Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:7][C:8]1[C:9]([O:23][C@H:24]2[CH2:70][N:27]3[C:28](=[O:69])[C@@H:29]([NH:48][C:49]([O:51][C@@H:52]4[CH2:54][C@H:53]4[CH2:55][CH2:56][CH2:57]/[CH:58]=[CH:59]/[B:60]4[O:64][C:63]([CH3:66])([CH3:65])[C:62]([CH3:68])([CH3:67])[O:61]4)=[O:50])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH:36][C@@H:37]4[CH2:42][C@@:38]4([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:39][C:40](=[O:41])[C@@H:26]3[CH2:25]2)=[N:10][C:11]2[C:16]([C:17]=1[O:18][CH2:19][CH2:20][CH2:21]Br)=[CH:15][CH:14]=[CH:13][CH:12]=2>CS(C)=O>[Br:7][C:8]1[C:9]([O:23][C@H:24]2[CH2:70][N:27]3[C:28](=[O:69])[C@@H:29]([NH:48][C:49]([O:51][C@@H:52]4[CH2:54][C@H:53]4[CH2:55][CH2:56][CH2:57]/[CH:58]=[CH:59]/[B:60]4[O:61][C:62]([CH3:68])([CH3:67])[C:63]([CH3:66])([CH3:65])[O:64]4)=[O:50])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH:36][C@@H:37]4[CH2:42][C@@:38]4([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:39][C:40](=[O:41])[C@@H:26]3[CH2:25]2)=[N:10][C:15]2[C:16]([C:17]=1[O:18][CH2:19][CH2:20][CH2:21][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)O[C@@H]1C[C@H]1CCC/C=C/B1OC(C)(C)C(C)(C)O1)C(=O)N1C[C@H](Oc3nc4ccccc4c(OCCCBr)c3Br)C[C@H]1C(=O)N2
Reactant: C1CCNCC1
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)O[C@@H]1C[C@H]1CCC/C=C/B1OC(C)(C)C(C)(C)O1)C(=O)N1C[C@H](Oc3nc4ccccc4c(OCCCBr)c3Br)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)O[C@@H]1C[C@H]1CCC/C=C/B1OC(C)(C)C(C)(C)O1)C(=O)N1C[C@H](Oc3nc4ccccc4c(OCCCN4CCCCC4)c3Br)C[C@H]1C(=O)N2
Solvent: CS(C)=O
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)O[C@@H]1C[C@H]1CCC/C=C/B1OC(C)(C)C(C)(C)O1)C(=O)N1C[C@H](Oc3nc4ccccc4c(OCCCN4CCCCC4)c3Br)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Piperidine (317 μl) was added to a solution of bromide from Step 1 (326 mg) in DMSO (2 mL) and the resulting mixture was stirred for 2 hours at room temperature. The reaction was quenched with water and extracted with ethyl acetate (3×). The combined organic fractions were washed with water then brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ISCO reverse phase, 0 to 95% acetonitrile in water) to give the title compound (262 mg) as a mixture with the boronic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C@@:11]2([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[C:23]([F:32])[CH:22]=3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[O:14][CH2:13][CH2:12]2)=[O:9])=[N:6][CH:7]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].CCN(C(C)C)C(C)C>C(Cl)Cl.[OH-].[Na+]>[F:32][C:23]1[CH:22]=[C:21]([C@:11]2([NH:10][C:8](=[O:9])[C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:7][N:6]=3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[O:14][CH2:13][CH2:12]2)[CH:26]=[CH:25][C:24]=1[O:27][C:28]([F:31])([F:30])[F:29]
Reactant: Nc1ccc(C(=O)N[C@]2(c3ccc(OC(F)(F)F)c(F)c3)CCOc3cccnc32)nc1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccc(C(=O)N[C@]2(c3ccc(OC(F)(F)F)c(F)c3)CCOc3cccnc32)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-5-amino-N-(4-(3-fluoro-4-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)picolinamide (44 mg, 0.098 mmol) in DCM (0.6 mL) were added methanesulfonyl chloride (8.40 μl, 0.128 mmol) and DIEA (0.022 mL, 0.128 mmol). The resulting mixture was stirred at room temperature overnight. A solution of NaOH (10 N, 2 drops) was added, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by prep HPLC (0-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 527.0 (MH+). 1H NMR (400MHz, d4-MeOH) δ: 8.48 (d, J=2.3 Hz, 1H), 8.30 (dd, J=4.5, 1.4 Hz, 1H), 8.05 (d, J=8.6 Hz, 1H), 7.83 (dd, J=8.6, 2.5 Hz, 1H), 7.37-7.62 (m, 4H), 7.25 (d, J=8.6 Hz, 1H), 4.47 (dt, J=11.9, 4.4 Hz, 1H), 4.05-4.26 (m, 1H), 3.12-3.25 (m, 2H), 3.10 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([C:8]12[CH2:15][O:14][C:11]([CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)([O:12][CH2:13]1)[O:10][CH2:9]2)[CH2:6][CH3:7].N1C=CC=CC=1>ClCCl>[C:1]([N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([C:11]23[O:10][CH2:9][C:8]([CH2:5][CH2:6][CH3:7])([CH2:13][O:12]2)[CH2:15][O:14]3)[CH2:17]1)(=[O:3])[CH3:2]
Reactant: CCCC12COC(C3CCCNC3)(OC1)OC2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC12COC(C3CCCN(C(C)=O)C3)(OC1)OC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetyl chloride (81 μl) was added to a stirred solution of 3-(4-n-propyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)piperidine (0.25 g.) and pyridine (92 μl) in dichloromethane (15 ml) at 0°. The mixture was stirred at room temperature for 3 hours. The mixture was washed with water, saturated aqueous sodium hydrogen carbonate solution and finally brine. The dichloromethane extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by chromatography on alumina (Alumina Woelm TSC) eluting with 1:3 dichlormethane:hexane, saturated with ammonia. N-Acetyl- 3-(4-n-propyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)piperidine (0.15 g.) was obtained as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C2CCCCO2)[N:13]=[C:12]3[C:24]2[N:29]=[C:28]([O:30][C@@H:31]3[CH2:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]3)[CH:27]=[N:26][CH:25]=2)[C:5]([F:8])=[N:6][CH:7]=1.Cl.CC(O)C>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[C:24]2[CH:25]=[N:26][CH:27]=[C:28]([O:30][C@@H:31]3[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]3)[N:29]=2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5cc(Cl)cnc5F)cc34)n2)C1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Fc1ncc(Cl)cc1-c1ccc2[nH]nc(-c3cncc(O[C@@H]4CCCNC4)n3)c2c1
Temperature: 65 °C

Procedure:
(3R)-tert-butyl 3-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate 10a (270 mg, 0.48 mmol), 5-chloro-2-fluoropyridin-3-ylboronic acid (97 mg, 0.56 mmol) (Combi-Blocks, Catalog# BB-3818), potassium phosphate tribasic (308 mg, 1.45 mmol) (Sigma-Aldrich, Catalog# P5629-25G, Lot#069K0110), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (13.8 mg, 0.03 mmol) (Strem, Catalog#15-1149, Batch# A0183078), and Pd2(dba)3 (13.3 mg, 0.02 mmol) (Strem, Catalog#46-3000, Lot# A8761089) were weighed into a 10 mL glass microwave vial. The vial was purged with argon, the solids were treated with dioxane (4 mL) and water (1 mL) and the vial was sealed. The contents were heated in Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 115° C. for 30 min. The reaction mixture was treated with 2 mL of water and extracted with EtOAc (2×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated, affording (3R)-tert-butyl 3-(6-(5-(5-chloro-2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate as a light yellow solid. MS (ESI, pos. ion) m/z: 609.2 (M+1). The material was used without purification. To a solution of (3R)-tert-butyl 3-(6-(5-(5-chloro-2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (292 mg, 0.48 mmol) in THF (2.2 mL) and EtOH (2.2 mL) was added HCl, 5-6N in IPA (0.8 mL, 26.40 mmol). The solution was heated in an oil bath at 65° C. for 1 h. The crude reaction was concentrated to a yellow solid that was dissolved in 5 mL of DMSO and purified on a reverse phase HPLC, using a gradient of 10-90% [0.1% TFA in ACN] in [0.1% TFA in water]. The desired fractions were collected, concentrated, and basified with 1 N NaOH, extracted with EtOAc. The EtOAc solution was washed with brine, dried with Na2SO4 and concentrated to afford (R)-5-(5-chloro-2-fluoropyridin-3-yl)-3-(6-(piperidin-3-yloxy)pyrazin-2-yl)-1H-indazole as an off white crystalline solid. MS (ESI, pos. ion) m/z: 425.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][C:31]=4[F:32])[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].C1COCC1.Cl>CO.O>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][C:31]=4[F:32])[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2ccc3nnn(Cc4cc5cccnc5cc4F)c3n2)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2ccc3nnn(Cc4cc5cccnc5cc4F)c3n2)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.9 %

Procedure:
To a solution of Example 131 (0.185 g, 0.412 mmol) in methanol (2 ml), lithium hydroxide (0.161 g, 3.84 mmol) in water (2 ml), THF (4 ml) were added and stirred at RT. After 12 h, pH was adjusted to ca.7 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as a pale brown solid (0.150 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.CN1CCN(C)C1=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][N:13]([CH2:18][C:19]4[CH:26]=[CH:25][C:22]([CH3:23])=[CH:21][CH:20]=4)[CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CN1CCN(C)C1=O
Product: COc1ccc2c3c(c(=O)oc2c1)CN(Cc1ccc(C)cc1)CC3
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
A solution of 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one (1.2 g, 5.2 mmol) and 4-methylbenzaldehyde (0.68 g, 5.7 mmol) in 20 mL of tetrahydrofuran and 7 mL of 1,3-dimethyl-2-imidazolidinone is treated with glacial acetic acid (0.29 mL, 5.2 mmol). The mixture is stirred for 10 minutes, and then sodium triacetoxyborohydride (1.6 g, 7.5 mmol) is added in portions over 30 minutes. The mixture is stirred for 16 hours, then added to 300 mL of ice water. The precipitated solid is filtered, washed with water, and recrystallized from ethyl acetate to yield 1.2 g (70%) of product, mp 147°-149° C.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH2:14]([O:21][C:22]([NH:24][CH:25]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=O)[CH2:26]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>COCCOC.O>[CH2:14]([O:21][C:22]([NH:24][CH:25]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[CH:3][C:1]#[N:2])[CH2:26]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(NC1CC(=O)c2ccccc2C1)OCc1ccccc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#CC=C1CC(NC(=O)OCc2ccccc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl (cyanomethyl)phosphonate (0.189 mL) in 1,2-dimethoxyethane (1 mL) at room temperature under nitrogen was added 60% sodium hydride oil dispersion (46 mg). Upon completion of addition, the mixture was stirred for 1 h. After this time, a solution of 3-benzyloxycarbonylamino-1-oxo-1,2,3,4-tetrahydronaphthalene (69 mg) in 1,2-dimethoxyethane was added (1 mL). The reaction mixture was stirred at room temperature for 1 h, and then heated to reflux for 4 h. At the conclusion of this period, the reaction mixture was cooled to room temperature, diluted with water, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated under vacuum to yield a residue. The residue was purified by reverse phase preparative HPLC (trifluoroacetic acid containing solvents were used) to obtain the title compound (38 mg) as a mixture of olefin isomers.
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(CN2C(=O)C3=CC=CC=C3C2=O)C(=O)N(CC(C)C)N=1.[C:32]([C:35]1[C:36](=[O:56])[N:37]([CH2:50][CH:51]2[CH2:55][CH2:54][CH2:53][CH2:52]2)[N:38]=[C:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[CH:42]=2)[CH:40]=1)(O)=[O:33]>>[CH:51]1([CH2:50][N:37]2[C:36](=[O:56])[C:35]([CH2:32][OH:33])=[CH:40][C:39]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[CH:42]=3)=[N:38]2)[CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: COc1ccc(-c2cc(C(=O)O)c(=O)n(CC3CCCC3)n2)cc1F
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2C(=O)c3ccccc3C2=O)c1=O
Product: COc1ccc(-c2cc(CO)c(=O)n(CC3CCCC3)n2)cc1F
Yield: 47.3 %

Procedure:
Following the procedure of Example 1 (8), 4-carboxy-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as a yellow powder (yield: 47.3%).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:11]([Br:12])=[CH:10][C:9]([C:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[N:14]=2)=[CH:8][C:7]=1[Br:29].O>C(O)C.Br>[Br:29][C:7]1[CH:8]=[C:9]([C:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[N:14]=2)[CH:10]=[C:11]([Br:12])[CH:6]=1
Reactant: Nc1c(Br)cc(C2=NN(C(=O)c3ccc(Cl)c(Cl)c3)CCC2)cc1Br
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(c1ccc(Cl)c(Cl)c1)N1CCCC(c2cc(Br)cc(Br)c2)=N1

Procedure:
NaNO2 (0.24 g, 3.43 mmol) was added to a suspension of 3-(4-amino-3,5-dibromophenyl)-1-(3,4-dichlorobenzoyl)-1,4,5,6-tetrahydropyridazine (1.0 g, 1.98 mmol, HBr (25%, 3 mL) and water (6 mL)in ethanol (50 mL). The resulting mixture was stirred and heated at a low temperature for 1.5 hours. CuBr2 in HBr (48%, 6 mM) was added to the reaction mixture and the resulting mixture was stirred for 3 hours at room temperature. Water was added to the reaction and a solid precipitated from this mixture. The solid was purified by column chromatography to give the title compound as a white solid: mp 179°-182° C.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[NH:4]1.CCN(C(C)C)C(C)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1.O>C(Cl)Cl>[F:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]([N:4]2[CH:3]([CH3:2])[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]2[C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:17][CH:18]=2)=[O:41])=[CH:35][CH:34]=1
Reactant: CC1Cc2ccccc2C(c2ccc(C(F)(F)F)cc2)N1
Reactant: O=C=Nc1ccc(F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC1Cc2ccccc2C(c2ccc(C(F)(F)F)cc2)N1C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline hydrogen chloride (370 mg, 1.27 mmol) and DIEA (1.1 mL, 6.35 mmol) in DCM (5 mL) was added 4-fluorophenyl isocyanate (143 μL, 1.27 mmol). The mixture was then stirred at RT for 0.5 h. Water (10 mL) was added and the mixture was extracted with DCM (2×15 mL). The combined organic extracts were dried over MgSO4 and concentrated to give the title compound as a light yellow solid. MS (ESI, positive ion) m/z: 429 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH2:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[CH:13](OCC)=[O:14].Cl>>[CH:13]([NH:8][CH2:7][CH2:6][C:4]1[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[O:1][CH:5]=1)=[O:14]
Reactant: NCCc1coc2ccccc12
Reactant: CCOC=O
Agent: Cl
Product: O=CNCCc1coc2ccccc12

Procedure:
A solution of 2.35 g (0.015 mole) of 2-(3-benzo[b]furanyl)ethylamine and 5 mL of ethyl formate was heated at 60° C. for 3 hours, poured into 2N HCl and washed with methylene chloride which in turn was washed with 5% sodium hydroxide (w/v), dried (MgSO4), filtered and concentrated to give 2.70 g of product.
Reaction SMILES: [OH-].[CH2:2]([N+:9](C)(C)C)[C:3]1C=CC=C[CH:4]=1.[CH:13]1[C:26]2[NH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[S:18][C:17]=2[CH:16]=[CH:15][CH:14]=1.C(#N)C=C.CC(C1C(O)=C(C(C)(C)C)C=C(CCC(OCC(COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)(COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)=O)C=1)(C)C>CC(C)=O.C(#N)C>[C:2]([CH2:3][CH2:4][N:25]1[C:26]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[S:18][C:19]2[C:24]1=[CH:23][CH:22]=[CH:21][CH:20]=2)#[N:9]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: CC(C)(C)c1cc(CCC(=O)OCC(COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)(COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: [OH-]
Solvent: CC#N
Solvent: CC(C)=O
Solvent: C=CC#N
Product: N#CCCN1c2ccccc2Sc2ccccc21

Procedure:
4 ml of Triton B (40%) (benzyltrimethylammonium hydroxide) was dropwise added to an acetonitrile solution (200 ml) containing 199 g of phenothiazine, 106 g of acrylonitrile, and a small quantity of Irganox 1010 (made by Ciba Geigy Co.). Irganox 1010 has the formula ##STR4## After refluxing for 3 hours while heating, 53 g of acrylonitrile was added thereto, followed by refluxing for a further 2 hours while heating. After being allowed to cool, acetone was added to the reaction solution to crystallize the reaction product. Crystals thus formed were collected by filtration, and recrystallized from 900 ml of acetone to obtain 135 g of the desired compound. m.p. 158°-160° C.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:18])[NH:7][C:8]1[N:12]([CH3:13])[N:11]=[C:10]([C:14]([O:16]C)=[O:15])[CH:9]=1)[CH:2]([CH3:4])[CH3:3].[Li+].[OH-].O>CO>[CH2:1]([NH:5][C:6](=[O:18])[NH:7][C:8]1[N:12]([CH3:13])[N:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1cc(NC(=O)NCC(C)C)n(C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)CNC(=O)Nc1cc(C(=O)O)nn1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
To a solution of methyl 5-(3-isobutylureido)-1-methyl-1H-pyrazole-3-carboxylate (compound 351.5, 0.12 g, 0.47 mmol) in MeOH (5 ml) was added 1 M LiOH in H2O (1.42 ml, 1.42 mmol). The mixture was stirred at room temperature for 5 hours. TLC showed the reaction was complete. The mixture was acidified to pH 3-4 at 0° C. and then was extracted with EcOAc (2×50 ml). The combined organic layers were dried with Na2SO4, filtered, and concentrated to give 110 mg (100%) of a clear oil. m/z (ES+) 241 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1.[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23](F)[C:20]=1[C:21]#[N:22].CC(C)([O-])C.[K+]>CN(C)C=O>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:23]2[CH:24]=[CH:25][CH:26]=[C:19]([F:18])[C:20]=2[C:21]#[N:22])[CH2:7][CH2:6]1
Reactant: N#Cc1c(F)cccc1F
Reactant: OCC1CCC(Oc2c(F)cccc2F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCC1CCC(Oc2c(F)cccc2F)CC1
Temperature: 0 °C
Yield: 66 %

Procedure:
4-(2,6-Difluorophenoxy)cyclohexylmethanol (100 mg; 0.4 mmol) and 2,6-difluorobenzonitrile were combined in 3 mL of dimethylformamide under nitrogen flow and chilled to 0° C. Potassium t-butoxide (56 mg; 1.2 mmol) was added in portions. Mixture warmed to room temperature. After 4 hours reaction was quenched with 3 mL of water and mixture was extracted with 3×8 mL of ethyl acetate. Combined organics were washed with 5×8 mL of water, once with brine and dried over MgSO4. Crude oil was purified via flash chromatography using 0-20% ethyl acetate in hexanes to give 95 mgs of title compound. (66% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:27]1[C:28](=O)[C:29]2[C:34](C=1C1C=CC=CC=1)=CC=C(O)[CH:30]=2.CC(C)CCO.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:27][CH2:28][CH:29]([CH3:34])[CH3:30])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)CCO
Product: CC(C)CCOc1ccc2c(c1)C(=O)C(c1cccnc1)=C2c1cc(F)cc(F)c1
Reaction time: 4 h
Yield: 59 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 64 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 3-methylbutan-1-ol (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, being stirred for 4 h, and being purified by prep. HPLC (20% H2O/CH3CN) to provide the title compound (59%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][N:26]=1.C(=O)([O-])O.[Na+]>CC(O)C>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=3)[CH:7]=2)=[O:23])[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)O)cn1
Temperature: 90 °C

Procedure:
N-Cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (3.2 g), methyl 6-chloronicotinate (1.73 g), tetralcis(triphenylphosphine)palladium (210 mg) and aqueous sodium hydrogen carbonate (1M, 30 ml) were mixed in propan-2-ol (100 ml) and heated at 90° C. for 18 hours. The reaction was allowed to cool and the propan-2-ol removed under vacuum. The residue was partitioned between ethyl acetate and aqueous sodiumhydrogen carbonate (1M). The aqueous phase was acidified with hydrochloric acid (2N) and extracted with ethyl acetate (x2). The organic extracts were washed with brine, dried (magnesium sulphate) and reduced to dryness under vacuum. The resulting foam was triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinic acid as a solid.
Reaction SMILES: C([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]=[CH:14][C:15]1[CH:26]=[CH:25][C:18]2[N:19]=[C:20]([NH:22][CH2:23][CH3:24])[O:21][C:17]=2[CH:16]=1)C1C=CC=CC=1.Cl>[Pd].CO>[CH2:23]([NH:22][C:20]1[O:21][C:17]2[CH:16]=[C:15]([CH2:14][CH2:13][C:9]3[NH:8][CH:12]=[CH:11][N:10]=3)[CH:26]=[CH:25][C:18]=2[N:19]=1)[CH3:24]
Reactant: CCNc1nc2ccc(C=Cc3nccn3Cc3ccccc3)cc2o1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCNc1nc2ccc(CCc3ncc[nH]3)cc2o1
Reaction time: 6 h
Yield: 19.4 %

Procedure:
10% Palladium on carbon (0.5 g) was added to a mixture of 6-[2-[1-benzylimidazol-2-yl)vinyl]-2-ethylaminobenzoxazole (0.9 g) in a solution of methanol (50 ml) and conc. hydrochloric acid (6 ml), and the mixture was subjected to catalytic reduction under atmospheric pressure for 6 hours at ambient temperature. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was purified by a column chromatography on alumina and eluted with a chloroform. The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was triturated with diethyl ether to give 2-ethylamino-6-[2-(2-imidazolyl)ethyl]benzoxazole (0.13 g).