Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]2[N:22]([CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:21]3[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:20]=3[N:19]=2)=[C:6]([CH:17]=1)[O:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13].[N-:36]=[N+:37]=[N-:38].[Na+].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]2[N:22]([CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:21]3[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:20]=3[N:19]=2)=[C:6]([O:7][CH2:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([C:12]3[NH:38][N:37]=[N:36][N:13]=3)[CH:10]=2)[CH:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc2nc(-c3ccc(Cl)cc3OCc3cccc(-c4nnn[nH]4)c3)n(CC3CCCCC3)c2cc1F
Temperature: 120 °C
Yield: 14 %

Procedure:
To a stirred solution of 3-[5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenoxymethyl]-benzonitrile (0.15 g, 0.30 mmol) in N,N-dimethylformamide (10 ml) was added sodium azide (27 mg, 0.42 mmol) and ammonium chloride (22 mg, 0.42 mmol) and the reaction mixture was heated for 12 h at 120° C. The solvent was evaporated under reduced pressure, the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography over silica gel (4-5% methanol/dichloromethane) to yield the desired compound as a colorless powder (14%). MS (Turbo Spray): m/z=535.2 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3]([O:5][CH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[CH:10][C:11]3[CH2:20][CH2:19][C:18](=O)[C:12]=3[CH:13]=2)[N:8]=1)=[O:4].[NH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1.[B][B][B][B][B][B][B][B][B][B]>CO.C(Cl)Cl>[CH3:22][C:2]([CH3:23])([CH3:1])[C:3]([O:5][CH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[CH:10][C:11]3[CH2:20][CH2:19][CH:18]([NH:24][C:25]4[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=4)[C:12]=3[CH:13]=2)[N:8]=1)=[O:4]
Reactant: CC(C)(C)C(=O)OCc1nc2cc3c(cc2c(=O)[nH]1)C(=O)CC3
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(NC2CCc3cc4nc(COC(=O)C(C)(C)C)[nH]c(=O)c4cc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.3 %

Procedure:
A suspension of 2-(2,2-dimethylpropionyloxymethyl)-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4,6-dione (0.47 g, 1.50 mmol) in anhydrous methanol (33 ml) and anhydrous CH2Cl2 (5 ml) was treated with tert-butyl 4-aminobenzoate (0.34 g, 1.78 mmol) followed by decaborane (0.07 g, 0.58 mmol) and the mixture stirred at room temperature under argon for 18 h. The solvent was removed in vacuo and the residue purified by column chromatography (50 g of silica gel) eluting with 30% ethyl acetate in CH2Cl2 to yield the desired product as a white solid (0.43 g, 58%); m.p. 231° C.; 1H-NMR (CDCl3) δ 1.26 (s, 9H, CMe3), 1.58 (s, 9H, CO2CMe3), 2.00 (m, 1H, 7-H), 2.72 (m, 1H, 7-H), 3.08 (m, 2H, 8-H), 5.10 (s, 2H, 2-CH2), 5.15 (m, 1H, 6-H), 6.67 (d, J=8.8 Hz, 2H, 3′-H, 5′-H), 7.58 (s, 1H, 9-H), 7.87 (d, J=8.8 Hz, 2H, 2′-H, 6′-H), 8.24 (s, 1H, 5-H); MS (FAB, m/z): Found 491 [(M+H)+, 25%], 514 [(M+Na)+, 100%]. Found C, 68.37; H, 6.86; N, 8.35. C28H33N3O5 requires C, 68.41; H, 6.77; N, 8.55%.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].BrC1C=CC([Cl:26])=CC=1C(O)=O>>[Cl:26][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: O=C(O)c1cc(Cl)ccc1Br
Product: O=C(O)c1cc(Cl)ccc1-n1nccn1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 2-bromo-5-chlorobenzoic acid. MS (ESI) 224 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[CH2:6]CO.P(Br)(Br)[Br:20]>C(Cl)Cl>[N+:16]([C:4]1[C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[C:10]([O:14][CH3:15])=[CH:9][C:5]=1[CH2:6][Br:20])([O-:18])=[O:17]
Reactant: COc1cc(CCO)c([N+](=O)[O-])c(OC)c1OC
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COc1cc(CBr)c([N+](=O)[O-])c(OC)c1OC
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred solution of the 3,4,5-Trimethoxy-2-nitrobenzoic acid (5 g, 19.40 mmol) in THF (30 ml) was added by BH3 (1.0 M in THF, 29.1 ml) under nitrogen. The mixture was stirred and refluxed for 2 hours. After cooling, the reaction mixture was extracted with water and CH2Cl2. The combined organic layers were dried over MgSO4, and then evaporated to afford 3,4,5-Trimethoxy-2-nitrobenzyl methanol. The crude 3,4,5-trimethoxy-2-nitrobenzyl methanol was dissolved in anhydrous CH2Cl2 (20 mL) and was subjected to PBr3 (2.40 ml, 25.22 mmol) in an ice bath. After 2 h, the mixture was extracted with water and CH2Cl2. The organic layers were combined and evaporated. The residue was purified by flash chromatography (EtOAc:n-hexane=1:2) to afford B1 as a pale yellow oil, yield 68%. 1H NMR (500 MHz, CDCl3) δ 3.90 (s, 3H), 3.92 (s, 3H), 3.98 (s, 3H), 4.44 (s, 2H), 6.72 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([Cl:14])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([Cl:15])[CH:5]=1)(=O)[NH2:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1>O>[Cl:14][C:12]1[CH:13]=[C:4]([C:1]#[N:2])[CH:5]=[C:6]([Cl:15])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1c(Cl)cc(C(N)=O)cc1Cl
Solvent: O
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1c(Cl)cc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.5 %

Procedure:
A mixture of methyl 4-carbamoyl-2,6-dichlorobenzoate (57 g, 230 mmol), trifluoroacetic anhydride (46 mL) and pyridine (46 mL) in dixoane (400 mL) was stirred at room temperature for 24 hours, diluted with water (300 mL) and extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with petroleum-diethyl ether (10:1) to give methyl 2,6-dichloro-4-cyanobenzoate (32 g, yield: 61%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 3.91 (s, 3H), 7.95 (s, 2H). LCMS (ESI) m/z: 230.1 [M+H+].
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7](=[N:9][O:10][CH2:11][CH2:12][OH:13])[CH3:8])=[CH:3][CH:2]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[O:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCNCC1)=O)=NC(N1CCNCC1)=O>>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7](=[N:9][O:10][CH2:11][CH2:12][O:13][C:21]2[CH:53]=[CH:52][C:24]([CH2:25][CH:26]3[O:30][C:29](=[O:31])[N:28]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]3=[O:51])=[CH:23][CH:22]=2)[CH3:8])=[CH:3][CH:2]=1
Reactant: CC(=NOCCO)c1ccc(-c2ccccc2)cc1
Reactant: O=C1OC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCNCC1)N1CCNCC1
Product: CC(=NOCCOc1ccc(CC2OC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccccc2)cc1
Yield: 50.7 %

Procedure:
Following a procedure similar to that described in Example 3(a), but using 0.23 g of 2-[1-(4-biphenylyl)-ethylideneaminooxy]ethanol (prepared as described in Preparation 15), 0.40 g of 5-(4-hydroxybenzyl)-3-trityloxazolidine-2,4-dione, 0.40 g of tributylphosphine and 0.50 g of 1,1'-(azodicarbonyl)dipiperazine, 0.31 g of the title compound was obtained as a crystalline powder, melting at 193°-195° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:46]=[CH:45][CH:44]=[CH:43][C:5]=1[O:6][CH2:7][CH2:8][O:9][CH:10]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:18][CH:17]=2)[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11]1.[N:47]1([C:52](N2C=CN=C2)=[O:53])[CH:51]=[CH:50][N:49]=[CH:48]1>C(#N)C.COC(C)(C)C>[N:47]1([C:52]([O:1][CH2:2][CH2:3][C:4]2[CH:46]=[CH:45][CH:44]=[CH:43][C:5]=2[O:6][CH2:7][CH2:8][O:9][CH:10]2[CH:15]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:20][CH:21]=3)[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:11]2)=[O:53])[CH:51]=[CH:50][N:49]=[CH:48]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCO)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: COC(C)(C)C
Solvent: CC#N
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCOC(=O)n2ccnc2)cc1
Temperature: 25 °C

Procedure:
A solution of 0.100 g of tert-butyl 3-{2-[2-(2-hydroxyethyl)phenoxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 26c) and 0.049 g of diimidazol-1-ylmethanone in 4 ml of acetonitrile is stirred at reflux over 5 hours. The reaction mixture is cooled at room temperature, diluted with tert-butyl methyl ether, washed with 1N HCl and 0.5N NaOH, dried over sodium sulphate and concentrated by evaporation. The crude title compound is obtained as a yellow oil from the residue. Rf=0.41 (2:1 EtOAc-heptane); Rt=5.61.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:50]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)[CH:57]=2)[CH:52]=[CH:51]1>CN(C=O)C>[NH:50]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([C:59]3[CH:60]=[C:61]([NH:65][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=3)[CH:57]=2)[CH:52]=[CH:51]1
Reactant: Nc1cccc(-c2ccc3cc[nH]c3c2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5cc[nH]c5c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 52.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-indol-6-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.014 g of product in 53% yield: LCMS (ESI) m/z 411 (MH+).
Reaction SMILES: COC1C=C(C2ON=C(CSC3NC4C=CC=CC=4N=3)N=2)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:31][C:32]1[S:36][CH:35]=[C:34]([C:37]2[O:41][N:40]=[C:39]([CH2:42]ON3C4C=CC=CC=4N=N3)[N:38]=2)[CH:33]=1.[CH2:53]([N:55]1[C:59]([C:60]2[O:61][CH:62]=[CH:63][CH:64]=2)=[N:58][NH:57][C:56]1=[S:65])[CH3:54]>CCCCCCC.CCOC(C)=O>[Cl:31][C:32]1[S:36][CH:35]=[C:34]([C:37]2[O:41][N:40]=[C:39]([CH2:42][S:65][C:56]3[N:55]([CH2:53][CH3:54])[C:59]([C:60]4[O:61][CH:62]=[CH:63][CH:64]=4)=[N:58][N:57]=3)[N:38]=2)[CH:33]=1
Reactant: CCn1c(-c2ccco2)n[nH]c1=S
Reactant: Clc1cc(-c2nc(COn3nnc4ccccc43)no2)cs1
Agent: COc1cccc(-c2nc(CSc3nc4ccccc4[nH]3)no2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCn1c(SCc2noc(-c3csc(Cl)c3)n2)nnc1-c1ccco1

Procedure:
The title compound was prepared according to method for 2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazole, with the exception of using molar equivalent cesium carbonate instead of potassium carbonate as the base, from 1-[5-(5-chloro-thiophen-3-yl)-[1,2,4]oxadiazol-3-ylmethoxy]-1H-benzotriazole (32.3 mg, 0.097 mmol) and 4-ethyl-5-furan-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione (23 mg) by using 50% EtOAc in n-heptane as chromatography eluent to yield 21 mg. 1H NMR (CDCl3) d (ppm): 7.95 (d, 1H), 7.57 (dd, 1H), 7.44 (d, 1H), 7.07 (dd, 1H), 6.56 (dd, 1H), 4.56 (s, 2H), 4.22 (q, 2H), 1.35 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:24]2[CH:28]=[N:27][N:26]=[N:25]2)=[C:6]([CH:23]=1)[CH2:7][NH:8][C:9]([C@@H:11]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[NH:12]1)=[O:10].[C:29]1([C@@H:35]([O:39][Si](C)(C)C)[C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:24]2[CH:28]=[N:27][N:26]=[N:25]2)=[C:6]([CH:23]=1)[CH2:7][NH:8][C:9]([C@@H:11]1[CH2:15][CH2:14][NH:13][N:12]1[C:36](=[O:37])[C@H:35]([OH:39])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)NCc2cc(Cl)ccc2-n2cnnn2)N1
Reactant: C[Si](C)(C)O[C@@H](C(=O)Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCNN1C(=O)[C@H](O)c1ccccc1
Temperature: 25 °C
Yield: 58.8 %

Procedure:
To a solution of tert-butyl (3S)-3-{[5-chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}pyrazolidine-1-carboxylate (82 mg, 0.200 mmol) in DCM (2 mL) and pyridine (0.080 mL) was added a solution of (R)-2-phenyl-2-(trimethylsilyloxy)acetyl chloride (ca 0.3 M in DCM, 1 mL, 0.3 mmol, see Preparation 2). The resulting solution was stirred at rt over night. TFA (ca 1 mL) was added and the mixture was stirred for one more hour and then evaporated. The residue was purified using flash chromatography (DCM/MeCN gradient from 2:1 to 1:1) to give (3S)—N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-2-phenylacetyl]pyrazolidine-3-carboxamide (52 mg, 59%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2I)[CH:5]=[CH:6][N:7]=1.C(OC([N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[C:36]1B(O)O)=O)(C)(C)C.COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O.O>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2[C:36]2[NH:35][C:43]3[C:38]([CH:37]=2)=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c(C3CCN(C(=O)OCc4ccccc4)CC3)nc(I)c12
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1nccn2c(C3CCN(C(=O)OCc4ccccc4)CC3)nc(-c3cc4ccccc4[nH]3)c12
Temperature: 100 °C

Procedure:
A mixture of benzyl 4-(8-amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate (1.149 g, 0.002191 mol), 1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid (0.629 g, 0.00241 mol), 1,2-dimethoxyethane (9.3 mL), water (1.8 mL) and cesium carbonate (1.43 g, 0.00438 mol) was degassed three times and then treated with tetrakis(triphenyl phosphine)palladium(0) (200 mg, 0.0002 mol). The mixture was once more degassed and then heated at 100° C. overnight. The resulting reaction mixture was diluted with EtOAc (30 mL) then washed with water (2×30 mL) and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was chromatographed over silica gel eluting with hexane→EtOAc:hexane 1:1:0.05 2M NH3/MeOH to afford the desired product. 1H NMR (400 MHz, CDCl3): δ 2.02-2.06 (m, 4H), 3.03-3.17 (m, 3H), 4.29-4.33 (m, 2H), 5.16 (s, 2H), 5.66 (br, 2H), 6.79-6.80 (m, 1H), 7.11-7.16 (m, 2H), 7.20-7.25 (m, 2H), 7.31-7.45 (m, 5H), 7.44 (m, 1H), 7.64 (d, J=7.6 Hz, 1H), 8.96 (br, 1H). MS (ES+): m/z 467.12 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][CH2:11][C@@H:12]3[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]3[C:19]([O:21]CC=C)=O)=[N:7][C:6]=2[CH:25]=1.NC[C@@H]1[C@H](C)CCCN1C([C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=1[N:44]1[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]1)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][CH2:11][C@@H:12]3[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]3[C:19]([C:37]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=3[N:44]3[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]3)=[O:21])=[N:7][C:6]=2[CH:25]=1
Reactant: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for (2S,3R)-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-1-carboxylate in Example A27, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)methanone. ESI-MS (m/z): 478 [M+1]+.
Reaction SMILES: FC1C=C([CH2:12][C:13](=[O:15])C)C=CC=1S(C)(=O)=O.FC1C=C(C=CC=1S(C)(=O)=O)C=O.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][C:31]=1[O:38][CH3:39]>>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][C:13](=[O:15])[CH3:12])=[CH:32][C:31]=1[O:38][CH3:39]
Reactant: CC(=O)Cc1ccc(S(C)(=O)=O)c(F)c1
Reactant: COc1cc(C=O)ccc1F
Agent: CS(=O)(=O)c1ccc(C=O)cc1F
Product: COc1cc(CC(C)=O)ccc1F

Procedure:
The title compound is prepared via an analogous procedure to 1-((3-fluoro-4-methanesulfonyl-phenyl)-propan-2-one (64c) (steps 64b-64c) by replacing 3-fluoro-4-methanesulfonyl-benzaldehyde in step 64b with 4-fluoro-3-methoxy-benzaldehyde.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH2:9]([NH:8][C:6]1[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=[C:2]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:7]=1)[CH3:10]
Reactant: CCNc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Reactant: C1COCCN1
Product: CCNc1nc(N2CCOCC2)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 120 °C
Yield: 80 %

Procedure:
A mixture of 80 mg (0.25 mmol) 6-chloro-2-ethylamino-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide and 433 mg (5.0 mmol) morpholine was heated in the microwave to 120° C. for 10 h. After cooling to RT, purification of the residue by CC (hexane/EtOAc 2:1) provided 73 mg (0.2 mmol, 78%) 2-Ethylamino-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 20). [M+H]+ 373.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[O:21][CH3:22])O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(#N)C.O1CCCC1>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[C:13]=1[CH2:11][C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(OC)c1C(O)c1c(OC)cccc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: COc1cccc(OC)c1Cc1c(OC)cccc1OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of bis(2,6-dimethoxyphenyl)methanol (4.37 g, 0.014 mol) in acetonitrile (50 mL) and tetrahydrofuran (65 mL) was added p-toluenesulfonic acid monohydrate (2.73 g, 0.014 mol) at 0° C. The resulting solution was warmed to room temperature and stirred for 17 hours, after which water (60 mL) was added and the solvent removed under reduced pressure. The residue was extracted with diethyl ether and the combined extracts dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave bis(2,6-dimethoxyphenyl)methane.
Reaction SMILES: [CH3:1][CH:2]1[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3]1.Cl.[CH3:18][C:19]1[C:20]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1>>[CH3:18][C:19]1[C:20]([N:26]2[CH2:27][CH2:28][N:29]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([N:4]4[CH2:3][CH:2]([CH3:1])[O:6][C:5]4=[O:7])=[CH:16][CH:15]=3)=[O:14])[CH2:30][CH2:31]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: CC1CN(c2ccc(C(=O)O)cc2)C(=O)O1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)OC4=O)cc3)CC2)c(C)c1
Yield: 34.5 %

Procedure:
By reaction and treatment in the same manner as in Example 49 and using 4-(5-methyl-2-oxooxazolidin-3-yl)benzoic acid (442 mg) described in Preparation Example 40 and 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (455 mg) described in Preparation Example 64, the title compound (272 mg) was obtained.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.C(N(CC)CC)C.Br[C:19]1[C:20]2[N:21]([C:26]([F:29])=[CH:27][N:28]=2)[N:22]=[C:23]([Cl:25])[CH:24]=1>CCO>[Cl:25][C:23]1[CH:24]=[C:19]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=2)[C:20]2[N:21]([C:26]([F:29])=[CH:27][N:28]=2)[N:22]=1
Reactant: Fc1cnc2c(Br)cc(Cl)nn12
Reactant: CCOc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOc1ccc(Nc2cc(Cl)nn3c(F)cnc23)cc1
Temperature: 80 °C

Procedure:
p-Phenetidine (0.044 ml, 0.34 mmol) and triethylamine (0.1 ml, 0.75 mmol) were added to a mixture of 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine (0.085 g, 0.34 mmol) from 1a in EtOH (1.7 mL). The mixture was heated to 80° C. and stirred for 16 hors. The solution was then concentrated in vacuo to give crude 6-chloro-N-(4-ethoxyphenyl)-3-fluoroimidazo[1,2-b]pyridazin-8-amine.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.[CH3:8]O.S(Cl)([Cl:12])=O>C1C=CC=CC=1>[ClH:12].[NH:1]1[CH2:4][CH:3]([C:5]([O:7][CH3:8])=[O:6])[CH2:2]1
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CNC1
Solvent: c1ccccc1
Product: COC(=O)C1CNC1
Product: Cl
Reaction time: 8 h

Procedure:
To a slurry of azetidine-3-carboxylic acid (20 g, 198 mmol) in 500 mL anhyd. MeOH under nitrogen at 0° C. was added slowly dropwise thionyl chloride (36 mL, 495 mmol) over 4 h. The resulting clear, light yellow solution was sealed and placed in a 0° C. freezer overnight. In the morning the reaction mixture was concentrated in vacuo, and the resulting oil was treated with 100 mL anhydrous benzene and concentrated in vacuo to give a solid. This was repeated anhydrous benzene. The resulting light yellow solid was dried in vacuo to give methyl azetidine-3-carboxylate hydrochloride. 1H NMR (400 MHz, MeOH-d4) δ ppm 4.21-4.30 (m, 4H), 3.78 (s, 3H), 3.71-3.78 (m, 1H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@@H:9](O)[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[N+:2]=[N-:3].N12CCCN=C1CCCCC2.[F:32]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F>C1(C)C=CC=CC=1>[N:1]([CH2:4][C@@H:5]1[C@H:9]([F:32])[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Reaction time: 1 h

Procedure:
Process (B): (3R,4R)-3-Azidomethyl-1-benzyloxycarbonyl-4-hydroxypyrrolidine (1.79 g) was dissolved in toluene (56 mL). While this solution was cooled on an ice bath, 1,8-diazabicyclo[5.4.0]undec-7-ene (2.03 mL) was added. This was followed by dropwise addition of perfluoro-1-octanesulfonyl fluoride (2.80 mL) and stirring for another 1 hour. Insoluble materials were removed from the reaction mixture by filtration and were washed with toluene. The filtrate and the washing solution were combined and the combined organic layer was concentrated under reduced pressure. The resulting residue was then purified on a silica gel column (eluant=hexane:ethyl acetate=2:1) to give 1.58 g of (3R,4S)-3-azidomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine as a pale brown syrup-like product. The compound was identical to the compound obtained by Process (A).