Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13]Cl)[CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>CN(C)C=O>[CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][N:18]([CH2:19][CH3:20])[CH2:16][CH3:17])[CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(CCl)CN1Cc1ccccc1
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)CC1CC(=O)N(Cc2ccccc2)C1

Procedure:
A mixture of 14 g (0.06 mol) of crude 1-benzyl-4-chloromethyl-pyrrolidin-2-one, prepared as in Example 1(a), 10 g of diethylamine and 50 ml of dimethylformamide was stirred or shaken for 2 hours at 150° C. in an autoclave. The reaction mixture was evaporated to dryness in vacuo, the residue was taken up in methylene chloride, and the solution was washed first with water and finally the title compound was extracted twice with 25 ml of 2N HCl. The aqueous phase was separated, made alkaline with sodium hydroxide and the organic base was extracted with methylene chloride. The methylene chloride phase was evaporated, and the residue was distilled in vacuo.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:33])=[C:19]([NH:23][S:24]([C:27]3[N:31]([CH3:32])[N:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:35].Cl>CCOC(C)=O>[ClH:1].[NH2:35][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:33])=[C:19]([NH:23][S:24]([C:27]3[N:31]([CH3:32])[N:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cn1nccc1S(=O)(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cn1nccc1S(=O)(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(N)n2)c1F

Procedure:
N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrazole-5-sulfonamide (530 mg, 1.04 mmol) and ammonium hydroxide (26%, 15 ml) was heated in a steal reactor to 100° C. for 3 h. The reaction mixture was cooled and concentrated under reduced pressure, the residue was dissolved in methanol, and purified by Pre-HPLC (A=10 m MNH4HCO3/H2O, B=Acetonitrile), then the white solid obtained was dissolved in EtOAc, treated with HCl (g) for 30 min. The mixture was concentrated under reduced pressure, and then the residue was suspended in ether (20 ml), treated with ultrasonic for 3 min, filtered, the solid was suspended in ether (20 ml) again, treated with ultrasonic for 3 min, filtered to afford the title compound was obtained as a white solid (142 mg, 26%). 1HNMR (MEOD-d4): δ ppm 8.05 (br s, 1H), 7.61-7.65 (ddd, J1=7.7 Hz, J2=1.6 Hz, 1H), 7.42-7.46 (m, 2H), 7.32-7.36 (t, J=8.0 Hz, 1H), 6.70-6.71 (d, J=2.0 Hz, 1H), 6.25-6.27 (d, J=6.4 Hz, 1H), 4.04 (s, 3H), 1.50 (s, 9H). MS: 488.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:11]([C:13]1[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=1)#[CH:12].CCN(CC)CC>C1COCC1>[C:11]([C:13]1[CH:14]=[C:15]([NH:19][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[CH:16]=[CH:17][CH:18]=1)#[CH:12]
Reactant: C#Cc1cccc(N)c1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#Cc1cccc(NC(=O)c2ccccc2C)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
A dry 25 mL flask was charged with 2-methylbenzoyl chloride (0.155 g, 1.00 mmol) was cooled to room temperature, and THF (10 mL) was added. 3-Ethynyl-phenylamine (0.117 g, 1.00 mmol) was added to the THF solution of the acid chloride followed by NEt3 (0.272 mL, 2.00 mmol), and the mixture was allowed to stir at 55° C. The reaction mixture was then allowed to cool to room temperature and partitioned between EtOAc (10 mL) and H2O (15 mL). The organic layer was washed with then washed once with 1M HCl (20 mL) followed by of saturated aqueous NaHCO3 (˜20 mL) and of brine (˜20 mL). The organic extracts were concentrated and the crude residue was purified by chromatography (silica gel, gradient elution EtOAc/hexanes 10 to 70%). The product containing fractions were concentrated to give the title compound as a tan solid (434 mg, 0.88 mmol, 88%).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([C:12]2[N:13]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36](=S)[NH2:37])[CH:31]=3)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:16][CH:15]=3)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[C:41]([O-:44])(=[O:43])[CH3:42].[NH4+:45].CO>CC(C)=O>[C:41]([OH:44])(=[O:43])[CH3:42].[C:1]1([C@H:7]([NH:9][C:10]([C:12]2[N:13]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36](=[NH:37])[NH2:45])[CH:31]=3)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:16][CH:15]=3)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: C[C@@H](NC(=O)c1cc2cc(OCc3ccccc3)ccc2n1Cc1cccc(C(N)=S)c1)c1ccccc1
Reactant: CC(=O)[O-]
Solvent: CO
Solvent: CC(C)=O
Solvent: CI
Product: CC(=O)O
Product: C[C@@H](NC(=O)c1cc2cc(OCc3ccccc3)ccc2n1Cc1cccc(C(=N)N)c1)c1ccccc1
Yield: 28 %

Procedure:
This compound was prepared from (R)-5-benzyloxy-1-(3-thiocarbamoyl-benzyl)-1H-indole-2-carboxylic acid (1-phenyl-ethyl)-amide, methyl iodide, and ammonium acetate as described in example 1/5, but for the methylation acetone was used as solvent and in the last step methanol and acetone were used as solvents. The crude material was purified by flash chromatography on silica gel with dichloromethane/methanol/acetic acid 9:0.25:0.5 to give the desired product in 28% yield. M.p. 72° C. (dec.). MS: 503.3 (M+H+).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C([O:13][C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)O)(=O)O.C(=O)=O>>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]1([CH3:5])[O:13][C:14]2[CH:15]=[CH:17][CH:18]=[CH:19][C:20]=2[O:4]1)[CH3:9]
Reactant: O=C(O)Oc1ccccc1O
Reactant: CCOC(=O)CC(C)=O
Agent: O=C=O
Product: CCOC(=O)CC1(C)Oc2ccccc2O1

Procedure:
13 g of ethyl acetoacetate and 13.6 g of pyrocatechol carbonate are heated until evolution of CO2 ceases. The residue is distilled under reduced pressure, b.p. 83°-86°C/0.3 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12](C4CN(C(OC(C)(C)C)=O)C4)[C:11]=3[C:10](=[O:28])[N:9]2[C:29]2[CH:30]=[C:31]([CH3:39])[C:32]3[N:33]([C:35]([CH3:38])=[N:36][N:37]=3)[CH:34]=2)=[CH:4][CH:3]=1.CO.ClC1C=CC(C2C3C(C4CC4)=NNC=3C(=O)N2C2C=C(C)C3N(C(C)=NN=3)C=2)=CC=1>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:15]3[C:14]([CH3:16])=[N:13][NH:12][C:11]=3[C:10](=[O:28])[N:9]2[C:29]2[CH:30]=[C:31]([CH3:39])[C:32]3[N:33]([C:35]([CH3:38])=[N:36][N:37]=3)[CH:34]=2)=[CH:4][CH:3]=1
Reactant: Cc1nn(C2CN(C(=O)OC(C)(C)C)C2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Agent: Cc1cc(N2C(=O)c3[nH]nc(C4CC4)c3C2c2ccc(Cl)cc2)cn2c(C)nnc12
Solvent: CO
Solvent: CCOCC
Product: Cc1n[nH]c2c1[C@@H](c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O

Procedure:
The title compound (133 mg, 44% yield) was obtained enantiomerically pure (>99% ee) after chiral preparative SFC (system: Thar SFC200; column: Chiralpak OD-H, 30×250 mm; mobile phase: scCO2/MeOH 70:30; flow: 120 g/min; detection UV: 265 nm) of the racemic mixture of 4-(4-chlorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 129) and subsequent trituration in diethyl ether.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11]C(=O)OC(C)(C)C)[CH:2]=1.Cl>CO>[N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc2cccnc2c1
Agent: Cl
Solvent: CO
Product: Nc1cnc2cccnc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 1,5-naphthyridin-3-ylcarbamate (D-12) (4.040 g, 16.5 mmol, 1.0 eq) in methanol (24 mL), concentrated hydrochloric acid (36.5%, 10 mL, 120 mmol, 7.27 eq) was added. The resulting mixture was stirred at 50° C. for 2 h. The reaction was complete based on TLC analysis. The mixture was concentrated under reduced pressure to afford the desired product 1,5-naphthyridin-3-amine (D-13), which was used for next reaction without. Further purification. 1HNMR (300 MHz, DMSO-d6) 8.85 (m, 1H), 8.77-8.75 (m, 2H), 7.63-7.69 (m, 1H), 7.4 (d, J=1.8 Hz, 1H); ESI-MS m/z: 146.10 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:16]2[N:17]=[N:18][C:19]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:24][CH:23]=3)[CH:21]=2)[C@H:10]([O:39][CH3:40])[CH2:9]1)=O)(C)(C)C.[ClH:41]>C(Cl)Cl.O1CCOCC1>[ClH:41].[ClH:41].[CH2:35]([C:19]1[N:18]=[N:17][C:16]([O:15][CH2:14][C@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]2[O:39][CH3:40])=[CH:21][C:20]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)=[CH:26][CH:27]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCCc1nnc(OC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCc1nnc(OC[C@H]2CCNC[C@H]2OC)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of (±)-cis-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-3-methoxy-piperidine-1-carboxylic acid tert-butyl ester (0.36 mmol, 0.20 g) in DCM (1 mL) was added 4 N HCl in dioxane (1 mL). The solution was stirred for 1 hour. The solvents were removed with reduced pressure and the salt was triturated with diethyl ether and filtered to give (±)-cis-3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(3-methoxy-piperidin-4-ylmethoxy)-pyridazine dihydrochloride (0.17 g).
Reaction SMILES: [Cl:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]2[N:6]([C@@H:13]3[O:19][C@H:18]([CH3:20])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:7](OC(C)C)=[N:8][C:4]=2[CH:3]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>C1COCC1>[CH:24]1([NH:27][C:7]2[N:6]([C@@H:13]3[O:19][C@H:18]([CH3:20])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:5]3[CH:21]=[C:22]([Cl:23])[C:2]([Cl:1])=[CH:3][C:4]=3[N:8]=2)[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: CC(C)Oc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@H](C)[C@@H](O)[C@H]1O
Solvent: C1CCOC1
Product: C[C@H]1O[C@@H](n2c(NC3CC3)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 432 h
Yield: 82.6 %

Procedure:
A mixture of 5 (0.422 g, 1 mmol) and cyclopropylamine (0.694 mL, 10 mmol) in THF (10 mL) was stirred at room temperature for 18 days (with the addition of 0.694 mL of fresh cyclopropylamine on the 9th day). Volatile materials were removed by evaporation and the residue was treated with NH3/MeOH (15 mL, sat. at 0° C.) at room temperature for 18 h. The reaction mixture was again evaporated and the residue was chromatographed on a silica column (2×15 cm, eluted successively with CHCl3, 4%, 8% MeOH/CHCL3, v/v). Evaporation of fractions 23˜35 (15 mL per fraction) and recrystallization from MeCN gave 0.296 g (83%) of 6 as white crystals. MP: ˜210° C. (dec). HRMS: (EI, with DCI probe) m/z 357.0645 (51%, M+=357.0647). 1H NMR (DMSO-d-6): δ7.48 (s, 1, 4-H), 7.35 (s,1,7-H), 7.14 (d, 1,2′-NH—, J2′NH-1Cp=2 Hz), 5.62 (d, 1,1′-H, J1′-2′=6.5 Hz), 5.26 (d, 1,3′-OH, J3′-3′OH=4.5 Hz), 5.23 (d,1, 2′-OH, J2′-2′OH′=7.0 Hz),4.33 (m, 1,2′-H, J2′-3′=5.5 Hz), 3.90 (m, 1,4′H, J4′-3′=4.5 Hz, J4′-5′=6.5 hz), 3.79 (m, 1, 3′-HO, 2.76 (m, 1,1,-Cp), 1.37 (d, 3,5′-H), 0.71, 0.53 (2×m, 4, 2-Cp and 3-Cp). 13C NMR (DMSO-d-6): δ156.68 (C2), 143.53 (C3a), 132.05 (C7a), 123.27, 120.22 (C5 and C6), 116.38 (C4), 111.05 (C7), 87.56 (C1′), 80.00 (C4′), 73.65 (C3′), 70.85 (C2′), 25.17 (1-Cp), 18.93 (C5″) 6.49, 6.15 (2-Cp and 3-Cp). Anal. Calcd. for C15H17Cl2N3O3: C, 50.29, H, 4.78, N, 11.73. Found C, 50.42, H, 5.00, N, 11.99.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5](O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.P(Br)(Br)[Br:20].[Br-]>C(OCC)C>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5]([Br:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: OC(c1ccccc1)c1ccccc1C(F)(F)F
Agent: [Br-]
Solvent: CCOCC
Product: FC(F)(F)c1ccccc1C(Br)c1ccccc1
Reaction time: 16 h

Procedure:
2-(Trifluoromethyl)benzhydrol (20.2 g, 79.9 mmol) was dissolved in ethyl ether (195 mL), and cooled in an ice-H2O bath, under N2. To the resulting solution was added, dropwise, a solution of PBr3 (3.80 mL, 40.0 mmol) in ethyl ether (95 mL). After addition was complete, the reaction mixture was brought to room temperature and stirred for 16 hours. The reaction mixture was cooled in an ice-H2O bath and quenched with H2O (200 mL). The aqueous layer was extracted with ethyl ether (2×200 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated to dryness at low heat to give a quantitative yield of product bromide as a pale yellow oil. 300 MHz 1H NMR (CDCl3): δ6.69 (s, 1H, (Ph)2CH. MS: 235 (M+ -Br).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:23]([CH3:24])=[C:22]([CH3:25])[S:21][C:10]=3[NH:11][C:12](=O)[C@@:13]3([CH2:16][C@H:15]3[CH2:17][O:18][CH3:19])[N:14]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].P(Cl)(=O)(OCC)OCC.[C:41]([NH:44][NH2:45])(=O)[CH3:42]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:23]([CH3:24])=[C:22]([CH3:25])[S:21][C:10]=3[N:11]3[C:41]([CH3:42])=[N:44][N:45]=[C:12]3[C@@:13]3([CH2:16][C@H:15]3[CH2:17][O:18][CH3:19])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)NN
Reactant: COC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)NC2=O
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)-n1c(C)nnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of (1S,2R)-5′-(4-chlorophenyl)-2-(methoxymethyl)-6′,7′-dimethylspiro-[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepin]-2′(1′H)-one (3.7, 9.87 mmol) in anhydrous THF (200 mL) at −78° C. was slowly added a solution of potassium tert-butoxide (12.34 mL, 12.34 mmol). The resulting dark brown solution was warmed to rt and stirred for 30 min. The reaction was cooled to −78° C. before diethyl phosphorochloridate (2.85 mL, 19.74 mmol) was slowly added. Once the addition was completed, the reaction was warmed to rt for 60 to 90 min before acetohydrazide (2.193 mg, 29.6 mmol) was added. The reaction was then heated to 60° C. for 2 h before MeOH (5 mL) and silica gel were sequentially added. The solvent was removed under vacuum, the dry silica gel was packed, and the product was purified by flash chromatography (EtOAc/hexane 3:7 to 100:0) to give (1S,2R)-4′-(4-chlorophenyl)-2-(methoxymethyl)-2′,3′,9′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine] as a solid (3.54 g). LRMS (M+H)+: 413 m/z. 1H NMR (two conformers detected in ˜1:1 ratio) (400 MHz, DMSO-d6) δ 7.42-7.55 (m, 4H), 3.82 (dd, J=7.32, 10.99 Hz, 0.5H), 3.71 (dd, J=6.41, 11.22 Hz, 0.5H), 3.39 (s, 1.5H), 3.21 (dd, J=6.29, 10.87 Hz, 0.5H), 3.04 (dd, J=7.67, 10.87 Hz, 0.5H), 2.97 (s, 1.5H), 2.60 (s, 3H), 2.39 (s, 1.5H), 2.38 (s, 1.5H), 2.16-2.27 (m, 0.5H), 2.05 (dd, J=5.26, 9.38 Hz, 0.5H), 1.58 (s, 1.5H), 1.54 (s, 1.5H), 1.43-1.51 (m, 0.5H), 1.33-1.40 (m, 0.5H), 1.03 (dd, J=5.38, 9.27 Hz, 0.5H), 0.61 (t, J=6.07 Hz, 0.5H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[C:28]([CH3:35])[CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)=[C:28]([CH3:35])[CH:27]=1
Reactant: COc1ccc(B(O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(C)c1

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and 4-methoxy-2-methylphenylboronic acid (166 mg, 1.0 mmol) to afford after chromatographic purification the title compound (105 mg, 50%). 1H NMR (CDCl3, 300 MHz) δ7.04 (d, 1H, J=8.5 Hz), 6.65-6.79 (m, 4H), 3.75-4.22 (m, 2H), 3.74 (s, 3H), 3.58-3.68 (m, 1H), 3.18-3.42 (m, 4H), 2.76-3.16 (m, 3H), 2.17 (s, 3H), 1.70-1.84 (m, 2H), 1.40 (s, 9H) ppm. MS-ApCI: 421 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[C:26]([OH:27])=[CH:25][C:24]([C:28]([O:30][CH3:31])=[O:29])=[N:23][N:22]4[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:39](I)[CH3:40].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:20]=[C:21]4[C:26]([O:27][CH2:39][CH3:40])=[CH:25][C:24]([C:28]([O:30][CH3:31])=[O:29])=[N:23][N:22]4[C:32]=3[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(O)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
A mixture of methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-hydroxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate that was in a manner analgous to that described for Intermediate Example Int-18 (0.16 g, 0.32 mmol), ethyl iodide (0.50 mL, 0.63 mmol, 2.0 equiv.) and cesium carbonate (0.31 g, 0.94 mmol, 3.0 equiv.) in DMF (6 mL) was stirred for 1 h at room temperature, followed by 3 h at 50° C. The reaction mixture was then added to ice water (20 mL). The aqueous mixture was extracted with a 4:1 DCM/isopropanol solution (2×25 mL). The combined organic phases were dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 10 g cartridge, 80% hexane/20% EtOAc 3.0 min, gradient to 55% hexane/45% EtOAc 2.0 min, 55%/45% EtOAc 3.0 min, gradient to 4% hexane/96% EtOAc 5.5 min, gradient to 100% EtOAc 0.5 min, 100% EtOAc 7.2 min) to give methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-ethoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate (0.072 g, 42%):
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:33])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:28][CH:29]([CH3:31])[CH3:30])([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)[CH2:9][C:8]2=[O:32])(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:4][C:5]1[C:6]([CH3:33])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:9][C:8]2=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(COc1ccc([N+](=O)[O-])cc1)(CC(C)C)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(COc1ccc(N)cc1)(CC(C)C)O2

Procedure:
1.4 g of 6-acetoxy-2-isobutyl-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one (prepared as described in Preparation 7) was dissolved in 35 ml of methanol, and, in the presence of 1 g of 10% w/w palladium-on-carbon, it was reduced for 3 hours under about 1 atmosphere (about 1 bar) pressure of hydrogen. The catalyst was filtered off, and the solvent was then distilled off under reduced pressure to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:15]=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]Br.O.[OH-].[Na+]>CCO>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([Br:18])=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: c1ccc(COc2cccn3ccnc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Brc1cnc2c(OCc3ccccc3)cccn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of crude 8-(benzyloxy)imidazo[1,2-a]pyridine (8.73 g, 38.9 mmol) in 100 mL of EtOH was added, dropwise, 4.8 mL (46.7 mmol) of a solution of 1:1 Br2/H2O at ambient temperature under an atmosphere of N2. The resulting dark orange suspension was stirred at ambient temperature for 30 min, added 60 mL 1N NaOH, and the reaction mixture extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 30% EtOAc/hexanes) to provide 7.04 g of product.
Reaction SMILES: S([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(O)(=O)=O.CNCCCCC=CC.C(N1C[C@@H](O)C[C@H]1C(O)=O)(OC(C)(C)C)=O.[CH2:37]([N:43](C)[C:44]([C@@H:46]1[CH2:50][C@@H:49]([OH:51])[CH2:48][N:47]1[C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[O:45])CCCC=C>>[CH2:9]([N:43]([CH3:37])[C:44]([C@@H:46]1[CH2:50][C@@H:49]([OH:51])[CH2:48][N:47]1[C:52]([O:54][C:55]([CH3:57])([CH3:56])[CH3:58])=[O:53])=[O:45])[CH2:8][CH2:10][CH2:11][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Agent: CC=CCCCCNC
Product: C=CCCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C

Procedure:
Compound 70a was synthesized from compound 32b and cis-N-Boc-4-hydroxy-L-proline as orange oil in quantitative yield, following the procedure as described for compound 48.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[NH2:8].C([O-])([O-])=O.[K+].[K+].[C:18](Cl)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].CC(O)=O.CC#N.O>O>[CH2:21]([O:20][C:18]([NH:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(Cc1cccs1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccs1)C(=O)O)OCc1ccccc1
Reaction time: 1 h
Yield: 98 %

Procedure:
Into a 500 ml flask was placed 3.0 g of 3-(2-Thienyl)-D,L-alanine (optically active material in the L-form is available 4from Aldrich or SIGMA and could be used to obtain an optically active product) in 75 ml H2O/60 ml dioxane, and 5.6 g K2CO3 was added, followed by 2.85 ml of carbobenzyloxy chloride. The mixture was stirred rapidly for 1 hour. TLC (21/7/7/9, EtoAc/AcOH/CH3CN/H2O) showed that the starting material was gone. A new higher Rf product was seen. The dioxane was concentrated off and the aqueous layer was washed with Et2O (75 ml). The aqueous layer was mixed with CH2Cl2 (150 ml) and acidified to pH=2.0 with 5N HCl. The desired N-(Benzyloxycarbonyl)-3-(2-thienyl)-D,L-alanine was extracted with CH2Cl2. The organic layer was separated and dried with Na2SO4, filtered, and concentrated to give 5.05 g of desired N-(Benzyloxycarbonyl)-3-(2-thienyl)-D,L-alanine (98% yield).