Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[I:34]I>C(OCC)C.C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][C:13]=1[I:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc(-c2ccccc2)cc1I
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 11 %

Procedure:
A solution of (6-phenylpyridin-3-yl)carbamic acid tert-butyl ester (5.54 g, 20.5 mmol) and TMEDA (6.49 mL, 43.0 mmol) in 100 mL of anhydrous diethyl ether was treated with n-BuLi at −78° C. After 15 minutes at −78° C., the mixture was warmed to −10° C. and stirred for an additional 3 hours. The reaction mixture was then cooled to −78° C. and a solution of iodine in a mixture of 10 mL of THF and 100 mL of diethyl ether was added dropwise. After 2 hours at −78° C., the mixture was allowed to warm to 0° C. and was quenched with 400 mL of saturated aqueous ammonium chloride solution. The organic layer was washed with five 100 mL portions of saturated aqueous sodium thiosulfate. The combined aqueous layers extracted with three 200 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SiO2 (0% to 70% ethyl acetate in hexanes, gradient) afforded 900 mg of the title product as yellow oil that solidified over time (11% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[C:13]([NH:26][CH2:27][CH:28]([OH:30])[CH3:29])=[N:14][C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:16][C:11]=2[NH:10][N:9]=1.C(N(CC)C(C)C)(C)C.NN>O1CCOCC1.CCO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[C:13]([NH:26][CH2:27][C@@H:28]([OH:30])[CH3:29])=[N:14][C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:16][C:11]=2[NH:10][N:9]=1
Reactant: CC(O)CNc1nc(Oc2ccc(F)cc2F)cc2[nH]nc(-c3ccccc3Cl)c12
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCO
Product: C[C@H](O)CNc1nc(Oc2ccc(F)cc2F)cc2[nH]nc(-c3ccccc3Cl)c12
Temperature: 90 °C
Yield: 35.7 %

Procedure:
1-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[4,3-c]pyridin-4-ylamino]-propan-2-ol (690 mg, 1.6 mmol) was taken up in a mixture of 15 mL dioxane and 2 mL EtOH. N,N-diisopropylethylamine (0.3 mL) and anhydrous hydrazine (0.15 mL) were added, and the reaction mixture was slowly heated to 90° C. with stirring. The reaction mixture was stirred for six hours at 90° C., then was cooled to room temperature and quenched by addition of water and partitioned with ethyl acetate, followed by back extraction of the aqueous phase with additional ethyl acetate. The combined organic phases were were washed with saturated brine and water, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by preparative scale TLC (3.5% MeOH in methylene chloride), then recrystallized from methylene chloride/hexanes to give 246 mg of (S)-1-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[4,3-c]pyridin-4-ylamino]-propan-2-ol. Mass spec., M+1=432. Mp=171.2-172° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:53]=[C:54]1[NH:58][C@H:57]([C:59](O)=[O:60])[CH2:56][CH2:55]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][C:59]([C@@H:57]4[CH2:56][CH2:55][C:54](=[O:53])[NH:58]4)=[O:60])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNC(=O)[C@@H]1CCC(=O)N1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a DCM (10 ml) solution of (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3, 0.45 g, 1.17 mmol) and HBTU (0.44 g, 1.17 mmol) cooled at 0° C. was added a solution of (S)-5-oxopyrrolidine-2-carboxylic acid (0.15 g, 1.17 mmol) in DMF (5 ml), followed by the addition of DIEA (0.14 g, 1.17 mmol). The reaction was then stirred at room temperature for 1 hour and quenched with 20 ml of aqueous NaHCO3, and extracted with DCM (2×30 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=20:1) to give the title compound (0.30 g, 51%). 1H NMR (400 MHz, CD3OD) δ 7.35-7.32 (m, 2H), 7.10 (d, J=10.9 Hz, 1H), 7.00-6.96 (m, 2H), 5.80-5.65 (br s, 1H), 5.06-5.05 (m, 1H), 4.30-4.15 (m, 3H), 2.45-2.24 (m, 3H), 2.05-2.00 (m, 1H), 1.85-1.80 (m, 1H), 1.48 (d, J=6.8 Hz, 3H), 0.91-0.89 (m, 2H), 0.63-0.62 (m, 2H). MS: Calcd.: 495. Found: [M+H]+ 496.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([N:8]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:39])C=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([N:8]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)(=[O:21])=[O:22])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][N+:17]([O-:39])=[CH:18][CH:19]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2ccncc2)c2cccc(Cl)c2C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2cc[n+]([O-])cc2)c2cccc(Cl)c2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
330 mg of N2-(3-chloro-2-methylphenyl)-N2-[(4-methylphenyl)sulfonyl]-N-(pyridine-4-ylmethyl)glycinamide was dissolved in 5.0 mL of methylene chloride, and 166 mg of m-chloroperbenzoic acid was added thereto, followed by stirring at room temperature for 4 hours. To the reaction liquid was added an aqueous saturated sodium hydrogen carbonate solution, and then extracted with chloroform. The organic layer was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform:methanol=99:1), and the obtained residue was crystallized from hexane/ethyl acetate to obtain 179 mg of N2-(3-chloro-2-methylphenyl)-N2-[(4-methylphenyl)sulfonyl]-N-[(1-oxidopyridine-4-yl)methyl]glycinamide.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=2)[CH2:15][CH:16]=1
Reactant: C1=C(c2cc3ccccc3s2)CCNC1
Reactant: Fc1ccc(CBr)cc1
Agent: Cl
Product: Fc1ccc(CN2CC=C(c3cc4ccccc4s3)CC2)cc1
Yield: 4.3 %

Procedure:
4-(Benzothiophen-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (250 mg, 0.99 mmol) was reacted with 4-fluorobenzyl bromide (0.12 ml, 0.99 mmol) as exemplified in Example 1. The crude product was triturated with hot methanol to give the title compound as a pale yellow solid mp 142°-144° C. (Found: C, 73.78; H, 5.57; N, 4.36. C20 H18FNS. 0.1H2O requires C, 73.86; H, 5.64; N, 4.30%). δH (CDCl3) 2.64 (2H, m, NH2CH2), 2.72 (2H, m, NCH2CH2), 3.18 (2H, m, NCH2CH2), 3.61 (2H, s, NCH2Ar), 6.19 (1H, m, NCH2CH), 7.02 (2H, t, J 8.6Hz, ArH), 7.12 (1H, s, ArH), 7.30 (4H, m, ArH), 7.67 (1H, d of d, J 6.7Hz, ArH), 7.73 (1H, d of d, J 6.8Hz, ArH). m/z (ES+) 324 (M+1)+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:12][C:13]1[N:17]([CH3:18])[C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][CH:39]([CH3:41])[CH3:40])=[O:37])=[CH:31][C:30]=3[F:42])[CH:20]=2)=[N:15][CH:14]=1)[CH2:8][CH2:9][O:10][CH3:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:42][C:30]1[CH:31]=[C:32]([NH:35][C:36]([NH:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH:33]=[CH:34][C:29]=1[O:28][C:25]1[CH:24]=[CH:23][N:22]=[C:21]2[CH:20]=[C:19]([C:16]3[N:17]([CH3:18])[C:13]([CH2:12][NH:7][CH2:8][CH2:9][O:10][CH3:11])=[CH:14][N:15]=3)[S:27][C:26]=12
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC(C)C)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNCc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC(C)C)cc4F)c3s2)n1C
Yield: 55.9 %

Procedure:
The solution of urea 314 (150 mg, 0.245 mmol) and TFA (1 mL, 12.98 mmol) in DCM (20 mL) was stirred 4 hr at room temperature and concentrated. The residue was partitioned between EtOAc/NaHCO3 sat. solution. The solid was collected by filtration and combined with organic layer. The mixture was concentrated and the residue was purified via Biotage (EA/MeOH 0-40%, 12 g Silicycle HR column). Collected fractions gave the desired product 315 (70 mg, 0.137 mmol, 55.8% yield) as a white solid. 1HNMR (dmso-d6) δ(ppm) 1H:8.67 (s, 1H), 8.48 (d, 1H, J=5.5 Hz), 7.91 (s, 1H), 7.65 (dd, 1H, J1=13.7 Hz, J2=2.6 Hz), 7.32 (t, 1H, J=9.0 Hz), 7.07 (m, 2H), 6.63 (d, 1H, J=5.5 Hz), 6.13 (d, 1H, J=7.6 Hz), 4.04 (s, br, 2H), 3.08 (s, 3H), 3.72 (m, 1H), 3.47 (t, 2H, J=5.2 Hz), 3.24 (s, 3H), 2.94 (m, 2H), 1.07 (s, 3H, 1.05 (s, 3H) (presumably a mono-TFA salt). MS: 513.4 (MH)+
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:11]([O:12]CC2C=CC(OC)=CC=2)[C@H:10]([O:22][C:23]([C:25]2[C:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@@H:9]([CH2:37][O:38][Si:39]([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:8][C@H:5]1[S:6][CH3:7])=[N+:2]=[N-:3].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl.O>[N:1]([C@@H:4]1[C@@H:11]([OH:12])[C@H:10]([O:22][C:23]([C:25]2[C:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@@H:9]([CH2:37][O:38][Si:39]([C:52]([CH3:55])([CH3:54])[CH3:53])([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[O:8][C@H:5]1[S:6][CH3:7])=[N+:2]=[N-:3]
Reactant: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@H]2OC(=O)c2ccccc2-c2ccccc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CS[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OC(=O)c2ccccc2-c2ccccc2)[C@H](O)[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
A mixture of methyl 2-azido-4-O-biphenylcarbonyl-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-62-D-glucopyranoside (11) (150 mg, 0.19 mmol) and DDQ (52 mg, 0.23 mmol) in CH2Cl2—H2O 9:1 (5 mL) was stirred at room temperature for 3 hours. The reaction mixture was washed with saturated NaHCO3 solution (3×3 ml), dried over MgSO4 and evaporated. The residue was purified by chromatography using EtOAc—hexane 15:85 as the mobile phase to give methyl 2-azido-4-O-biphenylcarbonyl-6-O-tert-butyldiphenylsilyl-2-deoxy-1-thio-β-D-glucopyranoside (41) (116 mg, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[C:12]([OH:14])=[O:13].[H-].[Na+].Br[CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C)C=O.O>[CH:19]1([CH2:18][N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[C:8]([C:12]([OH:14])=[O:13])=[CH:9]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1cccc2c(C(=O)O)c[nH]c12
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c(C(=O)O)cn(CC3CCCCC3)c12
Temperature: 60 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
7-Methoxyindole-3-carboxylic acid (3.0 g, 16.6 mmol) was added portionwise to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 1.56 g, 39 mmol) in dimethylformamide (75 ml). After 1 h, bromomethylcyclohexane (5.7 g, 32.3 mmol) was added. The mixture was heated to 60° C. with stirring for 1 h. The mixture was diluted with water (250 ml) and washed with ethyl acetate and then diethyl ether. The aqueous phase was acidified to pH 1 using 5 M hydrochloric acid and the precipitate filtered off. The crude product was recrystallised from ethyl acetate to afford 1-(cyclohexylmethyl)-7-methoxyindole-3-carboxylic acid (3.75 g) as a crystalline solid.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2=[S:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][C:25]#[C:26][CH2:27][OH:28]>CC(C)=O.C1C=CC=CC=1>[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[S:16][CH2:24][CH:25]=[CH:26][CH2:27][OH:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC#CCCl
Reactant: S=C1Cc2ccccc2N1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: OCC=CCSc1cc2ccccc2n1-c1ccccc1
Reaction time: 4 h
Yield: 107.5 %

Procedure:
To a solution of the product of the above (1)(2.2 g) in acetone (20 ml) are added potassium carbonate (1.54 g) and 4-chloro-2-butyn-1-ol (1.03 g). The mixture is stirred for 4 hours and filtered. The filtrate is condensed at below the room temperature. The oily residue is dissolved in benzene and evaporated at below the room temperature. Ether is added to the residue and then a 30% solution (1.5 ml) in methylamine in methanol on ice bath. The mixture is stirred for 30 minutes and after addition of ether, washed with ice-cooled 3 N-hydrochloric acid, water, an aqueous solution of sodium bicarbonate and water successively. The ether layer is dried and evaporated to give the title compound as an oil (3.1 g). The oil is chromatographed on a column of silica gel and eluted with hexane-benzene (1:10) benzene and ether-benzene (1:100) successively. The title compound is obtained as colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6](O)([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=1)=O)[C:7](OCC)=[O:8])=[O:5])C.O.[NH2:25][NH2:26].[OH-].[Na+].Cl>C(O)(C)C>[C:4]([C:6]1[C:7](=[O:8])[NH:25][N:26]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=2)[CH:12]=1)([OH:3])=[O:5]
Reactant: CCOC(=O)C(O)(CC(=O)c1ccc(C)c(F)c1)C(=O)OCC
Reactant: NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)c(=O)[nH]n2)cc1F
Reaction time: 6 h

Procedure:
To a solution of ethyl 2-ethoxycarbonyl-4-(3-fluoro-4-methylphenyl)-2-hydroxy-4-oxobutanoate (8.41 9, 25.8 mmol) in isopropanol (100 mL) was added hydrazine monohydrate (2.84 g, 56.8 mmol), and the mixture was heated under stirring at 100 for 6 hours. Then, 2 mol/L sodium hydroxide was added, and the mixture was stirred further at the same temperature for 4 hours. The reaction mixture was ice-cooled, and concentrated hydrochloric acid was added to acidify the system. The precipitate was collected by filtration, thoroughly washed with water and dried to yield the title compound as a slightly yellow crystalline powder (5.67 g, 87.7%).
Reaction SMILES: [C:1]1(=[O:7])[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:8]([O:6][C:3]1[CH2:4][CH2:5][C:1](=[O:7])[CH:2]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C=C(OCc2ccccc2)CC1

Procedure:
A mixture of cyclopentane-1,3-dione (2.00 g, 20.4 mmol), benzyl alcohol (2.11 mL, 20.4 mmoL) and para-toluenesulfonic acid (35 mg, 0.20 mmol) in toluene (10.0 mL) is heated at reflux over night. Water is added, and the mixture is extracted with dichloromethane. The organic layer is concentrated, and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 9:1 to cyclohexane/ethyl acetate 1:4). Yield: 1.66 g; ESI mass spectrum: [M+H]+=189; Retention time HPLC: 0.51 min (X012_S01).
Reaction SMILES: O.[NH2:2][C:3]1[C:8]2[CH2:9][CH2:10][O:11][C:7]=2[C:6]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH:23][CH3:24])[CH2:17][C@H:16]2[O:25][CH3:26])=[O:13])=[CH:5][C:4]=1[Cl:27].ClC(Cl)Cl.[N:32]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1>C(N(CC)CC)C>[OH2:11].[NH2:2][C:3]1[C:8]2[CH2:9][CH2:10][O:11][C:7]=2[C:6]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]([CH3:24])[C:37]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:38])[CH2:17][C@H:16]2[O:25][CH3:26])=[O:13])=[CH:5][C:4]=1[Cl:27]
Reactant: O=C(Cl)N1CCCC1
Reactant: CNCCN1CC[C@H](NC(=O)c2cc(Cl)c(N)c3c2OCC3)[C@H](OC)C1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CO[C@@H]1CN(CCN(C)C(=O)N2CCCC2)CC[C@@H]1NC(=O)c1cc(Cl)c(N)c2c1OCC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.6 %

Procedure:
To a cooled (ice-bath) mixture of 3.8 parts of cis-4-amino-5-chloro-2,3-dihydro-N-[3-methoxy-1-[2-(methylamino)ethyl]-4-piperidinyl]-7-benzofurancarboxamide monohydrate in 104.3 parts of trichloromethane were added 1.3 parts of 1-pyrrolidinecarbonyl chloride. After stirring for 15 min. at 0° C., there were added dropwise 1.31 parts of N,N-diethylethanamine, keeping the temperature below 10° C. Stirring was continued for 20 hours at room temperature. The reaction mixture was washed with water, dried, filtered and evaporated. The residue was crystallized from acetonitrile (to which some water was added). The product was filtered off at 0° C. and dried in vacuo at 40° C., yielding 3.3 parts (73.6%) of cis-4-amino-5-chloro-2,3-dihydro-N-[3-methoxy-1-[2-[methyl(1-pyrrolidinylcarbonyl)amino]ethyl]-4-piperidinyl]-7-benzofurancarboxamide monohydrate; mp. 112.0° C. (comp. 43).
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:9]2[CH:21]=[CH:22][CH:23]=[C:8]2[C:7]=1[OH:24])=[O:5])C.[NH2:25][CH2:26][C:27]([O-:29])=[O:28].[Na+]>>[F:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])=[C:7]([OH:24])[C:8]2=[CH:23][CH:22]=[CH:21][N:9]12
Reactant: NCC(=O)[O-]
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2cccc(F)c2)c1=O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2cccc(F)c2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(3-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 360 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:23]=[C:22]([O:24][CH3:25])[C:19]([C:20]#[N:21])=[C:18](F)[CH:17]=2)[CH:9]=1)[CH3:2].CCN(C(C)C)C(C)C.[NH2:36][NH2:37]>CCO>[CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:17]=[C:18]3[C:19]([C:20]([NH2:21])=[N:36][NH:37]3)=[C:22]([O:24][CH3:25])[CH:23]=2)[CH:9]=1)[CH3:2]
Reactant: CC[C@@H]1CCCN1c1cc(-c2cc(F)c(C#N)c(OC)c2)nc(NC)n1
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC[C@@H]1CCCN1c1cc(-c2cc(OC)c3c(N)n[nH]c3c2)nc(NC)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
In a microwave tube, 4-[6-[(2R)-2-ethyl-1-pyrrolidinyl]-2-(methylamino)-4-pyrimidinyl]-2-fluoro-6-(methyloxy)benzonitrile (129 mg, 0.363 mmol), 5 mL of EtOH, Hunig's base (0.063 mL, 0.363 mmol), and hydrazine anhydrous (0.068 mL, 2.178 mmol) were added. The yellow suspension mixture was heated to 100° C. in an oil bath overnight. When the temperature of the reaction reached 100° C., the solid in the mixture was all dissolved. After overnight, there was a white colored solid formed. LCMS showed no more starting material. The reaction was cooled to room temperature, then the white solid was filtered from the yellow solution, washed by CH3CN (2 mL), and dried under reduced pressure to afford the title compound (70 mg) as a white solid. LC-MS (ES) m/z=368 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.90 (t, J=7.3 Hz, 3H), 1.37 (m, 1H), 1.80 (m, 2H), 1.93 (m, 3H), 2.82 (d, J=4.6 Hz, 3H), 3.39 (m, H), 3.47-3.63 (m, 1H), 3.93 (s, 3H), 4.05 (m, 1H), 5.02 (s, 2H), 6.19 (s, 1H), 6.41 (s, 1H), 6.92 (s, 1H), 7.46 (s, 1H), 11.51 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[CH2:17])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2.CC(N=NC(C#N)(C)C)(C#N)C.CCCC[SnH](CCCC)CCCC>C1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(NC(=O)OCc1ccccc1)C(=O)OC
Reactant: BrC12CCC(CC1)CC2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: COC(=O)C(CC12CCC(CC1)CC2)NC(=O)OCc1ccccc1
Yield: 14.6 %

Procedure:
methyl 2-(benzyloxycarbonylamino)acrylate (2.05 g, 0.0095 mol, 1 eq.), 1-bromobicyclo[2.2.2]octane (1.8 g, 0.0095 mol, 1 eq.) and AIBN (0.312 g, 0.0019 mol, 0.2 eq.) were dissolved in benzene (30 mL) and heated to reflux. Bu3SnH (5.53 g, 0.019 mol, 2 eq.) was then added. The resulting mixture was stirred at reflux for 14 hrs. The solvent was removed and the residue was purified via preparative TLC (EtOAc/Petroleum ether=1:9) to give methyl 2-(benzyloxycarbonylamino)-3-(bicyclo[2.2.2]octan-1-yl)propanoate (480 mg, 15%) as a foam. 1H NMR (CDCl3, 400 MHz) δ 7.35 (m, 5H), 5.13 (m, 2H), 4.42 (m, 1H), 3.73 (s, 3H), 1.8-1.1 (m, 15H), 1.28 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH2:19][N:20]2C(=O)C3=CC=CC=C3C2=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.NN>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH2:19][NH2:20])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCn2c(C)ccc2CN2C(=O)c3ccccc3C2=O)cc1OC
Agent: NN
Solvent: O
Product: COc1ccc(CCn2c(C)ccc2CN)cc1OC

Procedure:
6.0 g (0.015 mol) of 1-(2-(3,4-dimethoxyphenyl)-ethyl)-2-(phthalimido-methyl)-5-methyl-pyrrole (compare Example 4) and 7 ml (0.15 mol) of hydrazine hydrate are heated under reflux for 30 minutes. After the mixture has been concentrated, the residue is taken up in methylene chloride, the mixture is filtered, the filtrate is concentrated and the residue is chromatographed over a silica gel column.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([O:18]C)=[O:17])[CH:15]=[C:10]3[C:9]([CH2:20][O:21][CH3:22])=[CH:8]2)=[CH:4][CH:3]=1.O.[OH-].[Li+].O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=[O:17])[CH:15]=[C:10]3[C:9]([CH2:20][O:21][CH3:22])=[CH:8]2)=[CH:23][CH:24]=1
Reactant: COCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)OC)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)O)cc12
Temperature: 40 °C
Yield: 72 %

Procedure:
To a solution of methyl 1-(4-fluorobenzyl)-3-(methoxymethyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate. (960 mg 1.2.924 mmol) in methanol (10 mL) was added lithium hydroxide monohydrate (246 mg 5.847 mmol, 2 eq.) and water (5 mL), and the clear solution was warmed to 40° C. for 15 hours. Methanol was removed under vacuum and 1 M HCl added (5.8 mL 5.847 mmol, 2 eq.). The crude product precipitated and was filtered under vacuum, washed with ether (40 ml) and dried in vacuo at 75° C. to give the title product as a white powder 664 mg (72%). LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—3 minutes, ESI, +mode): RT-0.828 min, m/e=315.2 (M+H+, base). 1H-NMR (300 MHz, DMSO): δ=3.28 (s, 3H), 4.64 (s, 2H), 5.62 (s, 2H), 7.20 (t, 2H), 7.38 (m, 2H), 7.94 (s, 1H), 8.36 (s, 1H), 8.97 (s, 1H).