Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]([CH2:13][CH2:14][OH:15])[C:10](=[O:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([O:16][C:22]3[CH:23]=[CH:24][C:19]([C:18]([F:27])([F:26])[F:17])=[CH:20][CH:21]=3)[N:11]([CH2:13][CH2:14][OH:15])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: O=c1cc(-c2cccc(Br)c2)[nH]n1CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: OCCn1nc(-c2cccc(Br)c2)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: 160 °C
Reaction time: 13 h

Procedure:
5-(3-Bromophenyl)-2-(2-hydroxyethyl)-1,2-dihydro-3H-pyrazol-3-one (21 g, 74 mmol), 4-trifluoromethyl-1-fluorobenzene (28 mL, 220 mmol), and K2CO3 (30.6 g, 220 mmol) were combined in 140 mL of dry DMA. The mixture was heated at 160° C. with stirring in a sealed vessel for 13 h. The reaction was cooled to ambient temperature and more 4-trifluoromethyl-1-fluorobenzene (5 mL, 39 mmol) was added. The mixture was heated at 160° C. with stirring in a sealed vessel for 18 h. The reaction was cooled to ambient temperature and diluted with EtOAc. The mixture was washed with water and brine, then dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The dark residue was chromatographed on a 330 g silica gel column using 0-40% EtOAc:hexanes over 70 min at 100 mL/min. The product-containing fractions were combined and the solvent was removed under reduced pressure to give 2-{3-(3-bromophenyl)-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-1-yl}ethanol as an oil which solidified on standing. Calcd (M−1-1)+: 428.2. Found: 428.3
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[CH2:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)[CH2:12][CH3:13].C(N(CC)CC)C>C1COCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([CH2:11][CH2:12][CH3:13])=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CCCc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1ccc(C(=O)Nc2ccc(C(C)=O)cc2)cc1
Yield: 78.6 %

Procedure:
Reaction of 4-aminoacetophenone (76 mg, 0.56 mmol) in THF (6 mL) with 4-propylbenzoyl chloride (100 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(4-acetyl-phenyl)-4-propyl-benzamide (125 mg, 0.44 mmol, 78% yield) as a white powder after washing by dichloromethane and hexane.
Reaction SMILES: COC([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([O:17]N3C(=O)CCC3=O)=O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=O.[N:25]1([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH2:33][CH2:34][CH:35]3[NH2:40])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.CO>CN(C=O)C.O>[NH:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:40][CH:35]3[C:36]4[C:32](=[C:31]([N:25]5[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]5)[CH:39]=[CH:38][CH:37]=4)[CH2:33][CH2:34]3)=[O:17])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: NC1CCc2c1cccc2N1CCCCC1
Reactant: COC(=O)n1ncc2c(NC(=O)ON3C(=O)CCC3=O)cccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: O=C(Nc1cccc2[nH]ncc12)NC1CCc2c1cccc2N1CCCCC1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
4-(2,5-Dioxopyrrolidin-1-yl-oxycarbonylamino)-indazole-1-carboxylic acid methyl ester (5.57 g, 16.8 mmol) was added to a solution of 4-piperidin-1-ylindan-1-ylamine (3.81 g, 17.6 mmol) and DIPEA (3.0 mL, 17.2 mmol) in DMF (80 mL) under nitrogen atmosphere at ambient temperature. After 30 minutes the reaction solution was diluted with water (350 mL), the resulting beige precipitate was filtered off, washed with water and air-dried. The wet cake was added to a solution of methanol (200 mL), water (3 mL) and TEA (7.0 mL, 50.2 mmol). The mixture was refluxed for 90 minutes, cooled to room temperature, diluted with water (200 mL), collected the beige precipitate by filtration, rinsed with water and air-dried. The wet cake was vacuum dried to constant weight, yielding 1-(1H-indazol-4-yl)-3-(4-piperidin-1-ylindan-1-yl)-urea (5.89 g, 93%) as a beige solid. MS (ESI) m/z: 376.00 [M+H]+. 1H NMR (DMSO-d6) δ: 1.56 (m, 2H), 1.65 (m, 4H), 1.78 (m, 1H), 2.44 (m, 1H), 2.77 (m, 1H), 2.85 (m, 3H), 2.95 (m, 2H), 5.16 (q, 1H), 6.66 (d, 1H), 6.81 (d, 1H), 6.95 (d, 1H), 7.07 (d, 1H), 7.22 (m, 2H), 7.68 (d, 1H), 8.05 (s, 1H), 8.62 (s, 1H), 13.00 (s, 1H). Anal Calcd for C22H25N5O: C, 70.38; H, 6.71; N, 18.65. Found: C, 70.24; H, 6.72; N, 18.47.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16](=[O:36])[NH:17][C@@H:18]([CH3:35])[C:19]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C[SiH](C)C1C=CC=CC=1.[OH-].[K+]>CCOC(C)=O.[Cl-].[Na+].O.C1COCC1>[CH2:8]([O:15][C:16](=[O:36])[NH:17][C@@H:18]([CH3:35])[CH:19]([C:21]1[CH:22]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)[OH:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[SiH](C)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (11 mL) was cooled to −5° C. [(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-1-methyl-2-oxo-ethyl]-carbamic acid benzyl ester (5 g, 11.9 mmol) was added slowly, followed by dimethylphenylsilane (2.2 mL, 14.3 mmol), and the mixture was stirred for 4 hours. Once no starting material was seen by analytical tlc, the mixture was cooled to 0° C. and treated with 50% aqueous KOH (12 mL), followed by THF (16 mL). After stirring at room temperature for 5 hours, only starting material was seen by analytical tlc, and so the solution was diluted with EtOAc and brine. The organic layer was separated and concentrated, and the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH2:11])=[CH:4][CH:3]=1.CN1CCOCC1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]2.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O.CN(C)C=O>[NH:25]1[C:26]2[C:22](=[CH:21][C:20]([NH:19][C:7](=[O:9])[C:6]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[NH2:11])=[CH:28][CH:27]=2)[CH:23]=[N:24]1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: Nc1ccc2[nH]ncc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
171 mg of 5-chloroanthranilic acid is introduced into 10 ml of dimethylformamide under argon and in a moisture-free environment and mixed in succession with 253 mg of N-methylmorpholine, 266 mg of 5-aminoindazole and 456 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and stirred for 4 hours at room temperature. After standing overnight, it is mixed with 50 ml of water and extracted with 30 ml of ethyl acetate. The organic phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate as an eluant. 266 mg of N-(indazol-5-yl)-5-chloroanthranilic acid amide is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([F:20])[C:18]=1[F:19].C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl.Cl[Pd]Cl>[F:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:16]=[C:17]([F:20])[C:18]=1[F:19]
Reactant: COC(=O)c1ccnc(Br)c1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccnc(-c2cc(F)c(F)c(F)c2)c1
Temperature: 100 °C
Yield: 52.9 %

Procedure:
Methyl 2-bromoisonicotinate (4 g, 18.52 mmol), 3,4,5-trifluorophenylboronic acid (4.89 g, 27.77 mmol), potassium carbonate (3.84 g, 27.77 mmol) and PdCl2 (dppf) (0.402 g, 0.56 mmol) were mixed in methanol (30 mL) in two separate 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. Water and DCM were added and the phases were separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a brown solid. The residue was dissolved in DCM and purified by SCX-2 cation exchange chromatography. Methyl 2-(3,4,5-trifluorophenyl)isonicotinate (2.62 g, 52%) was isolated as a slightly yellow solid. MS m/z 268 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:17](=[O:32])[C@@H:18]([N:23](C)[C:24](=O)OC(C)(C)C)[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1.O1CCOCC1>Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:17](=[O:32])[C@H:18]([CH2:19][CH:20]([CH3:21])[CH3:22])[NH:23][CH3:24])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1
Reactant: CC(C)C[C@@H](C(=O)N[C@H]1CC[C@@H]2CN(c3ccccc3F)C[C@@H]21)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@@H](CC(C)C)C(=O)N[C@H]1CC[C@@H]2CN(c3ccccc3F)C[C@@H]21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 4 mL vial tert-butyl(S)-1-((3aR,4S,6aS)-2-(2-fluorophenyl)octahydrocyclopenta[c]pyrrol-4-ylamino)-4-methyl-1-oxopentan-2-yl(methyl)carbamate from Step 2 (72 mg, 0.161 mmol) was dissolved in 4 N HCl in 1,4-dioxane (1 mL, 4.00 mmol). An oil slowly gummed out of solution. The reaction was stirred at room temperature for 18 hours, and the solvent was removed under a stream of nitrogen. The crude material was purified using a 12 g silica gel cartridge with 1-10% methanol (2 N ammonia)/dichloromethane to give N-[(3aR,4S,6aS)-2-(2-fluorophenyl)octahydrocyclopenta[c]pyrrol-4-yl]-N2-methyl-L-leucinamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.29 (d, J=7.4, 1H), 7.16-7.09 (m, 1H), 7.06 (tt, J=4.8, 2.4, 1H), 6.86-6.78 (m, 2H), 4.49-4.41 (m, 1H), 3.67 (d, J=9.6, 1H), 3.31-3.23 (m, 2H), 3.21 (d, J=9.5, 1H), 3.11 (dd, J=9.3, 7.0, 1H), 2.71-2.63 (m, 2H), 2.45 (s, 3H), 2.14-1.95 (br m, 1H), 2.10 (td, J=12.1, 6.1, 1H), 1.99-1.87 (m, 2H), 1.74 (ddd, J=13.7, 7.8, 5.9, 1H), 1.69-1.57 (m, 2H), 1.49-1.40 (m, 1H), 0.94 (t, J=4.5, 3H), 0.87 (d, J=6.6, 3H); MS (ESI+) m/z 348 (M+H)+.
Reaction SMILES: C(OC([N:11]1[CH2:22][CH2:21][C:14]2([O:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH3:32]>CS(C)=O>[CH2:30]([N:16]1[C:15](=[O:20])[C:14]2([CH2:13][CH2:12][NH:11][CH2:22][CH2:21]2)[O:18][C:17]1=[O:19])[CH2:31][CH3:32]
Reactant: CCCBr
Reactant: O=C1NC(=O)C2(CCN(C(=O)OCc3ccccc3)CC2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCN1C(=O)OC2(CCNCC2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 124.9 %

Procedure:
To a solution of 2,4-dioxo-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylic acid benzyl ester (24.4 g, 80 mmol) in DMSO (240 ml), potassium carbonate (16.5 g, 120 mmol) and bromopropane (11 ml, 120 mmol) are added to the mixture at ambient temperature. The reaction mixture is stirred at ambient temperature for 12 h, quenched with water and extracted with AcOEt:ether (1:1 (v/v)). The combined extracts are washed with brine, dried over magnesium sulfate, filtrated and concentrated. The residue is purified by column chromatography on silica gel using n-hexane:AcOEt=2:1 (v/v). to give 21.2 g of desired product in 76% yield. Rf=0.8 (n-hexane:AcOEt=1:1). To white solid (21.2 g) and 10% Pd/C (3 g), MeOH (300 ml) is added. The reaction mixture is stirred at ambient temperature for 18 h under H2. After the filtration, the solvent is evaporated down to give the desired product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:12])[CH3:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[BH4-].[Na+].CC(=O)OCC>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:12])[CH3:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(=O)c1ccc2c(c1)OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(O)c1ccc2c(c1)OCO2
Yield: 86.3 %

Procedure:
To a solution of 1-benzo[1,3]dioxol-5-yl-ethanone (2.5 gm; 15.2 mmol) in methanol (50 mL) is added sodium borohydride (634 mg; 16.7 mmol) in portions allowing for gas evolution. The reaction is stirred at room temperature for 3 hours before additional sodium borohydride is added to give a complete reaction by TLC (20% EA/Hex). The reaction is quenched with saturated ammonium chloride and extracted with ethyl acetate. The organics are separated, washed with water, dried over magnesium sulfate, and the solvent is removed to give 2.18 grams of 1-benzo[1,3]dioxol-5-yl-ethanol.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH:21]=[O:22])[C@H:12]([CH3:23])[N:11]1[C:24](=[O:34])[CH2:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:35][Mg]Cl>C1COCC1>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH:21]([OH:22])[CH3:35])[C@H:12]([CH3:23])[N:11]1[C:24](=[O:34])[CH2:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[Mg]Cl
Reactant: C[C@H]1c2cccc(CC=O)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(Cl)cccc1Cl
Solvent: C1CCOC1
Product: CC(O)Cc1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(Cl)cccc1Cl)[C@H]2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
Dissolve 2-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-(2,6-dichlorophenyl)acetyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)acetaldehyde (138 mg, 0.27 mmol) in THF (2.7 mL). Cool to 0° C., add MeMgCl (0.097 mL, 0.29 mmol, 3M in Et2O). Stir 30 min at 0° C. Add water and extract with ethyl acetate three times. Combine the ethyl acetate extracts, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 2-60%) to give the title compound as a white foam (122 mg, 0.23 mmol). MS (m/z): 536.2 (M+1).
Reaction SMILES: [CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][NH:5]1)([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>C(O)CC>[CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][N:5]1[C:20]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=1)([CH3:3])[CH3:2]
Reactant: CSc1ccc2cc3n(c2c1)CCNC3C(C)C
Reactant: FC(F)(F)c1ccnc(Cl)n1
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccc2cc3n(c2c1)CCN(c1nccc(C(F)(F)F)n1)C3C(C)C
Temperature: 100 °C
Reaction time: 4 h
Yield: 58.3 %

Procedure:
To a solution of 1-isopropyl-7-(methylthio)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (50 mg, 0.19 mmol) in PrOH (2 mL) was added 2-chloro-4-(trifluoromethyl)pyrimidine (105 mg, 0.58 mmol) and DIEA (185 mg, 0.96 mmol). The mixture was stirred at 100° C. for 4 h. The mixture was concentrated under vacuum and the residue was purified by preparative TLC to afford 1-isopropyl-7-(methylthio)-2-(4-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (45 mg, 57.7% yield) as a yellow oil. LC-MS MS (ESI) m/z 407.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][C:24]([O:27][CH3:28])=[CH:25][N:26]=2)=[N:10]1.Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH:31]1[C:36]([OH:38])=[O:37]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][C:24]([O:27][CH3:28])=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]2[C:36]([OH:38])=[O:37])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncc(OC)s2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncc(OC)s2)=NC1c1ccc(F)cc1Br
Yield: 51.4 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-methoxythiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.53 g, 1 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.2 g, 1.2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellowish solid (0.30 g, 52%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]2[C:10](=[O:19])[NH:11][C:12]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:13][C:8]=2[CH:7]=[N:6]1)([CH3:4])[CH3:3].[CH3:20][C:21]1[C:29]2[C:24](=[C:25]([CH3:33])[CH:26]=[C:27]([C:30](O)=[O:31])[CH:28]=2)[NH:23][N:22]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:20][C:21]1[C:29]2[C:24](=[C:25]([CH3:33])[CH:26]=[C:27]([C:30]([N:16]3[CH2:17][CH2:18][C:12]4([NH:11][C:10](=[O:19])[C:9]5[N:5]([CH:2]([CH3:4])[CH3:3])[N:6]=[CH:7][C:8]=5[CH2:13]4)[CH2:14][CH2:15]3)=[O:31])[CH:28]=2)[NH:23][N:22]=1
Reactant: Cc1n[nH]c2c(C)cc(C(=O)O)cc12
Reactant: CC(C)n1ncc2c1C(=O)NC1(CCNCC1)C2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1n[nH]c2c(C)cc(C(=O)N3CCC4(CC3)Cc3cnn(C(C)C)c3C(=O)N4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
To a solution of 1′-isopropyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(1′H)-one hydrochloride salt (Intermediate 2, 430 mg, 1.3 mmol) and 3,7-dimethyl-1H-indazole-5-carboxylic acid (306 mg, 1.6 mmol) in dimethylformamide (2 mL) was added triethylamine (0.75 mL, 5.4 mmol), 4-dimethylaminopyridine (33 mg, 0.37 mmol), and 1-propanephosphonic acid cyclic anhydride (0.52 mL, 1.74 mmol, 50% solution in ethyl acetate), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated to a solid. The solid was purified via flash column chromatography (0-15% methanol/dichloromethane) to afford a glassy solid. The glassy solid was stirred in ethyl acetate for 16 hours and the resulting solid collected by vacuum filtration to afford the desired product as a white solid (138 mg). +ESI (M+H) 421.0; 1H NMR (400 MHz, CD3OD, δ): 7.65 (s, 1H) 7.42 (s, 1H) 7.21 (s, 1H) 5.50 (m, 1H) 3.95 (br. s., 1H) 3.50-3.62 (br. s., 3H) 2.97 (s, 2H) 2.56 (m, 6H) 1.83 (br. s., 4H) 1.44 (d, 6H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:30](OC)=[O:31])=[C:12]2[C:16]=1[N:15]=[C:14]1[CH:17]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[O:18][CH2:19][CH2:20][CH2:21][N:13]21.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Cl:7][C:8]1[C:16]2[N:15]=[C:14]3[CH:17]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])[O:18][CH2:19][CH2:20][CH2:21][N:13]3[C:12]=2[C:11]([CH2:30][OH:31])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a suspension of lithium aluminum hydride (35.7 mg, 0.940 mmol) in tetrahydrofuran (2 mL) was added a solution of methyl 10-chloro-1-(2,4-dichlorophenyl)-4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-a]benzimidazole-7-carboxylate (200 mg, 0.470 mmol) in tetrahydrofuran (2 mL) at 0° C. After 5 min, sodium sulfate decahydrate was added. After 30 min, the resultant mixture was filtrated and concentrated in vacuo to give the title compound as a colorless solid (187 mg, 0.470 mmol, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].[BH4-].[Na+].[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C(O)C.C(Cl)Cl>[CH3:21][S:22]([O:11][CH2:10][C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=2[O:2][CH3:1])[CH:8]=1)(=[O:24])=[O:23]
Reactant: COc1ccccc1COc1cccc(C=O)c1
Reactant: CS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: COc1ccccc1COc1cccc(COS(C)(=O)=O)c1
Yield: 95.3 %

Procedure:
530 mg of 3-(2-methoxybenzyloxy)benzyl alcohol obtained by reducing 3-(2-methoxybenzyloxy)benzaldehyde with sodium borohydride in ethanol was dissolved in 8 ml of methylene chloride. The solution was stirred at -5° to 0° C., 0.20 ml of methanesulfonyl chloride and 0.65 ml of triethylamine were added. The mixture was stirred at this temperature for 5 minutes. The reaction mixture was diluted with methylene chloride, washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 660 mg (yield 95.3%) of the captioned compound as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]3[CH:13]=[CH:14][CH:15]=[C:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][C:19](=[O:22])[CH2:20]Br)C.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.CC(=O)OCC>[CH3:16][O:18][C:19](=[O:22])[CH2:20][N:12]1[CH2:11][CH2:10][N:9]2[CH:13]=[CH:14][CH:15]=[C:8]2[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CBr
Reactant: c1ccc(C2NCCn3cccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COC(=O)CN1CCn2cccc2C1c1ccccc1
Reaction time: 0.25 h
Yield: 102.1 %

Procedure:
A mixture of (1.0 g, 5.0 mmol) of 1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine, 2-bromoacetic acid ethyl ester (587 μl, 5.3 mmol) and potassium carbonate (1.74 g, 12.6 mmol) in acetonitrile (20 ml) was heated for 2 h under reflux. Water (10 ml) and EA (20 ml) were then added, stirring was carried out for 15 min, and the phases were separated. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. 1.38 g of 2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)acetic acid methyl ester were obtained as residue and used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@H:12]([CH:13]=[CH:14][C:15](=[O:21])[C@@H:16]3[CH2:20][CH2:19][CH2:18][O:17]3)[C@H:11]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10]2=[O:32])=[CH:5][CH:4]=1>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@H:12]([CH2:13][CH2:14][C:15](=[O:21])[C@@H:16]3[CH2:20][CH2:19][CH2:18][O:17]3)[C@H:11]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10]2=[O:32])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2C=CC(=O)[C@@H]2CCCO2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CCC(=O)[C@@H]2CCCO2)cc1
Yield: 94.4 %

Procedure:
A solution of (3S,4R)-1-(4-methoxyphenyl)-4-[3-oxo-3-[(S)-tetrahydro-furan-2-yl]propenyl]-3-phenylacetamidoazetidin-2-one (12.1 g, 27.9 mmol) in tetrahydrofuran (250 ml) was hydrogenated over 10% palladium on carbon (1.0 g) for 3h. After filtration through celite, the partially insoluble product was dissolved in dichloromethane and methanol (1: 1) and re-filtered through celite to remove the catalyst. Concentration of the filtrate in vacuo provided the title compound as an amorphous white solid (11.5 g, 95%); (Found: M+ 436.1997. C25H27N2O5 requires M436.1998); νmax (KBr) 3277, 1758, 1708, 1655, 1542, 1510 and 1246 cm-1 ; δH (CDCl3) 1.43 (1H, m), 1.78-1.95 (3H, m), 2.10-2.50 (4H, m), 3.62 (2H, s), 3.75 (3H, s), 3.91 (2H, m), 4.17 (1H, m), 4.24 (1H, m), 5.29 (1H, dd, J 7.8, 5.0 Hz), 6.73 (1H, d, J 7.8 Hz, exch.), 6.81 (2H, d, J 9.0 Hz) and 7.25-7.36 (7H, m).