Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:10]=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].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>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:13]=[N:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=4)[N:10]=[C:4]3[C:3]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:32][CH:31]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccncc3)c(Cl)ccn12
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: [Na+]
Solvent: Cc1ccccc1
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Temperature: 100 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a suspension of 7-chloro-8-(pyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (165 mg, 0.40 mmol), 4-chlorophenylboronic acid (190 mg, 1.20 mmol) in toluene (3.0 mL) and 2.0 M aqueous sodium carbonate (0.66 mL) was added (Ph3P)4Pd (70 mg, 0.06 mmol) in one portion, and the resulting yellow mixture was vigorously stirred under argon in a 100° C. oil bath for 2 h. HPLC/MS analysis indicated that the reaction was complete. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The EtOAc phase was washed with water, then saturated aqueous NaCl twice, dried over Na2SO4, and concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel (12 g) column chromatography eluting with a gradient of EtOAc (0-100%) in hexanes to provide the title compound as a light yellow foam (160 mg), which was crystallized from hot methanol to afford 60 mg of pure product. The mother liquor was concentrated, and the residue was purified by preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 40% to 80% B over 8 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The resulting residue was dissolved in EtOAc, washed with saturated aqueous Na2CO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford an additional 88 mg of pure title compound as a light yellow powder. HPLC/MS: retention time=2.70 min, [M+H]+=482. 1H NMR (CDCl3, 400 MHz): δ 8.78 (s, 1H), 8.57 (d, J=6.2 Hz, 2H), 7.91 (dd, J=1.8, 7.9 Hz, 1H), 7.86 (d, J=7.0 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.17 (d, J=6.2 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 6.65 (d, J=7.5 Hz, 1H), 5.25 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:20](OCC)=[O:21])[CH:5]=[CH:4][C:3]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH2:20][OH:21])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)C(C)(C)CCC3(C)C)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(C3=C(CO)CCCC3)ccc21

Procedure:
Ethyl 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-cyclohexene-1-carboxylate described in Example 1 is stirred with excess lithium aluminum hydride in diethyl ether at reflux temperature for 3 hours. The mixture is cooled and water is added dropwise. The ether layer is dried over sodium sulfate and evaporated to give 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-cyclohexenylmethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+]>O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: BrCCCCCCBr
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(CCOCCCCCCBr)cc1
Yield: 1851.4 %

Procedure:
4-Nitrobenzeneethanol (10.25 g), 1,6-dibromohexane (27 ml) tetra-n-butylammonium bisulphate (1.7 g) and 12.5M aqueous sodium hydroxide (55 ml) were stirred together for 40 h. The mixture was diluted with water (250 ml), extracted with ER (3×350 ml) and the combined extracts were washed consecutively with water (250 ml) and brine (250 ml), dried and evaporated to give an oil (42.6 g). The oil was purified by FCC eluting with ER-CX (0:100→1:19) to give the title compound as a yellow oil (9.52 g). T.l.c. (ER-CX 1:19) Rf 0.11. The following compounds were similarly prepared:
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:18]([O-])=O>CO.C1CCCCC=1.[Pd]>[N+:15]([C:14]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:7]=[C:6]2[C:5]=1[NH:4][CH2:3][CH2:2][NH:18]2)([O-:17])=[O:16]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NCCCl)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CO
Product: COC(=O)c1cc2c(c([N+](=O)[O-])c1)NCCN2
Temperature: 25 °C
Yield: 32.9 %

Procedure:
To a solution of crude methyl 4-[(2-chloroethyl)amino]-3,5-dinitrobenzoate (D208) (9 g, 19.2 mmol, 1 equiv) in MeOH (75 ml) and cyclohexene (150 ml) was added 10% palladium on charcoal (50% wet, 4.5 g, 25% w/w) and the resulting mixture was refluxed for 3 h then cooled to room temperature. The catalyst was filtered off through a pad of celite and most of the solvent was removed in vacuo. The residue was partitioned between AcOEt and a 2N aqueous HCl solution and the two layers were separated. The aqueous phase was extracted twice with AcOEt and the combined organic layers were washed with a saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 1/1) gave methyl 8-nitro-1,2,3,4-tetrahydro-6-quinoxalinecarboxylate (D209) (1.5 g, 34%) as a red solid. [M−H]−=236.2, RT=2.65 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][C:5]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:4][O:3]1.[ClH:19].C(OCC)(=O)C.C(OCC)(=O)C>CO>[ClH:19].[O:1]=[C:2]1[CH2:6][C:5]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:4][O:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)COC(=O)C2
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CC2(CCNCC2)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.16 g of tert-butyl 3-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate was dissolved in 2.3 ml methanol, 4.6 ml of 4 N hydrochloric acid/ethyl acetate was added thereto, and the mixture was stirred at room temperature for 1 hr. 5 ml ethyl acetate was added thereto, and the resulting crystals were collected by filtration to give 700 mg of 3-oxo-2-oxa-8-azaspiro[4.5]decane hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[N:8]3.C(N(CC)CC)C.CC[O:29][C:30]([C:32]([F:35])([F:34])[F:33])=O>C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:30](=[O:29])[C:32]([F:35])([F:34])[F:33])=[N:8]3
Reactant: Cc1nc2cccc3nc(SCCCCCN)c1n23
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc2cccc3nc(SCCCCCNC(=O)C(F)(F)F)c1n23
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 275 mg (1.00 mmol) of 3-methyl-2-[5-(amino)pentan-1-ylthio]-1,4,7b-triazacyclopent[cd]indene in 30 ml of acetonitrile were added 0.19 ml (1.36 mmol) of triethylamine and 171 mg (1.20 mmol) of ethyl ester of trifluoroacetic acid. The mixture was stirred for 15 hours at room temperature. The solvent was distilled off. To the residue was added ethyl acetate, which was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to afford 267 mg (72.0%, a pale yellow solid) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH2:14]1COCC1>>[Cl:11][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][CH3:14])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CNc1nccc(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
2-Amino-4-chloro-3-nitropyridine (590 mg, 4 mmol) was dissolved in dry THF (15 mL), the solution was cooled to 0° C. and NaH (240 mg, 6 mmol) was added. The reaction mixture was stirred for 2 hours, and allowed to warm at room temperature. The solvent was evaporated and the residue extracted between AcOEt and water. The organic layer was dried (MgSO4) and evaporated. The crude mixture was purified by column chromatography (eluent DCM) to afford the title compound (190 mg, 25%). 1H-NMR (6, ppm, DMSO-d6): 2.88 (d, 3H, Me, J=4.55 Hz), 6.86 (d, 1H, HPy,5, J=5.31 Hz), 7.44 (broad s, 1H, NH), 8.21 (d, 1H, HPy,5, J=5.30 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH:6]2[C:9]([OH:11])=[O:10])[O:3]1.[CH3:12]I>CC(C)=O.[Ag-]=O>[CH3:12][O:10][C:9]([CH:6]1[CH2:5][CH:4]2[CH2:8][CH:7]1[C:2](=[O:1])[O:3]2)=[O:11]
Reactant: CI
Reactant: O=C(O)C1CC2CC1C(=O)O2
Agent: O=[Ag-]
Solvent: CC(C)=O
Product: COC(=O)C1CC2CC1C(=O)O2
Reaction time: 3 h
Yield: 63.5 %

Procedure:
Compound 32 (1.014 g, 6.50 mmol) was dissolved in acetone (35 mL) before methyl iodide (13.68 g, 96.4 mmol) and silver (I) oxide (1.61 g, 6.95 mmol) were added. After stirring for 3 h the mixture was filtered through celite and the filtrate was evaporated before purification by flash column chromatography (toluene/ethyl acetate 4:1) was performed yielding the methyl ester 41 (702 mg, 64%) as white crystals.
Reaction SMILES: Cl[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:24])[N:5]([CH2:25][CH3:26])[C:4]=2[N:3]=1.[Na]>C(O)CC>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:24])[N:5]([CH2:25][CH3:26])[C:4]=3[N:3]=[C:2]2[O:19][CH2:8][CH2:9][CH3:4])=[CH:13][CH:14]=1
Reactant: CCn1c(=O)n(CCCO)c(=O)c2c1nc(Cl)n2Cc1ccc(Cl)cc1
Agent: [Na]
Solvent: CCCO
Product: CCCOc1nc2c(c(=O)n(CCCO)c(=O)n2CC)n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
To a solution of 8-chloro-3-ethyl-7-(4-fluorobenzyl)-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (50 mg, 0.117 mmol, intermediate 78) in propanol (5 mL) was added sodium (10 mg, 0.43 mmol). The reaction was stirred at room temperature for 1 h. The reaction was partitioned between ethyl acetate and brine. The organic phase was dried and concentrated to give a crude product, which was purified via preparative HPLC to give 7-(4-chlorobenzyl)-3-ethyl-1-(3-hydroxypropyl)-8-propoxy-1H-purine-2,6(3H,7H)-dione (11.6 mg, 24.4% yield) as white solid. 1H-NMR (CD3OD) δ 7.24-7.29(s, 4H), 5.21(s, 2H), 4.39-4.42(t, 2H), 3.98-4.05(m, 4H), 3.49-3.53(m, 2H), 1.73-1.81(m, 4H), 1.20-1.23(m, 3H), 0.90-0.94(m, 3H). LCMS retention time 2.881; LCMS MH+ 421.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([CH3:26])([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH:28]1([C:34]2[O:35][C:36]([CH3:52])=[C:37]([CH2:39][CH2:40]OS(C3C=CC(C)=CC=3)(=O)=O)[N:38]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[K+].[Br-]>>[CH:28]1([C:34]2[O:35][C:36]([CH3:52])=[C:37]([CH2:39][CH2:40][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([CH3:26])([O:14][C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:19][CH:20]=4)[C:4]([OH:3])=[O:27])=[CH:8][CH:9]=3)[N:38]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(OC(F)(F)F)cc1
Agent: [Br-]
Agent: [K+]
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(OC(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 3-(4-hydroxyphenyl)-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester using the procedure of Example 42. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, 2H, J=8.4 Hz), 7.13 (d, 2H, J=8.4 Hz), 6.90 (d, 2H, J=8.4 Hz), 6.79 (d, 2H, J=8.4 Hz), 4.43 (bs, 1H), 4.16 (t, 2H, J=6.0 Hz), 3.25 and 3.13 (d of Abq, 2H, J=14.0 Hz), 3.02 (t, 2H, J=6.0 Hz), 3.02-2.98 (m, 1H), 2.36 (s, 3H), 2.09-2.00 (m, 2H), 1.88-1.79 (m, 2H), 1.78-1.69 (m, 1H), 1.64-1.52 (m, 2H), 1.43 (s, 3H), 1.40-1.23 (m, 3H). IR (KBr) 3600, 2980, 1725, 1601, 1500, 1268 cm−1. HRMS (ES+) m/z exact mass calcd for C29H33NO6F3 548.2260, found 548.2274.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].CO.Cl>O1CCCC1>[NH2:6][CH2:5][C:4]1[C:3]([NH:2][CH3:1])=[N:10][CH:9]=[CH:8][CH:7]=1
Reactant: CNc1ncccc1C#N
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CNc1ncccc1CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
Borane/THF complex (1.44 mol) as a 1M solution in tetrahydrofuran was added, dropwise, to a solution of 2-(methylamino)-nicotinonitrile (63.9 g, 480 mmol) in tetrahydrofuran (480 mL). This mixture was stirred at room temperature for 1 hour then heated to reflux for 3 hours. The reaction mixture was quenched by dropwise addition of methanol (136 mL, 3.36 mol) followed by 6M HCl (80 mol, 480 mmol) and 10% HCl (400 mL). The phases were separated and the organic phase washed with brine (2×480 mL). The aqueous phase was made alkaline with 50% aqueous NaOH (250 g). The aqueous phase was extracted with dichloromethane (2×480 mL) and the organic extracts dried over Na2SO4. Concentration in vacuo gave 44.85 g of 3-(aminomethyl)-2-methylaminopyridine as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])=[CH:5][NH:4][N:3]=1.[C:15](OCC)(=[O:20])[CH2:16][C:17]([CH3:19])=O>O1CCOCC1>[Cl:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[C:6]1[CH:5]=[N:4][N:3]2[C:15]([OH:20])=[CH:16][C:17]([CH3:19])=[N:1][C:2]=12
Reactant: Nc1n[nH]cc1-c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(O)n2ncc(-c3ccc(Cl)cc3Cl)c2n1

Procedure:
3-Amino-4-(2,4-dichlorophenyl)pyrazole and ethyl acetoacetate (2 equivalents) were dissolved in dioxane and heated under reflux overnight. The mixture was concentrated in vacuo and diluted with ethyl acetate. An off-white solid formed after 2 days standing was collected by vacuum filtration, yielding 3-(2,4-dichlorophenyl)-5-methyl-7-hydroxypyrazolo[2,3-a]pyrimidine (intermediate 1).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:51])[NH:10][CH:11]([CH3:50])[CH2:12][C:13]([NH:15][CH:16]([C:29](=[O:49])[N:30]([CH2:41][CH:42](OCC)OCC)[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:40]=1[NH:39][N:38]=[CH:37]2)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C(C)(C)C)=[CH:20][CH:19]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)=O>[CH2:1]([NH:8][C:9]([N:10]1[CH:11]([CH3:50])[CH2:12][C:13](=[O:14])[N:15]2[CH:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)[C:29](=[O:49])[N:30]([CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[C:36]4[C:40]=3[NH:39][N:38]=[CH:37]4)[CH2:41][CH:42]12)=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(CN(Cc1cccc2cn[nH]c12)C(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)CC(C)NC(=O)NCc1ccccc1)OCC
Solvent: O=CO
Product: CC1CC(=O)N2C(Cc3ccc(O)cc3)C(=O)N(Cc3cccc4cn[nH]c34)CC2N1C(=O)NCc1ccccc1
Yield: 33.7 %

Procedure:
A solution of crude 3-(3-Benzyl-ureido)-N-{2-(4-tert-butoxy-phenyl)-1-[(2,2-diethoxy-ethyl)-(1H-indazol-7-ylmethyl)-carbamoyl]-ethyl}-butyramide (3.46 g, 4.95 mmol) in formic acid (100 mL) was stirred at room temperature for 13 h. The solvent was removed under reduced pressure and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography and recrystallized on ethyl acetate and hexane to give the 6-(4-Hydroxy-benzyl)-8-(1H-indazol-7-ylmethyl)-2-methyl-4,7-dioxo-hexahydro-pyrazino[1,2-a]pyrimidine-1-carboxylic acid benzylamide (0.923 g, 3 step yield: 29%). 1H NMR (CDCl3, 300 MHz) δ 8.30 (s, 1H), 7.4˜7.26 (m, 3H), 7.2 (d, J=7.01, 2H), 6.98 (t, J=8.0, 1H), 6.85 (m, 3H), 6.8 (t, J=7.0, 1H), 6.5 (d, J=8.76, 2H), 5.6 (m, 1H), 5.25 (t, J=4.7, 1H), 4.55 (m, 1H), 4.5˜4.25 (m, 4H), 3.5˜3.3 (m, 2H), 3.25-3.1 (m, 2H), 2.2 (t, J=7.2, 2H) 1.45 (m, 3H) MS ESI 553 (M+H), 575 (M+Na).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([C:13](OC)=[O:14])[CH:11]=[N:12][C:6]=2[N:5]2[CH2:17][CH2:18][CH2:19][CH:4]2[CH2:3]1.[H-].[Na+].[H-].[Li+].[Al+3].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.O.CO>[OH:14][CH2:13][C:10]1[CH:11]=[N:12][C:6]2[N:5]3[CH2:17][CH2:18][CH2:19][CH:4]3[CH2:3][C:2](=[O:1])[NH:8][C:7]=2[CH:9]=1
Reactant: COC(=O)c1cnc2c(c1)NC(=O)CC1CCCN21
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C1CC2CCCN2c2ncc(CO)cc2N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.4 %

Procedure:
Methyl 6-oxo-6,7,7a,8,9,10-hexahydro-5H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]diazepine-3-carboxylate (0.900 g, 3.44 mmol) was suspended in THF (Volume: 11.48 ml) under nitrogen atmosphere and NaH (276 mg, 6.9 mmol) was added in several portions over 2 min. The reaction mixture was stirred at room temperature for 10 min and cooled to below −50° C. aluminum(III) lithium hydride (3.10 ml, 6.20 mmol) was added over the period of 5 min and the reaction was kept at a temperature between −30 and −20° C. for 1 h (LCMS: >95% conversion). The mixture was cooled to below −50° C. and MeOH (4 mL) was added. Water (1 mL) was added and the reaction mixture was stirred at rt for 10 min. Rochelle salt (20% solution) was added (10 mL) and the mixture was extracted with THF (4×10 mL). The combined organic extracts were dried (Na2SO4 and MgSO4), filtered and concentrated in vacuo. The residue was recrystallized from THF/Ethyl ether (1:1, 20 mL). The solid was filtered off and dried in vacuum to afford 3-(hydroxymethyl)-7a,8,9,10-tetrahydro-5H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]diazepin-6(7H)-one (0.654 g, 2.80 mmol, 81% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (m, J=11.62, 11.62, 9.73, 6.69 Hz, 1 H) 1.74-1.85 (m, 1 H) 1.86-1.96 (m, 1 H) 2.14 (m, J=11.91, 5.98, 5.98, 1.89 Hz, 1 H) 2.52-2.58 (m, 1 H) 2.58-2.67 (m, 1 H) 3.49 (ddd, J=10.93, 8.15, 2.15 Hz, 1 H) 3.66 (td, J=10.61, 6.82 Hz, 1 H) 3.81-3.93 (m, 1 H) 4.31 (d, J=5.31 Hz, 2 H) 5.01 (t, J=5.43 Hz, 1 H) 7.14 (d, J=2.02 Hz, 1 H) 7.77 (d, J=2.02 Hz, 1 H) 9.60 (d, 1 H). [M+H] calc'd for C12H15N3O2, 233; found, 233.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([S:15][C:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH3:26])[CH:6]=1)[CH3:2].Br[C:29]1[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=1>>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:8]=[C:7]([S:15][C:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[N:18]([C:29]3[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=3)[C:17]=2[CH3:26])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Sc2c(C)[nH]c3cc(Cl)ccc23)cc(C(F)(F)F)c1
Reactant: Cn1cc(Br)cn1
Product: CCOC(=O)c1cc(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-5-trifluoromethyl-benzoic acid ethyl ester and 4-bromo-1-methylpyrazole.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([N:11]([CH:13]([CH3:15])[CH3:14])[CH3:12])[CH2:8][CH2:7][C@@H:6]1[N:16]1[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OCC2C=CC=CC=2)[C:17]1=[O:32])(=[O:3])[CH3:2].Cl>CC(O)C.[Pd]>[NH2:21][C@H:18]1[CH2:19][CH2:20][N:16]([C@H:6]2[CH2:7][CH2:8][C@@H:9]([N:11]([CH:13]([CH3:15])[CH3:14])[CH3:12])[CH2:10][C@H:5]2[NH:4][C:1](=[O:3])[CH3:2])[C:17]1=[O:32]
Reactant: CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reaction time: 8 h
Yield: 130.5 %

Procedure:
Example 1, Alternative Preparation, Step 6: To a solution containing acetamide 10 (˜61 g) in i-PrOH (˜625 mL) was added 10% Pd/C wet catalyst (2.5 g) and the suspension was hydrogenated at 30 psig and approx. 25° C. for at least 2 h. Upon completion (HPLC), the catalyst was removed by filtration and the filtrate was concentrated to approx. 550 mL. Water (8.8 mL) was added, followed by 5.6 N hydrochloric acid in i-PrOH solution (69.5 mL). The resulting slurry was held at room temperature overnight. The product was isolated by filtration and the cake was rinsed with i-PrOH (2×100 mL) and dried in vacuo to constant weight at ˜50° C. to give N-[(1R,2S,5R)-2-((S)-3-amino-2-oxo-pyrrolidin-1-yl)-5-(isopropyl-methyl-amino)-cyclohexyl]-acetamide 11 (55.6 g, 97% yield) as its hydrochloric acid salt (73.6% free base assay, HPLC).
Reaction SMILES: C([NH:14][P:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:17])[OH:16])(C1C=CC=CC=1)C1C=CC=CC=1>Cl>[NH2:14][P:15]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:16])[OH:17]
Reactant: O=P(O)(Cc1ccccc1)NC(c1ccccc1)c1ccccc1
Agent: Cl
Product: NP(=O)(O)Cc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 20 g of the compound from step 1 and 160 ml of 6N HCl is boiled under reflux for 2 hours. After cooling, the reaction medium is concentrated by half and extracted with 3×1.5 l of ethyl ether. The solution is evaporated to dryness and the oily residue is taken up with 160 ml of ethanol. The solution is cooled to 0° C. and 40 ml of propylene oxide is added. A white solid precipitates. The precipitate is dewatered, washed with ethanol (2×20 ml), ethyl ether (2×10 ml) and dried. White solid, 7.25 g (95.3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=2)=[CH:4][CH:3]=1.[C:20]([N:28]=C=O)(=[O:27])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([NH2:28])=[O:27])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: Nc1cc(N2CCCC2c2ccc(F)cc2)ccn1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: NC(=O)Nc1cc(N2CCCC2c2ccc(F)cc2)ccn1
Temperature: 50 °C
Yield: 55.5 %

Procedure:
4-[2-(4-Fluoro-phenyl)-pyrrolidin-1-yl]-pyridin-2-ylamine (61 mg, 0.24 mmol) and benzoyl isocynate (52 mg, 0.36 mmol) are mixed in DCM (2.0 mL). The reaction is sealed and heated at 50° C. for 16 hrs. Then the solvent is removed and to the residue are added ethanol (2.0 mL) and potassium carbonate (49 mg, 0.36 mmol). The mixture is then heated at 80° C. for 45 min. The solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (55 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) followed by re-crystallization from DCM/heptane affords 40 mg of the titled product.