Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][CH2:10][C:11]1([O:42][C@H:41]([CH2:43][O:44][C:45](=[O:52])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:31]([O:32]C(=O)C2C=CC=CC=2)[C@@H:21]1[O:22]C(=O)C1C=CC=CC=1)OC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:53]([Si](C)(C)C)[C:54]#[CH:55].B(F)(F)F.CCOCC>C(#N)C>[C:45]([O:44][CH2:43][C@@:41]1([O:42][C@H:11]([CH2:10][OH:9])[C@@H:21]([OH:22])[C@@H:31]1[OH:32])[CH:53]=[C:54]=[CH2:55])(=[O:52])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: O=C(OC[C@H]1OC(COC(=O)c2ccccc2)(OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: C#CC[Si](C)(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: C=C=C[C@@]1(COC(=O)c2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
In accordance with Flowchart G, D-fructofuranose pentabenzoate 57 and propargyltrimethylsilane in acetonitrile at 0° C. are reacted with boron trifluoride etherate, giving 4,7-anhydro-4-C-[(benzoyloxy)methyl]-1,2,3-trideoxy-D-manno-octa-1,2-dienitol, tribenzoate 58, which is treated with sodium methoxide in methanol, giving 4,7-anhydro-1,2,3-trideoxy-4-C-(hydroxymethyl)-D-oluco (or D-manno)-octa-1,2-dienitol 59. Compound 59 is treated with cupric sulfate and sulfuric acid in acetone followed by sodium carbonate in pyridine, giving 4,7:41,5-dianhydro-1,2,3-trideoxy-4-C-[(1-hydroxy-1-methylethoxy)methyl]-D-manno-octa-1,2-dienitol 60 which is reacted with sodium hydride in dimethylformamide at 0° C. and then with 15 benzyl bromide and methanol, giving 4,7:41,5-dianhydro-1,2,3-trideoxy-4-C-[(1-hydroxy-1-methylethoxy)methyl]-6,8-bis-O-(phenylmethyl)-D-manno-octa-1,2-dienitol 61. Compound 61 is ozonized at -78° C. in dichloromethane containing pyridine, then treated with zinc dust and acetic acid, giving 2,5:21,3-dianhydro--2-C-[(1-hydroxy-1-methylethoxy)methyl]-4,6-bis-O-(phenylmethyl)-D-mannose 62, which is dissolved in diethyl phosphite and reacted with sodium ethoxide in ethanol, followed by sodium dihydrogen phosphate in dichloromethane, giving 2,5-anhydro-2-C-[(diethoxyphosphinyl)hydroxymethyl]-1,3-0-(1-m®thylethylidene)-4,6--bis-O-(phenylmethyl)-D-glucitol 63. Compound 63 is treated with diisopropylethylamine and 2-(trimethylsilyl)ethoxymethyl chloride in dichloromethane, giving 2,5-anhydro-2-C-[(diethoxyphosphinyl)[[2-(trimethylsilyl)ethoxy]methoxy]methyl]-1,3-O-(1-methylethylidene)--4,6-bis-O-(phenylmethyl)-D-glucitol 64, which is hydrogenated in methanol over palladium hydroxide on carbon, giving 2,5-anhydro-2-C-[(diethoxyphosphinyl)-[[2-(trimethylsilyl)ethoxy]methoxy]methyl]-1,3-O-(1-methylethylidene)-D-glucitol 65. Compound 65 is reacted with diphenyl phosphorochloridate in pyridine at 0° C., giving 2,5-anhydro-2-C-[(diethoxyphosphinyl)-[[2-(trimethylsilyl)ethoxy]methoxy]methyl]-1,3-O-(1-methylethylidene)-D-glucitol, 6-(diphenyl phosphate) 66, which is reacted with bromotrimethylsilane in dichloromethane, then hydrogenated in ethanol over platinum oxide, giving 2,5-anhydro-2-C-(hydroxyphosphonomethyl)-D-glucitol, 6-(dihydrogen phosphate) 67. ##STR16##
Reaction SMILES: [NH2:1][N:2]([CH2:14][CH2:15][OH:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])=[S:4].C=O.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Cl:13][C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[NH:5][C:3]([N:2]1[CH2:14][CH2:15][O:16][CH2:19][NH:1]1)=[S:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NN(CCO)C(=S)Nc1ccc(Cl)cc1Cl
Agent: C=O
Solvent: ClCCl
Product: S=C(Nc1ccc(Cl)cc1Cl)N1CCOCN1

Procedure:
1.72 g (6.20 mmol) N-amino-N-(2-hydroxyethyl)-N'-(2,4-dichlorophenyl)thiourea was suspended in 40 mL methylene chloride. 0.52 g (37% aqueous, 6.4 mmol) formaldehyde and a small quantity of p-toluenesulfonic acid were added before the reaction mixture was heated for 17 h in a Dean-Stark apparatus. The solvent was then removed and the desired product isolated.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[F:23])C1C=CC=CC=1>Br.C(O)(=O)C.O.C(=O)(O)[O-].[Na+]>[F:23][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[OH:8])=[O:24]
Reactant: O=C(Nc1ccccc1OCc1ccccc1)c1ccncc1F
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1ccccc1O)c1ccncc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.3 %

Procedure:
Title compound 445 (1.99 g, 6.18 mmol) was dissolved in the solution of HBr (33% in AcOH, 15.0 mL) and acetic acid (10.0 mL). The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with water and basified with solid sodium bicarbonate until alkaline. More water was added to dissolve the salt and the aqueous layer was extracted with ethyl acetate (twice). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was triturated in 30% ethyl acetate in hexanes to afford title compound 446 (1.21 g, 84%) as a beige-yellow solid. 1H NMR (DMSO-d6) δ (ppm): 10.02 (s, 1H), 9.75 (s, 1H), 8.75 (d, J=2.0 Hz, 1H), 8.59 (dd, J=4.8, 1.3 Hz, 1H), 7.94 (dd, J=8.0, 1.6 Hz, 1H), 7.76 (dd, J=6.1, 4.9 Hz, 1H), 7.03 (ddd, J=8.0, 7.4, 1.6 Hz, 1H), 6.92 (dd, J=8.0, 1.4 Hz, 1H), 6.84 (td, J=7.6, 1.3 Hz, 1H). MS (m/z): 233.2 (M+H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([F:49])=[C:44](B(O)O)[CH:45]=1>>[NH2:30][C:29]1[S:28][C:27]([C:42]2[CH:41]=[C:40]([Cl:39])[CH:45]=[CH:44][C:43]=2[F:49])=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]1)=[O:24]
Reactant: OB(O)c1cc(Cl)ccc1F
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3cc(Cl)ccc3F)sc2N)c1N1CCC(CN)CC1
Yield: 31 %

Procedure:
Following the procedure for Example 278 starting with tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 5-chloro-2-fluorophenylboronic acid gave 314 as a grey solid (29.2 mg, 31%). 1H NMR (400 MHz, d4-MeOD) δ 8.34 (dd, J=6.4, 2.7 Hz, 1H), 7.47 (s, 1H), 7.43-7.37 (m, 1H), 7.27 (dd, J=10.9, 8.8 Hz, 1H), 3.74 (s, 3H), 3.27-3.11 (m, 4H), 2.63 (d, J=6.6 Hz, 2H), 1.86 (d, J=12.6 Hz, 2H), 1.56-1.47 (m, 1H), 1.38 (qd, J=11.9, 4.4 Hz, 2H). LCMS (ES+) m/z 480 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH3:13][C:14]1[C:15]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:16][CH:17]=[C:18]([CH3:20])[N:19]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[C:14]([CH3:13])=[N:19][C:18]([CH3:20])=[CH:17][N:16]=3)[CH2:22][CH2:23]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: Cc1cnc(N2CCNCC2)c(C)n1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)n1
Yield: 69.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 8 and using 4-bromo-2-fluorobenzoyl chloride (1.1 g) and 1-(3,5-dimethylpyrazin-2-yl)piperazine hydrochloride (915 mg) described in Preparation Example 59, the title compound (1.1 g) was obtained.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7](Cl)(=[O:11])[CH2:8][CH2:9][CH3:10]>>[C:1]([O:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O
Reactant: CCCC(=O)Cl
Product: CCCC(=O)OC(=O)CCC
Reaction time: 7 h

Procedure:
Molar quantities of butyric acid and butyryl chloride are heated together on a water-bath for 1 hour and then boiled for 7 hours in an oil-bath. Butyric anhydride, b.p. 198°-199° C./765 mm, is obtained on distillation of the resulting mixture.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:32])[C@:4]1([OH:31])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@:18]([F:24])([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:26][CH2:27][C:28]([CH3:30])=[CH2:29].ClC1C=CC=C(C(OO)=[O:41])C=1>ClCCl>[Cl:1][CH2:2][C:3](=[O:32])[C@:4]1([OH:31])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@:18]([F:24])([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:26][CH2:27][C:28]1([CH3:30])[CH2:29][O:41]1
Reactant: C=C(C)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(CO[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@@]2(O)C(=O)CCl)CO1
Yield: 14.8 %

Procedure:
A solution of 3.0 g of 21-chloro-9-fluoro-11β,17-dihydroxy-16α-[ (2-methyl-2-propenyl)oxy]pregna-1,4-diene-3,20-dione in 100 ml of dichloromethane is stirred with 1.4 g of m-chloroperbenzoic acid for 210 minutes. The solution is washed with a mixture of 10% potassium carbonate solution and 10% sodium sulfite solution, dried, and evaporated in vacuo to give an oil which solidifies on standing. Recrystallization from acetone-hexane gives 1.94 g as a first crop, and 820 mg as a second crop. Recrystallization of 600 mg of crop 1 from acetone-hexane gives 460 mg of 21-chloro-9-fluoro-11β,17-dihydroxy-16α-[(2-methyloxiranyl)methoxy]pregna-1,4-diene-3,20-dione, melting point 193°-236°C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[C:29]([N:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:14]2[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]3[CH:10]=[C:9]([CH3:28])[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:12]=3[CH:13]=2)[CH2:23][CH2:24]1)(=[O:31])[CH3:30]
Reactant: Cc1cc2c(cc(NC3CCNCC3)c3nnc(C)n32)n1Cc1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(Nc2cc3c(cc(C)n3Cc3ccccc3)n3c(C)nnc23)CC1
Reaction time: 0.25 h

Procedure:
To 6-benzyl-1,7-dimethyl-N-piperidin-4-yl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-4-amine (10. mg, 0.027 mmol, from Example 206) in DCM (1.0 mL) was added acetyl chloride (2.3 μL, 0.032 mmol, Aldrich), followed by the addition of triethylamine (7.4 μL, 0.053 mmol). After 15 minutes, volatiles were removed in vacuo. The mixture was diluted with water and MeOH, and the product was isolated via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (7.6 mg, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1.C(N(C(C)C)C(C)C)C>CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:8])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13]
Reactant: Nc1ccc(C(=O)O)cc1OC(F)(F)F
Reactant: CN1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc(N)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a solution of 0.5 g (2.3 mmole) of 4-amino-3-trifluoromethoxy-benzoic acid, 0.31 g (2.8 mmole) of 4-amino-1-methyl-piperidine, 1.2 mL (69 mmole) of ethyldiisopropyl amine and 4 mL of dimethylformamide was added the solution of 1.2 g (2.8 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate in 2 mL of dimethylformamide. The mixture was stirred at room temperature for 2 hour, then diluted with ice water and saturated sodium carbonate. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-60:40) gave 0.7 g of 4-amino-N-(1-methyl-piperidin-4-yl)-3-trifluoromethoxy-benzamide as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([CH2:12][N:13]([C:21]3[N:22]=[N:23][C:24]([C:27]4[S:28][C:29]([CH2:32]O)=[CH:30][N:31]=4)=[CH:25][CH:26]=3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:36])=O>O1CCOCC1>[Cl:36][CH2:32][C:29]1[S:28][C:27]([C:24]2[N:23]=[N:22][C:21]([N:13]([CH2:12][C:8]3([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[CH2:11][CH2:10][CH2:9]3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:26][CH:25]=2)=[N:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CO)s2)nn1
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CCl)s2)nn1
Yield: 72 %

Procedure:
To a solution of t-butyl (1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(5-(hydroxymethyl)thiazol-2-yl)pyridazin-3-yl)carbamate (44.1 g, 93.8 mmol) in dioxane (235 mL) was added thionyl chloride (27.3 mL, 375.3 mmol). The reaction was stirred until it was homogeneous. The reaction was then slowly quenched by pouring into a mixture of saturated potassium carbonate solution and ethyl acetate. The organic layer was then separated, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (EtOAC/hexanes) to afford 33.1 g of t-butyl 6-(5-(chloromethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([N:17]=[CH:18][C:19]2[C:20]([NH2:27])=[N:21][C:22]([S:25][CH3:26])=[N:23][CH:24]=2)[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1>O1CCCC1>[CH3:16][O:15][C:13]1[CH:12]=[C:11]([NH:17][CH2:18][C:19]2[C:20]([NH2:27])=[N:21][C:22]([S:25][CH3:26])=[N:23][CH:24]=2)[CH:10]=[C:9]([O:8][CH3:7])[CH:14]=1
Reactant: COc1cc(N=Cc2cnc(SC)nc2N)cc(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(NCc2cnc(SC)nc2N)cc(OC)c1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
Into 18.2 mL (18.2 mmol) of a 1 M solution of lithium aluminum hydride (LAH) in tetrahydrofuran (THF) cooled to 5° C. was added a solution of 5.55 g (18.3 mmol) of 5-[(3,5-dimethoxy-phenylimino)-methyl]-2-methylsulfanyl-pyrimidin-4-ylamine in 94 mL of dry THF over 20 minutes. The reaction was stirred for 1.5 hours at 5° C., then quenched by slow sequential addition of 0.72 mL of water, 3.0 mL of 25% NaOH, and an additional 1.66 mL of water. The reaction mixture was filtered through Celite, and the filter pad was washed well with THF. The filtrate was concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate. The ethyl acetate solution was washed three times with a solution of saturated sodium chloride, dried over magnesium sulfate, and concentrated in vacuo to give 5.10 g (91%) of the title compound.
Reaction SMILES: [ClH:1].[CH3:2][NH:3][CH2:4][CH2:5][NH2:6].[Cl-].[NH4+].[CH2:9](O)[CH3:10]>>[ClH:1].[CH3:2][N:3]1[CH2:4][CH2:5][N:6]=[C:10]1[CH2:9][Cl:1]
Reactant: CNCCN
Reactant: CCO
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CN1CCN=C1CCl
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of chloracetimidoethylether, hydrochloride (1.58 g, 10 mmol) and N-methyl-ethylenediamine (0.74 g, 10 mmol) in 10 ml absolute ethanol is stirred at 0° C. and under a nitrogen atmosphere for one hour. A solution of hydrogen chloride in absolute ethanol (6.3 ml, 10 mmol) is added and the mixture is heated to 40° C. and stirred for additional two hour. After cooling to room temperature a precipitate of ammonium chloride is filtered of and the filtrate is concentrated in vacuo yielding the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:42])=[N:14][C:15]([CH3:41])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:42])=[N:14][C:15]([CH3:41])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccc(F)cc3)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCc2ccc(F)cc2)cc1
Yield: 89.2 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((4-fluorobenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0372 g, 0.065 mmol) and LiOH (0.015 g, 0.645 mmol) in 9:1 EtOH/H2O (2 mL) was refluxed for 2 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((4-fluorobenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0318 g, 0.058 mmol, 90% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.43-7.49 (m, 2H), 7.15-7.19 (m, 1H), 7.09-7.14 (m, 2H), 7.02-7.08 (m, 3H), 5.78 (br. s., 1H), 5.07-5.15 (m, 2H), 2.74 (s, 3H), 2.28 (s, 3H), 1.25-1.37 (m, 4H), 1.23 (s, 9H), 0.78 (br. s., 6H). 4H of piperidine are missing. LCMS (M+H)=549.5.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:14]([CH:15]=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>ClCCl>[CH:15]([C:14]1[C:9]([NH:8][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:16]
Reactant: Nc1ncccc1C=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ncccc1C=O
Temperature: 0 °C
Reaction time: 63 h
Yield: 90 %

Procedure:
Triethylamine (7.6 mL, 54 mmol), was added to a solution of 2-aminopyridine-3-carboxaldehyde (4.45 g, 36 mmol) in dichloromethane (70 mL). Mixture was cooled to 0° C. A solution of pivaloyl chloride (5.3 mL, 43 mmol) in dichloromethane (30 mL) was added to the mixture. Reaction was warmed to room temperature. Mixture stirred at room temperature for 63 hours. Mixture was washed successively with water (2×50 mL) and brine (30 mL). Organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography afforded the title compound as off-white solid in 90% yield. (M+H)+=207.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(NC2CCCc3c2[nH]c2ccc(Cl)cc32)cc1

Procedure:
6-Chloro-N-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-one and p-toluidine in a similar manner as described in Example 13 to give 59 mg (41% yield) of a yellow solid. 1H-NMR (CDCl3): δ 8.10 (s, 1H), 7.51 (m, 1H), 7.22 (d, 1H), 7.17-7.06 (m, 3H), 6.72 (d, 2H), 4.82 (m, 1H), 3.74 (s, 1H), 2.74 (m, 2H), 2.33 (s, 3H), 2.27 (m, 1H), 2.07 (m, 1H), 1.98-1.76 (m, 2H); MS m/z 309 (M−1).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[N:22]=[C:21]([N:23]5[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)[CH:20]=[N:19][CH:18]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4]1)[CH3:2].Cl>CO.O1CCOCC1>[N:23]1([C:21]2[N:22]=[C:17]([N:16]3[C:10]4[CH:9]=[C:8]([C:6]5[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=5)[N:13]=[CH:12][C:11]=4[CH:14]=[N:15]3)[CH:18]=[N:19][CH:20]=2)[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1
Reactant: CCn1cc(-c2cc3c(cn2)cnn3-c2cncc(N3CCCN(C(=O)OC(C)(C)C)CC3)n2)cn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCn1cc(-c2cc3c(cn2)cnn3-c2cncc(N3CCCNCC3)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
To a solution of tert-butyl 4-[6-[6-(1-ethylpyrazol-4-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-1,4-diazepane-1-carboxylate (0.2596 mmol; 127.1 mg) in Methanol (5 mL) was added hydrochloric acid, 4.0 M in 1,4-Dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 163 as an off-white solid (34.9 mg, 34%). 1H NMR (400 MHz, DMSO) δ 9.17-9.12 (s, 1H), 8.60-8.56 (s, 1H), 8.55-8.52 (s, 1H), 8.39-8.36 (s, 1H), 8.27-8.24 (s, 1H), 8.12-8.08 (s, 1H), 7.91-7.85 (s, 1H), 4.25-4.17 (q, J=7.3 Hz, 2H), 3.92-3.80 (dt, J=10.3, 5.5 Hz, 4H), 3.05-2.95 (m, 2H), 2.79-2.71 (m, 2H), 1.95-1.82 (m, 2H), 1.46-1.40 (t, J=7.3 Hz, 3H); MS (ESI) m/z: 390.2 [M+H]+
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[C:9]=2[N:10]=[C:11](Cl)[N:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH2:21])[CH:19]=[CH2:20].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CCCCCC>[CH2:18]([NH:21][C:11]1[N:12]=[C:7]([NH:6][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[C:9]=2[N:10]=1)[CH:19]=[CH2:20]
Reactant: C=CCN
Reactant: Cc1csc2c(NNC(C)(C)C)nc(Cl)nc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCNc1nc(NNC(C)(C)C)c2scc(C)c2n1
Yield: 31.6 %

Procedure:
270 mg (1.0 mmol) of 4-(2-t-butylhydrazino)-2-chloro-7-methylthieno[3,2-d]pyrimidine and 914 mg (16.0 mmol) of allylamine were heated in a sealed tube at 140° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by a silica gel chromatography (eluent: ethyl acetate-hexane=1/4] to give 92 mg (yield: 31.6%) of the title compound.
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.C([O-])([O-])=O.[Na+].[Na+].CC1(C)C(C)(C)OB([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])O1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:50]([O:49][C:48]([NH:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[C:2]1[N:3]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)=[O:54])([CH3:51])([CH3:52])[CH3:53]
Reactant: COC(=O)CCn1c(Br)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)CCn1c(-c2ccccc2NC(=O)OC(C)(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Yield: 60 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1-(3-methoxy-3-oxopropyl)-1H-indole-6-carboxylate in dioxane (0.15 M) was added Na2CO3 (4 eq, 2 M aqueous solution), tert-butyl [2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (1.5 eq) and bis(triphenylphosphine)palladium(II) dichloride (0.2 eq). The mixture was heated at reflux for 45 mins. The reaction mixture was filtered and then the filtrate was diluted with EtOAc. The organic phase was washed with H2O, brine and dried over Na2SO4 before being filtered and concentrated in vacuo. The crude was purified by flash chromatography (Biotage cartridge Si65i, 1:9 EtOAc/PE) to give the title compound as a white solid (60%); MS (ES+) m/z 535 (M+H)+.