Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([C:22]([N:24]1[CH2:28][CH2:27][C@H:26]([F:29])[CH2:25]1)=[O:23])[C@H:9]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Rh]>[C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([C:22]([N:24]1[CH2:28][CH2:27][C@H:26]([F:29])[CH2:25]1)=[O:23])[C@H:9]([CH:15]1[CH2:16][CH2:17][CH:18]([OH:21])[CH2:19][CH2:20]1)[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)[C@@H](c1ccc(O)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reactant: [H][H]
Agent: [Rh]
Solvent: CO
Product: CN(C)C(=O)[C@@H](C1CCC(O)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reaction time: 24 h

Procedure:
The material from Step B (0.33 g, 0.77 mmol) was hydrogenated at 50 psi hydrogen in the presence of 5% rhodium on alumina (0.33 g) in methanol (10 mL) using a Parr shaker. After 24 h, the reaction mixture was filtered by passage through a syringe filter. Concentration of the filtrate in vacuo afforded the title compound as a mixture of cis and trans isomers containing a small amount of the fully reduced cyclohexane. LC/MS 430.1 (M+1), 452.1 (M+Na).
Reaction SMILES: C[Si]([NH-])(C)C.[Na+].[CH3:7][O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C1COCC1>[CH3:13][O:12][C:10](=[O:11])[CH:9]([O:8][CH3:7])[CH:25]([C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:23]=1)[OH:26]
Reactant: COCC(=O)OC
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Agent: C[Si](C)(C)[NH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(OC)C(O)c1cccc(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Sodium trimethylsilylamide 1M in THF (20.73 mL, 20.73 mmol) was added to a 2-neck round bottom flask under nitrogen. The flask was placed in an acetone bath cooled to about −78° C. A solution of methyl 2-methoxyacetate (2.34 mL, 23.55 mmol) and 3-benzyloxybenzaldehyde (4.0 g, 18.85 mmol) in dry THF (24 mL) was added dropwise via cannula over 10 minutes. The mixture was stirred at −78° C. for 3 hours. HPLC-MS showed the presence of starting aldehyde at this time. Additional 10 mL of NaHDMS were added, and the mixture was stirred for another hour, and then HCl 3N (50 mL) was added to the mixture at −78° C. The bath was removed, and the mixture was extracted with diethyl ether (4×50 mL). The combined organic layers were dried over MgSO4 and concentrated to afford an oil that was purified by chromatography (silica gel, hexanes/ethyl acetate 3:1). Rf. 0.13. (two isomers) 1H-NMR (CDCl3, 200.15 MHz): 7.45–7.22 (m, 12H), 7.05–6.89 (m, 6H), 5.07 (d, 4H, J=1.1), 4.93 (dd, 2H, J=11.8, 5.9), 3.97 (d, 1H, J=5.6), 3.89 (d, 1H, J=5.4), 3.67 (s, 3H), 3.65 (s, 3H), 3.40 (s, 3H), 3.37 (s, 3H), 2.92 (br s, 1H), 2.83 (br s, 1H).
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([OH:30])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:31]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:36]=CC=C[CH:32]=1.C[CH:51]([O:53]C(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([O:30][C@H:31]([CH3:36])[CH2:32][O:53][CH3:51])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(Oc3ccc(C(=O)N4CCC4)nc3)c2)cn1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC[C@@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
A mixture of 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide (101 mg, 0.25 mmol), S-(+)-methoxy-2-propanol (0.049 mL, 0.50 mmol) and triphenyl phosphine (131 mg, 0.50 mmol) in dry THF (10 mL) was treated dropwise with DIAD (0.099 mL, 0.50 mmol) at 0° C. under an argon atmosphere. The mixture was allowed to warm to RT and stirred overnight. The THF was removed by evaporation under reduced pressure and the residue purified twice by chromatography on silica, eluting with 0-7% methanol in DCM. The desired fractions were combined and purified by elution through an SCX column, eluted with 5% methanol in DCM then 50% 7N ammonia (in methanol) in DCM. The desired fractions were purified by elution though an NH2 column, eluting with 5% methanol in DCM, to give the desired compound (35 mg) with a purity estimated to be 85%. 1H NMR δ (CDCl3): 1.26 (d, 3H), 2.28 (quin, 2H), 2.49 (s, 3H), 3.33 (s, 3H), 3.41-3.54 (m, 2H), 4.18 (t, 2H), 4.50-4.58 (m, 1H), 4.64 (t, 2H), 6.77 (s, 1H), 7.08 (s, 1H), 7.25 (s, 1H), 7.31 (d, 1H), 8.04 (d, 1H), 8.07 (s, 1H), 8.26 (d, 1H), 8.30 (s, 1H), 9.46 (s, 1H); m/z 478 (M+H)+
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.C[O:14][C:15](=O)[CH:16]([CH3:21])[CH2:17][C:18]#[C:19][CH3:20].C(O)(=O)C>O1CCCC1.CCCCCC>[CH3:4][O:3][P:2]([CH2:1][C:15](=[O:14])[CH:16]([CH3:21])[CH2:17][C:18]#[C:19][CH3:20])(=[O:7])[O:5][CH3:6]
Reactant: COP(C)(=O)OC
Reactant: CC#CCC(C)C(=O)OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC#CCC(C)C(=O)CP(=O)(OC)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
A solution of dimethyl methylphosphonate (22.47 g, 181.24 mmol) in 260 ml of tetrahydrofuran is cooled to -78° C. and treated dropwise with n-butyllithium (113 ml, 181.24 mmol), 1.6 M in hexane) over a 25-minute period. The mixture is stirred an additional 30 minutes at -78° C., then treated dropwise with 2-methyl-4-hexynoic acid methyl ester (7.25 g, 51.78 mmols) in 65 ml of tetrahydrofuran over a period of 10 minutes. The contents are stirred for another 3 hours at -78° C. and then 17 hours at ambient temperature. The reaction mixture is cooled to 8° C., treated with 14 ml of acetic acid, stirred at ambient temperature for 30 minutes, then concentrated in vacuo. The residue is treated with 100 ml of saturated brine and 100 ml of ice water to form a slurry and extracted 3 times with ether (1400 ml total) and once with 250 ml of ethyl acetate-ether (1:1). The combined organic extracts are washed with saturated brine (2×75 ml), the combined aqueous washings extracted with ethyl acetate-ether (1:1, 1×100 ml) and dried over anhydrous sodium sulfate, and concentrated at reduced pressure. Vacuum distillation gives 10.21 g of the title product, m.p. 121°-125° C., 0.15 mmHg.
Reaction SMILES: C[O-].[Na+].[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)#[N:5].C(O)(=O)C.[N:16]1([CH2:23][C:24]2[S:25][C:26]([C:29]([NH:31][NH2:32])=O)=[CH:27][CH:28]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CO>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[NH:32][N:31]=[C:29]([C:26]2[S:25][C:24]([CH2:23][N:16]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:28][CH:27]=2)[N:5]=1
Reactant: N#Cc1ccccn1
Reactant: NNC(=O)c1ccc(CN2CCCCCC2)s1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(-c2nc(-c3ccc(CN4CCCCCC4)s3)n[nH]2)nc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.7 %

Procedure:
81 mg (1.5 mmol) of sodium methoxide was added to 13.5 ml of methanol solution containing 1.56 g (15.0 mmol) of 2-cyanopyridine and stirred at room temperature for 3.5 hours. The reaction mixture was ice-cooled, 0.085 ml (1.5 mmol) of acetic acid and 1.52 g (6.0 mmol) of 2-(hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide were added with ice-cooling, and then the mixture was stirred at room temperature for 24 hours. The thus precipitated crystals were collected by filtration to give 1.97 g of the crystals. A 894 mg (2.5 mmol) portion of them was dissolved in 13 ml of acetic acid and heated under reflux for 6.5 hours. The solvent was evaporated, 28% aqueous ammonia and chloroform were added, and then the thus separated organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by a silica gel column chromatography to give 715 mg of the title compound.
Reaction SMILES: [CH:1]([NH:3][NH2:4])=[O:2].C([N:8]([CH2:12][CH2:13][CH3:14])[CH2:9]CC)CC.C(C1C=[CH:20][S:19][C:18]=1[NH:22]C(=O)OC)#N>COCCO>[N:8]1[CH:9]=[N:4][N:3]2[C:12]=1[C:13]1[CH:14]=[CH:20][S:19][C:18]=1[NH:22][C:1]2=[O:2]
Reactant: NNC=O
Reactant: CCCN(CCC)CCC
Reactant: COC(=O)Nc1sccc1C#N
Solvent: COCCO
Product: O=c1[nH]c2sccc2c2ncnn12
Yield: 26 %

Procedure:
Formylhydrazine (2.08 g, 34.6 mmol) and tri-n-propylamine (3 mL) was added to a suspension of methyl 3-cyanothiophen-2-ylcarbamate (6 g, 32.9 mmol) in 2-methoxyethanol (70 mL) at room temperature. The mixture was heated at reflux overnight under nitrogen. The mixture was concentrated under vacuum to give a crude product, which was purified by preparative HPLC to give 1.8 g (26%) of thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one as a solid. 1H NMR (400 MHz, DMSO) δ 7.28-7.30 (d, 1H), 7.39-7.41 (d, 1H), 8.34 (s, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[Cl-].[Li+].[F:20][C:21]1[C:22](/[CH:27]=[N:28]/[S@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])=[N:23][CH:24]=[CH:25][CH:26]=1>C1COCC1>[F:20][C:21]1[C:22]([C@H:27]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)[NH:28][S@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: CC(C)(C)[S@](=O)/N=C/c1ncccc1F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccc(OC(F)(F)F)cc1)c1ncccc1F
Reaction time: 0.17 h

Procedure:
1-Iodo-4-(trifluoromethoxy)benzene (1.00 g, 3.47 mmol) was dissolved in dry THF (10 mL) and cooled in an ice bath. Isopropylmagnesium chloride, lithium chloride complex (14% solution in THF, Aldrich, 3.07 mL, 2.82 mmol) was added, and the mixture was stirred for 10 min. A solution of (S,E)-N-((3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (0.643 g, 2.82 mmol) in dry THF (10 mL) was added and the reaction was stirred. After 50 minutes, the reaction was quenched by addition of saturated aqueous NH4Cl (10 mL). H2O (100 mL) and EtOAc (150 mL) were added, and the phases were mixed and separated. The organic layer was dried with MgSO4 and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave the desired (S)—N—((S)-(3-fluoropyridin-2-yl)(4-(trifluoro-methoxy)phenyl)methyl)-2-methylpropane-2-sulfinamide.
Reaction SMILES: [CH3:1][O:2][Si](C)(C)C.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][CH:16]=[C:17]([CH:19]=[O:20])[N:18]=2)=[CH:10][CH:9]=1.[CH2:21](Cl)Cl>FC(F)(F)S(O[Si](C)(C)C)(=O)=O>[CH3:21][O:20][CH:19]([O:2][CH3:1])[C:17]1[N:18]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=2)[O:15][CH:16]=1
Reactant: O=Cc1coc(-c2ccc(F)cc2)n1
Reactant: ClCCl
Reactant: CO[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Product: COC(OC)c1coc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methoxytrimethylsilane (545 mg, 5.23 mmol) and trimethylsilyl trifluoromethanesulfonate (30 mg, 0.13 mmol) were added to a solution of 2-(4-fluorophenyl)oxazole-4-carbaldehyde (500 mg, 2.62 mmol) in dry CH2Cl2 (2 mL) at −78° C. The reaction mixture was allowed to warm up to room temperature and stirred for 24 h, quenched with saturated aqueous NaHCO3 solution, and the crude product was extracted with EtOAc. The organic layer was washed with 10% NaHCO3 solution, water and brine and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to get 4-(dimethoxymethyl)-2-(4-fluorophenyl)oxazole (400 mg, crude), which was carried through without further purification. 1H NMR (400 MHz, CDCl3) δ 8.08-8.05 (m, 2H), 7.71 (d, J=1.2 Hz, 1H), 7.16-7.12 (m, 2H), 5.50 (d, J=0.9 Hz, 1H), 3.41 (s, 6H). MS (ESI) m/z: Calculated for C12H12FNO3: 237.08. found: 259.9 (M+Na)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]1[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][C:27]=2[CH:28]=[C:29]([Br:31])[CH:30]=1)(=[O:20])=[O:19].[BH4-].[Na+]>C(Cl)Cl.CO>[NH3:1].[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][NH:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[C:22]3[CH:23]=[CH:24][N:25]=[CH:26][C:27]=3[CH:28]=[C:29]([Br:31])[CH:30]=2)(=[O:19])=[O:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=CCCc1ccc([N+](=O)[O-])cc1
Reactant: NCCNS(=O)(=O)c1cc(Br)cc2cnccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: N
Product: O=[N+]([O-])c1ccc(CCCNCCNS(=O)(=O)c2cc(Br)cc3cnccc23)cc1
Reaction time: 18 h

Procedure:
Add 3-(4-nitro-phenyl)-propionaldehyde (0.390 g, 2.18 mmol to 7-bromo-isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide, [0.75 g (87% purity), 1.98 mmol) in 110 ml (6:5) CH2Cl2/MeOH. Stir the mixture for 18 h, then placed in an icebath. Add NaBH4 (0.150 g, 3.96 mmol) and stir for 1 h at 0° C. and 2 h at room temperature. Concentrate the reaction mixture, dissolve the residue in CH2Cl2/MeOH and load onto a silica gel column. Elute with 100% CH2Cl2, then a gradient of 0-10% (2M NH3 in MeOH) in CH2Cl2 to give 0.677 g of 7-bromo-isoquinoline-5-sulfonic acid {2-[3-(4-nitro-phenyl)-propylamino]-ethyl}-amide, as a yellow gum in 68% yield. ES Positive Ion MS [M+H]+ ions observed: m/z 493 (79 Br) and m/z 495 (81Br).
Reaction SMILES: [CH2:1]([N:13]1[CH2:17][C@H:16]([OH:18])[CH2:15][C@H:14]1[C:19]([O:21][CH3:22])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[I:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1.C(N(CCOC1C=CC(CCC(OC)=O)=CC=1)C)CCCCCCCCCCC>>[CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:27]2[CH:28]=[CH:29][C:24]([I:23])=[CH:25][CH:26]=2)[CH2:15][C@H:14]1[C:19]([O:21][CH3:22])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN1C[C@H](O)C[C@H]1C(=O)OC
Reactant: Oc1ccc(I)cc1
Agent: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)OC)cc1
Product: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(I)cc2)C[C@H]1C(=O)OC
Yield: 86.8 %

Procedure:
(2S, 4R)-1-N-Dodecyl-4-hydroxypyrrolidine-2-carboxylic acid, methyl ester (1.75 g, 7.94 mmol) and 4-iodophenol (2.26 g, 7.22 mmol) were reacted under Mitsunobu conditions as described in the preparation of 3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]phenyl]propanoic acid, methyl ester. The residue was chromatographed on silica gel (hexane/ethyl acetate 15:1 to 10:1) to afford the title compound (3.23 g, 79%) as a white solid. [a]D=−30.80 (c 1.0, CHCl3)
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6].[N:9]1([NH:15][C:16]([C:18]2[N:19]=[C:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[Cl:38])[N:21]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C:22]=2[CH3:23])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N:9]1([NH:15][C:16]([C:18]2[N:19]=[C:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[Cl:38])[N:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH2:2][CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6])=[CH:28][CH:29]=3)[C:22]=2[CH3:23])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Reactant: FC(F)(F)CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OCCCC(F)(F)F)cc1
Yield: 46 %

Procedure:
1-Iodo-4,4,4-trifluorobutane (376 mg, 1.58 mmol) was added dropwise to a suspension of 2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide, from Ex 2, Step 1 (351 mg, 0.79 mmol) and K2CO3 (218 mg, 1.58 mmol) in 50 ml acetone. The reaction mixture was refluxed overnight, cooled, filtered and concentrated. Flash chromatography (silica, hexane:EtOAc 1:2) afforded 200 mg (46%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][O:11][C:5]=2[C:4]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:3]1.[C:16]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[O:22])#[N:17]>>[OH:22][CH:21]([C:10]1[O:11][C:5]2[C:4]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=2[CH:9]=1)[C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([C:16]#[N:17])[CH:19]=1
Reactant: CC(C)Cc1nn(C)c(=O)c2ccoc12
Reactant: N#Cc1cccc(C=O)c1
Product: CC(C)Cc1nn(C)c(=O)c2cc(C(O)c3cccc(C#N)c3)oc12

Procedure:
Prepared from 5-methyl-7-(2-methylpropyl)furo[2,3-d]pyridazin-4(5H)-one (example 35 step d) and 3-cyanobenzaldehyde following the method of Example 35 step e.
Reaction SMILES: [OH:1][CH:2]1[CH:8]([NH:9][C:10](=[O:17])[C@@H:11]([NH2:16])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:7][CH2:6][CH2:5][N:4]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:20])=[O:19])[CH2:3]1.C(N(CC)CC)C.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40](Cl)(=[O:42])=[O:41].CO>ClCCl>[OH:1][CH:2]1[CH:8]([NH:9][C:10](=[O:17])[C@@H:11]([NH:16][S:40]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=2)(=[O:42])=[O:41])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:7][CH2:6][CH2:5][N:4]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:20])=[O:19])[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: CC(C)C[C@H](N)C(=O)NC1CCCN(S(=O)(=O)c2ccccn2)CC1O
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NS(=O)(=O)c1ccccn1)C(=O)NC1CCCN(S(=O)(=O)c2ccccn2)CC1O
Yield: 26.3 %

Procedure:
To a solution of (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 28a (0.25 g) in dichloromethane was added triethylamine (0.27 mL) and 2-pyridinesulfonyl chloride (0.15 g). The reaction was stirred until complete. Workup and column chromatography (5% methanol:dichloromethane) provided the title compound (0.09 g): MS(EI) 525 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7]3[CH2:14][NH:13][CH2:12][C@@H:11]([CH3:15])[N:8]3[C:9]=2[CH:10]=1.[BH4-].[Na+].[OH-].[Na+]>O1CCCC1.FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@@H:7]3[CH2:14][NH:13][CH2:12][C@@H:11]([CH3:15])[N:8]3[C:9]=2[CH:10]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[CH2:14][NH:13][CH2:12][C@@H:11]([CH3:15])[N:8]3[C:9]=2[CH:10]=1
Reactant: C[C@@H]1CNCc2cc3ccc(Cl)cc3n21
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNC[C@@H]2Cc3ccc(Cl)cc3N21
Product: C[C@@H]1CNC[C@H]2Cc3ccc(Cl)cc3N21
Temperature: 0 °C
Reaction time: 2 h
Yield: 9 %
Yield: 45 %

Procedure:
(4R)-7-Chloro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole (0.180 g; 0.816 mmol) is dissolved in a tetrahydrofuran/trifluoroacetic acid mixture (1:2; 7.5 ml) and cooled to 0° C. Sodium borohydride (62 mg; 1.63 mmol) was added and the solution was stirred for 2 h. The reaction mixture was poured in an aqueous NaOH solution, basified to ph 14 and extracted twice with ethyl-acetate. Organic phases were pooled, dried with MgSO4 and the solvent was evaporated. Chromatography on silica gel (dichloromethane/methanol 9:1) gave (4R,10aR)-7-chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole (81 mg, 45%) and (4R,10aS)-7-chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole (17 mg, 9%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][N:5]2[CH:11]=1.[I:12]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][N:5]2[C:11]=1[I:12]
Reactant: Fc1ccc2nc(Cl)cn2c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Fc1ccc2nc(Cl)c(I)n2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the title compound from Example 2 Step B (1.0 g, 5.86 mmol) in acetonitrile (29.3 mL) was added N-iodosuccinimide (1.583 g, 7.04 mmol). The resulting mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. The resulting residue was diluted with dichloromethane, washed with saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (10-30% ethyl acetate in hexanes) provided the title compound: LCMS m/z 296.70 [M+H]+, 298.65 [M+2+H]+; 1H NMR (500 MHz, CDCl3) δ 8.03 (t, J=2.8 Hz, 1H), 7.56-7.51 (m, 1H), 7.22-7.18 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[Br:5][C:6]1[N:10]2[N:11]=[C:12]([NH:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1.[BH4-].[Na+]>CO>[Br:5][C:6]1[N:10]2[N:11]=[C:12]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][CH:2]([CH3:4])[CH3:1])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1
Reactant: NCCCNc1ccc2ncc(Br)n2n1
Reactant: CC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)NCCCNc1ccc2ncc(Br)n2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 45 %

Procedure:
Acetone [67-64-1] (2.0 mL, 43.5 mmol), then powdered, activated, 4 Angstrom molecular sieve were added to a solution of N1-(3-bromoimidazo[1,2-b]pyridazin-6-yl)propane-1,3-diamine (367.2 mg, 1.4 mmol) in methanol (4.8 mL). The reaction vessel was closed and the mixture allowed to rapidly stir, at ambient temperature, for 17 h then its content rapidly transferred into a stirring suspension of sodium borohydride [16940-66-2] (0.3 g, 6.9 mmol) in methanol (50 mL). After 1 h the mixture was gravity filtered and the filtrate evaporated. The crude product was then taken up in ethyl acetate, washed with brine, dried (MgSO4) and evaporated to provide 196.9 mg of yellow solid. LRMS (ESI) m/z 312.0/314.0 [(M+H)]+, calc'd for C12H18BrN5: 312.21.
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:9]1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:29][C:30]1C(F)=[N:32][CH:33]=[CH:34][CH:35]=1>ClCCl.FC(F)(F)C(O)=O.CS(C)=O>[S:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[NH:12][C@H:10]1[CH2:9][C@H:8]([NH:7][C:6]2[C:30]([Br:29])=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Reactant: Fc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1cccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 110 °C
Reaction time: 0.33 h

Procedure:
Tert-butyl(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)carbamate (intermediate 10, 1.16 g, 3.63 mmol) was dissolved in a mixture of dichloromethane (50 mL) and trifluoroacetic acid (10 mL). The solution was stirred for 20 minutes then evaporated to dryness under reduced pressure and further dried under high vacuum at 60° C. The crude amine was treated with cesium carbonate (2.85 g, 8.75 mmol) and dissolved in dry dimethylsulfoxide (5 mL). 3-Bromo-2-fluoropyridine (0.400 ml, 3.89 mmol) was added in one portion and the reaction heated at 110° C. After 2½ hours, another portion of 3-bromo-2-fluoropyridine (0.100 mL) was added and the reaction heated for another 12 hours. Additional 3-bromo-2-fluoropyridine (0.100 mL) was added and the heating continued for another 2 hours. The reaction was cooled and partitioned between 20% saturated sodium bicarbonate (200 mL) and ethyl acetate (200 mL). The organic phase was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the desired trans-N1-(benzo[d]thiazol-2-yl)-N3-(3-bromopyridin-2-yl)cyclobutane-1,3-diamine (0.869 g, 2.316 mmol, 63.8% yield) as a yellow oil that solidified on standing.