25][CH3:26])[CH3:23]>>[O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([NH:27][CH:24]([CH2:25][CH3:26])[CH2:22][CH3:23])=[O:20])=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1
Reactant: CCC(N)CC
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Product: CCC(CC)NC(=O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1

Procedure:
This compound, m.p. 312°-314° C., was prepared from 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid and 1-ethylpropylamine.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])O[C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH4+:15]>>[C:1]1([CH:7]2[C:8](=[O:9])[NH:15][C:11](=[O:13])[CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: O=C1CC(c2ccccc2)C(=O)O1
Agent: Cl
Product: O=C1CC(c2ccccc2)C(=O)N1
Reaction time: 1 h

Procedure:
10 g of phenylsuccinic anhydride was gradually added to 20 ml of 28% aqueous ammonium solution and the mixture was stirred for about 1 hour. To the reaction mixture was added aqueous hydrochloric acid solution so as to neutralize. After cooling, crystals thus formed were collected by filtration to obtain about 8.2 g of 3-phenylsuccinimide.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[S:10][C:9]2=[N:11][C:12]([Cl:14])=[CH:13][N:8]2[CH:7]=1.Cl[CH2:16][N:17]1[CH2:21][CH:20]([CH2:22][CH2:23][CH3:24])[CH2:19][C:18]1=[O:25].O>O1CCOCC1>[Cl:5][C:6]1[S:10][C:9]2=[N:11][C:12]([Cl:14])=[C:13]([CH2:16][N:17]3[CH2:21][CH:20]([CH2:22][CH2:23][CH3:24])[CH2:19][C:18]3=[O:25])[N:8]2[CH:7]=1
Reactant: CCCC1CC(=O)N(CCl)C1
Reactant: Clc1cn2cc(Cl)sc2n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: CCCC1CC(=O)N(Cc2c(Cl)nc3sc(Cl)cn23)C1
Yield: 74 %

Procedure:
At room temperature, AlCl3 (0.237 g, 1.78 mmol, 2 eq) is added to a solution of 2,6-dichloroimidazo[2,1-b][1,3]thiazole x172 (0.171 g, 0.89 mmol, 1 eq) and 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 (0.185 g, 1.06 mmol, 1.2 eq) in 1,4-dioxane (25 ml). The mixture is heated at reflux during 2 hours. After cooling, water (20 ml) is added and the aqueous layer is extracted with CH2Cl2 (3×20 ml). The combined organic layers are dried on anhydrous MgSO4, filtered and evaporated under reduced pressure. The crude is purified on silicagel (CH2Cl2/AcOEt: 9/1) yielding 200 mg of 1-[(2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one 93 as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][CH2:7][N:8]([CH2:25][CH2:26][NH:27][C:28](=[O:31])[CH2:29][NH2:30])[C:9](=[O:24])[C:10]1[C:18]([I:19])=[C:17]([NH:20][CH3:21])[C:16]([I:22])=[C:12]([C:13]([OH:15])=[O:14])[C:11]=1[I:23])=[O:4].[Br:32][CH:33]([CH3:37])[C:34](Br)=[O:35]>CC(N(C)C)=O>[Br:32][CH:33]([CH3:37])[C:34]([NH:30][CH2:29][C:28]([NH:27][CH2:26][CH2:25][N:8]([CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][NH:1][C:34](=[O:35])[CH:33]([Br:32])[CH3:37])[C:9](=[O:24])[C:10]1[C:18]([I:19])=[C:17]([NH:20][CH2:21][C:34](=[O:35])[CH:33]([Br:32])[CH3:37])[C:16]([I:22])=[C:12]([C:13]([OH:15])=[O:14])[C:11]=1[I:23])=[O:31])=[O:35]
Reactant: CC(Br)C(=O)Br
Reactant: CNc1c(I)c(C(=O)O)c(I)c(C(=O)N(CCNC(=O)CN)CCNC(=O)CN)c1I
Solvent: CC(=O)N(C)C
Product: CC(Br)C(=O)CNc1c(I)c(C(=O)O)c(I)c(C(=O)N(CCNC(=O)CNC(=O)C(C)Br)CCNC(=O)CNC(=O)C(C)Br)c1I
Temperature: 40 °C
Reaction time: 20 h

Procedure:
57.8 g (75 mmol) of N,N-bis-[2-(2-aminoacetylamino)ethyl]-5-(methylamino)-2,4,6-triiodoisophthalic acid amide is dissolved in 500 ml of dimethylacetamide, and 75.5 g (350 mmol) of 2-bromopropionic acid bromide (Aldrich) is added in drops over 15 minutes at 0° C. Then, it is stirred for 20 hours at 40° C. The reaction mixture is poured into 4000 ml of ice water, the solid that accumulates is filtered off, dissolved in 800 ml of ethyl acetate and extracted three times with 250 ml each of water. The organic phase is dried on sodium sulfate, and the solvent is evaporated to the dry state. The crude product is recrystallized from methyl-tert-butyl ether.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[N+:23]([O-])=O.[F:26][C:27]1[CH:28]=[CH:29][C:30]([O:37][CH3:38])=[C:31]([C:33](=[N:35]O)[NH2:34])[CH:32]=1.CCN(C(C)C)C(C)C>>[F:26][C:27]1[CH:28]=[CH:29][C:30]([O:37][CH3:38])=[C:31]([C:33]2[N:34]=[C:18]([C:17]3[CH:21]=[CH:22][C:14]([N:9]4[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]4[CH3:7])=[C:15]([CH:16]=3)[NH2:23])[O:20][N:35]=2)[CH:32]=1
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COc1ccc(F)cc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)c(N)c2)n1

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol; 3 eq.), Intermediate 8 (132 mg; 0.5 mmol; 1 eq.), Intermediate 23 (92 mg; 0.5 mmol; 1 eq.) and DIEA (194 mg; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. After purification by column chromatography (c-hexane/ethyl acetate, 80/20), the residue was taken up in EtOH (20 mL) and stannous chloride dihydrate (564 mg; 2.5 mmol; 5 eq.) was added. The resulting mixture was stirred at reflux for 3 hours then concentrated in vacuo. The residue was partitioned between NaOH 0.05M and ethyl acetate. The phases were separated and the organic layer was washed with brine, dried over magnesium and concentrated in vacuo. Purification by column chromatography (c-hexane/ethyl acetate, 75/25) afforded the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][C@H:14]2[C@@H:19]3[O:20]C(=O)[O:22][C@@H:18]3[C@@H:17]([O:24][CH3:25])[C:16]([CH3:27])([CH3:26])[O:15]2)[C:10]([CH3:28])=[C:9]2[C:4]=1[CH:5]=[C:6]([NH:30][C:31](=[O:40])OCC1C=CC=CC=1)[C:7](=[O:29])[O:8]2.CCN=C=NCCCN(C)C.[CH3:52][O:53][C:54]1[CH:55]=[C:56]([C:60]2[C:65]([O:66][CH3:67])=[CH:64][CH:63]=[C:62](C(O)=O)[CH:61]=2)[CH:57]=[CH:58][CH:59]=1.C(=O)([O-])[O-]>[Pd].C1COCC1.N1C=CC=CC=1.C(Cl)Cl.CO.C(Cl)Cl.C(N(CC)CC)C>[OH:20][C@@H:19]1[C@H:18]([OH:22])[C@@H:17]([O:24][CH3:25])[C:16]([CH3:26])([CH3:27])[O:15][C@H:14]1[O:13][C:11]1[C:10]([CH3:28])=[C:9]2[C:4]([CH:5]=[C:6]([NH:30][C:31]([C:62]3[CH:61]=[C:60]([C:56]4[CH:57]=[CH:58][CH:59]=[C:54]([O:53][CH3:52])[CH:55]=4)[C:65]([O:66][CH3:67])=[CH:64][CH:63]=3)=[O:40])[C:7](=[O:29])[O:8]2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COc1cc(O[C@@H]2OC(C)(C)[C@H](OC)[C@H]3OC(=O)O[C@@H]23)c(C)c2oc(=O)c(NC(=O)OCc3ccccc3)cc12
Reactant: COc1cccc(-c2cc(C(=O)O)ccc2OC)c1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COc1cccc(-c2cc(C(=O)Nc3cc4c(OC)cc(O[C@@H]5OC(C)(C)[C@H](OC)[C@@H](O)[C@H]5O)c(C)c4oc3=O)ccc2OC)c1
Reaction time: 12 h
Yield: 11.1 %

Procedure:
Palladium on carbon (10%, 40 mg) was added to 25d (200 mg, 0.36 mmol) in anhydrous THF (2.40 mL) and the solution was placed under an atmosphere of H2. After 12 hours, the solution was filtered through SiO2 (1:1 CH2Cl2:Acetone) and the eluent was concentrated to afford a yellow solid, which was used without further purification (150 mg, 99%). EDCI (57.5 mg, 0.30 mmol) and 3′,6-dimethoxybiphenyl-3-carboxylic acid (62 mg, 0.24 mmol) were added to the amine (50.6 mg, 0.12 mmol) in 30% pyridine/CH2Cl2 (3.30 mL). After 12 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 3:1 Hexane:Ether→40:1→10:1 CH2Cl2:Acetone) to afford a colorless solid, which was used without further purification (25.2 mg, 32%). Triethylamine (150 μL) was added to the carbonate (25.2 mg, 0.038 mmol) in MeOH (2.0 mL) and CH2Cl2 (2.0 mL). After 48 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to afford 26d as a colorless amorphous solid (17.0 mg, 70%, 22% over 3 steps): 1H NMR (CD2Cl2, 400 MHz) 9.02 (s, 1H), 8.97 (s, 1H), 8.66 (s, 1H), 7.96 (dd, J=8.6, 2.4 Hz, 1H), 7.91-7.90 (m, 1H), 7.39 (t, J=7.9 Hz, 1H), 7.16-7.11 (m, 2H), 6.96 (dd, J=8.3, 2.6 Hz), 6.85 (d, J=5.5 Hz, 1H), 5.70 (d, J=2.1 Hz, 1H), 4.36-4.33 (m, 1H), 4.27 (m, 1H), 3.99 (s, 3H), 3.93 (s, 3H), 3.88 (s, 3H), 3.62 (s, 3H), 3.41-3.38 (m, 1H), 2.24 (s, 3H), 1.41 (s, 3H), 1.19 (s, 3H); 13C NMR (CDCl3, 125 MHz) 164.2, 158.7, 158.6, 158.3, 155.3, 153.5, 148.6, 137.6, 129.9, 128.9, 128.1, 127.1, 125.1, 121.0, 119.4, 118.9, 114.2, 114.2, 112.1, 110.0, 104.9, 103.7, 96.7, 92.9, 83.2, 70.1, 67.5, 60.9, 60.8, 54.8, 54.3, 21.9, 21.4, 6.8; IR (film) νmax 3405, 2986, 2934, 1713, 1609, 1528, 1383, 1250, 1213, 1053, 999, 914, 878, 737 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C34H37NO11, 636.2445. found, 636.2482.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([C:14](=[O:20])[CH2:15][NH:16][CH:17]([CH3:19])[CH3:18])=[CH:6][C:5]=1[Br:21].[BH4-].[Na+]>>[NH2:3][C:4]1[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:7]([CH:14]([OH:20])[CH2:15][NH:16][CH:17]([CH3:18])[CH3:19])=[CH:6][C:5]=1[Br:21]
Reactant: CC(C)NCC(=O)c1cc(Br)c(N)c(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)NCC(O)c1cc(Br)c(N)c(C(F)(F)F)c1

Procedure:
m.p. 102°-103° C., m.p. of the hydrochloride: 177°-179° C. (decomp.), was prepared from 4'-amino-3'-bromo-2-isopropylamino-5'-trifluoromethyl-acetophenone hydrochloride and sodium borohydride analogous to Example 1.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:26].CO>>[ClH:26].[CH:21]1[C:22]2[C:17](=[C:16]([NH:15][C@H:12]3[CH2:11][CH2:10][C@@H:9]([NH2:8])[CH2:14][CH2:13]3)[CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2cccc3cnccc23)CC1
Agent: Cl
Solvent: CO
Product: N[C@H]1CC[C@@H](Nc2cccc3cnccc23)CC1

Procedure:
According to the method of Example 1, Step C, deprotection was performed (room temperature, 31 hours) by using Intermediate 39 (214 mg) and 10% hydrogen chloride/methanol solution (5 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (215 mg) as light yellow powdery solid.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[C:15]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=4)=[N:16][C:17]4[C:22]([C:23]=3[C:24](O)=[O:25])=[CH:21][C:20]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:41][C:42]([F:52])([F:51])[C@@H:43]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[NH2:44].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O1CCCC1>[N:1]1([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[C:15]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=4)=[N:16][C:17]4[C:22]([C:23]=3[C:24]([NH:44][C@H:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:42]([F:51])([F:52])[F:41])=[O:25])=[CH:21][C:20]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:19][CH:18]=4)[CH2:11][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCCCC4)CC3)c(C(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCCCC4)CC3)c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
A mixture of 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.100 g, 0.174 mmol), (1R)-2,2,2-trifluoro-1-phenylethanamine (0.046 g, 0.261 mmol), EDC (133 mg, 0.695 mmol), HOBT (26.6 mg, 0.174 mmol), and N,N-diisopropylethylamine (0.303 mL, 1.737 mmol) in N,N-dimethylformamide (2 mL) and tetrahydrofuran (2 mL) was stirred at 50° C. overnight. The solvent was removed in vacuo. The residue was dissolved in DMSO and purified via HPLC (Waters, 20-60% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3 and extracted with methylene chloride (3 times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.040 g, 30% yield). 1H NMR (400 MHz, CDCl3) δ 10.22 (br. s., 1H), 8.75 (s, 1H), 8.31 (d, J=9.03 Hz, 1H), 8.23 (dd, J=2.01, 8.78 Hz, 1H), 7.77-7.84 (m, 2H), 7.65-7.72 (m, 2H), 7.54-7.60 (m, 2H), 7.46 (dd, J=1.76, 5.02 Hz, 3H), 6.26 (br. s., 1H), 3.60-3.78 (m, 2H), 3.15 (s, 3H), 2.66 (br. s., 1H), 2.38 (br. s., 4H), 2.18 (br. s., 1H), 2.12 (br. s., 1H), 1.53-1.64 (m, 10H), 1.37-1.46 (m, 2H); MS (m/z) 733.3 (M+H+). Human TRPV4 FLIPR pIC50=8.5
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=2)[CH:10]=1
Reactant: O=C1C=C(Cl)CCC1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1C=C(c2cccnc2)CCC1
Temperature: 95 °C
Reaction time: 7 h

Procedure:
[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium-DCM complex (313 mg, 0.383 mmol) was added to a stirred mixture of 8a (500 mg, 3.83 mmol), pyridin-3-yl-boronic acid (565 mg, 4.60 mmol) and sodium carbonate (2.87 mL of a 2M aq. solution, 5.74 mmol) in dioxane (14.0 mL) and water (2.00 mL). The resulting mixture was degassed and heated to 95° C. After 7 h, the reaction mixture was cooled to rt, diluted with EtOAc, filtered through a short column of Celite®, eluting copiously with EtOAc. The organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (0-90% EtOAc/hexanes as eluent) to afford the title compound, 8b. m/z (ES) 174 (MH)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:12]=[C:13]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])[CH3:9])[CH:5]=[CH:6][CH:7]=1.Cl>ClCCl.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:12]=[C:13]([N:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])c1cccc(Cl)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(Nc1cc(N2CCNCC2)ccc1[N+](=O)[O-])c1cccc(Cl)c1
Reaction time: 4 h
Yield: 139 %

Procedure:
To a solution of t-butyl 4-(3-(1-(3-chlorophenyl)ethylamino)-4-nitrophenyl)piperazine-1-carboxylate (97 mg, 0.21 mmol) in dry dichloromethane (2.0 mL) was added a saturated solution of HCl in diethyl ether (15 mL). The reaction mixture was stirred for 4 hours. The product was collected by filtration and dried in vacuo to afford the title compound (58.0 mg, 70% yield). 1H NMR (400 MHz, CD3OD): δ 8.06 (d, 1H), 7.43 (s, 1H), 7.33 (m, 2H), 7.26 (m, 1H), 6.38 (d, 1H), 5.88 (s, 1H), 4.80 (m, 1H), 3.54-3.43 (m, 4H), 3.22 (m, 4H), 1.62 (d, 3H); MS (ESI) m/z: Calculated for C18H22ClN4O2: 360.14; Observed: 361.5 (M++1) [corresponding to the free base].
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][C:20]#[N:21]>CN(C=O)C.[Cl-].[Na+].O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:18][CH2:19][C:20]#[N:21])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Reactant: N#CCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCN(c1ccc(I)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, a solution of N-(4-iodophenyl)pyrimidin-2-amine (100 mg) in anhydrous DMF (1.0 ml) was added to a suspension of sodium hydride (16 mg) in anhydrous DMF (1.0 ml), and the resulting mixture was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 3-bromopropionitrile (0.04 ml) in anhydrous DMF (0.5 ml) was added, and the resulting mixture was stirred at room temperature overnight. Saturated brine was added to the reaction solution and the resulting mixture was extracted with chloroform. Organic layer was dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/chloroform=1/10) to obtain 3-(N-(4-iodophenyl)-N-(pyrimidin-2-yl)amino)propanenitrile (94 mg). NMR (H1, CDCl3): δ 2.82 (2H, t, J=6.8 Hz), 4.24 (2H, t, J=6.8 Hz), 6.68 (1H, t, J=4.9 Hz), 7.06-7.10 (2H, m), 7.74-7.78 (2H, m), 8.35 (2H, d, J=4.9 Hz)
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([N:20]1[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O)=[CH:23][N:22]=[CH:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH2:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH:33]1[NH:41][C:42]1[N:43]=[CH:44][C:45]2[CH2:51][NH:50][CH2:49][CH2:48][C:46]=2[N:47]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH2:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH:33]1[NH:41][C:42]1[N:43]=[CH:44][C:45]2[CH2:51][N:50]([C:29](=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][C:24]3[N:20]([C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[CH:21]=[N:22][CH:23]=3)[CH2:49][CH2:48][C:46]=2[N:47]=1
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Reactant: CC(C)(C)OC(=O)n1cncc1CCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1cncc1CCCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 40 °C
Yield: 32.3 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.092 g; 1.5 equiv; 0.48 mmoles) to a solution of 5-(3-tert-butoxycarbonylimidazol-4-yl)pentanoic acid (0.084 g; 1.0 equiv; 0.31 mmoles), N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.064 g; 0.77 equiv; 0.24 mmoles), 1-hydroxybenzotriazole (0.065 g; 1.5 equiv; 0.48 mmoles), and triethylamine (0.20 mL; 4.5 equiv; 1.44 mmoles) in dichloromethane (15 mL). Heat the mixture to 40° C. for 16 hours. Concentrate the mixture, and then purify the crude product by column chromatography (0 to 10% methanol in dichloromethane) to afford tert-butyl 5-[5-[2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-5-oxo-pentyl]imidazole-1-carboxylate (0.040 g; 25%) as a white solid: MS (m/z): 517 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.[N:36]([CH:39]([CH3:41])[CH3:40])=[C:37]=[O:38]>C1COCC1>[CH:39]([NH:36][C:37](=[O:38])[NH:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)([CH3:41])[CH3:40]
Reactant: CC(C)N=C=O
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(CN)ccc4c23)cccc1N1Cc2ccccc2C1=O
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(CNC(=O)NC(C)C)ccc4c23)cccc1N1Cc2ccccc2C1=O
Yield: 16.4 %

Procedure:
A solution of 7-(aminomethyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 33-1, 30 mg, 0.065 mmol) and 2-isocyanatopropane (0.019 mL, 0.195 mmol) in THF (3 mL) was stirred at 40° C. overnight. The mixture was concentrated and purified by preparative HPLC. The appropriate effluent fractions were concentrated and partitioned between EtOAc and NaHCO3 (aq). The organic phase was dried and concentrated to provide 7-((3-isopropylureido)methyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as a white solid (5.8 mg, 14%). 1H NMR (400 MHz, methanol-d4) δ 7.84 (1H, d, J=7.7 Hz), 7.77 (1H, d, J=7.5 Hz), 7.53-7.63 (2H, m), 7.38-7.51 (4 H, m), 7.30 (1H, dd, J=7.2, 1.7 Hz), 6.93-6.99 (2H, m), 6.85 (1H, dd, J=8.3, 1.4 Hz), 4.79-4.91 (2H, m), 4.33 (2H, s), 3.69-3.78 (1H, m), 1.79 (3H, s), 1.03 (6H, d, J=6.4 Hz). Mass spectrum m/z 546.3 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=2)=[CH:11][CH:12]=[C:13]2[C:21]=1[NH:20][C:19]1[C:18]3[CH:22]=[CH:23][C:24]([NH2:26])=[CH:25][C:17]=3[CH2:16][CH2:15][C:14]2=1.ClCCl.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>N1C=CC=CC=1>[F:8][C:9]1[C:10]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=2)=[CH:11][CH:12]=[C:13]2[C:21]=1[NH:20][C:19]1[C:18]3[CH:22]=[CH:23][C:24]([NH:26][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:25][C:17]=3[CH2:16][CH2:15][C:14]2=1
Reactant: Cc1cc(-c2ccc3c4c([nH]c3c2F)-c2ccc(N)cc2CC4)ccc1F
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(-c2ccc3c4c([nH]c3c2F)-c2ccc(NS(C)(=O)=O)cc2CC4)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A sample of 10-Fluoro-9-(4-fluoro-3-methyl-phenyl)-5,11-dihydro-6H-benzo[a]carbazol-3-ylamine trifluoroacetate (example 90) (17.8 mg, 0.038 mmol) is treated with dichloromethane (1 mL) and pyridine (0.5 mL). The reaction is then treated with methanesulfonyl chloride (8.6 mg, 7.5 mmol) and the reaction is stirred overnight at room temperature. The reaction is then concentrated and purified by reverse phase mass triggered HPLC to afford the title compound as a white solid after lyophilization: 1H NMR (400 MHz, d6-DMSO) δ 11.82 (s, 1H), 11.21 (s, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.55 (m, 2H), 7.45 (m, 1M), 7.38 (m, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.20 (m, 1H), 7.02 (dd, J=8.0, 7.0 Hz, 1H), 2.95 (m, 2H), 2.87 (m, 2H), 2.26 (s, 3H), 1.29 (s, 3H); LC/MS calculated for [M+H3O]+ C24H23F2N2O3S: 457.1, found: 457.0.