Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=O)=[CH:15][CH:16]=2)[CH2:11][CH2:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][C:23]1[CH:40]=[CH:39][C:26]2[N:27]([CH2:37][CH3:38])[C:28](=[O:36])[C:29]([CH3:35])([CH3:34])[C:30](=[O:33])[N:31]([CH3:32])[C:25]=2[CH:24]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][NH:21][CH2:22][C:23]3[CH:40]=[CH:39][C:26]4[N:27]([CH2:37][CH3:38])[C:28](=[O:36])[C:29]([CH3:35])([CH3:34])[C:30](=[O:33])[N:31]([CH3:32])[C:25]=4[CH:24]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2c(c1)CCC(=O)N2Cc1ccccc1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCc3ccc4c(c3)CCC(=O)N4Cc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
1-Benzyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-carbaldehyde (0.205 g) was added to a methanol solution (10 ml) of 7-(aminomethyl)-1-ethyl-3,3,5-trimethyl-1H-benzo[b][1,4]diazepine-2,4(3H, 5H)-dione (0.213 g). The mixture was stirred at room temperature overnight. Sodium borohydride (0.022 g) was added to the mixture, and the mixture was stirred at room temperature overnight. The liquid was then condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1). The purified product was condensed under reduced pressure to give the title compound (0.400 g) as a white amorphous. 1H NMR (CDCl3), δppm: 0.82 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.77-2.81 (2H, m), 2.96-3.00 (2H, m), 3.40 (3H, s), 3.73 (2H, s), 3.74-3.83 (1H, m), 3.81 (2H, s), 4.12-4.17 (1H, m), 5.17 (2H, s), 6.83 (1H, d, J=8.3 Hz), 7.05 (1H, dd, J=1.9, 8.3 Hz), 7.16 (1H, d, J=1.6 Hz), 7.19-7.25 (6H, m), 7.27-7.33 (2H, m)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH3:33][NH:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1>>[CH3:33][N:34]([C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)[C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([C:11]2[O:12][C:8]([CH3:7])=[C:9]([CH2:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:24])=[O:25])[N:10]=2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Reactant: CNc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)N(C)c4cccnc4)cc3)oc2C)cc1
Yield: 73.4 %

Procedure:
Reaction of oxalyl chloride (100 λL, 1.1 mmol) and benzoic acid 4 (275 mg, 0.7 mmol) with subsequent coupling to N-methyl-N-(3-pyridinyl)amine (88 mg, 0.8 mmol) gave benzamide 7 (237 mg, 69%) as a white powder: mp (MeOH) 195-197° C.; 1H NMR δ 8.37 (d, J=2.4 Hz, 1H, H-2′), 8.35 (dd, J=4.7, 1.5 Hz, 1H, H-6′), 7.72 (ddd, J=8.2, 2.4, 1.5 Hz, 1H, H-4′), 7.67 (br d, J=8.5 Hz, 2H, H-2, H-6), 7.63 (br d, J=8.2 Hz, 2H, H-2″, H-6″), 7.37-7.42 (m, J=8.2 Hz, 4H, H-3, H-5, H-3″, H-5″), 7.34 (ddd, J=8.2, 4.7 Hz, 1H, H-5′), 4.58 (s, 2H, CH2SO2), 3.42 (s, 3H, NCH3), 2.34 (s, 3H, CH3), 2.06 (s, 3H, CH3); 13C NMR δ 168.8, 157.8, 149.8, 148.1, 147.3, 144.4, 140.7, 137.4, 135.5, 134.2, 129.6 (2), 129.0 (2), 128.2 (2), 127.2, 125.9, 125.0 (2), 123.8, 52.9, 37.6, 21.0, 9.6; MS m/z 462.6 (MH+, 100%). Anal. calcd for C25H23N3O4S: C, 65.06; H, 5.02; N, 9.10. Found: C, 64.90; H, 4.92; N, 8.83%.
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C@@H:6]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH2:9][N:8]([CH2:21][CH3:22])[C:7]1=[O:23])#[N:2].Cl.Cl.[O:33]=[C:34]1[NH:42][C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[N:35]1[CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.C(N(CC)C(C)C)(C)C>C(O)CCCC>[C:1]([N:3]=[C:4]([N:46]1[CH2:45][CH2:44][CH:43]([N:35]2[C:36]3[C:37](=[N:38][CH:39]=[CH:40][CH:41]=3)[NH:42][C:34]2=[O:33])[CH2:48][CH2:47]1)[NH:5][C@@H:6]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH2:9][N:8]([CH2:21][CH3:22])[C:7]1=[O:23])#[N:2]
Reactant: CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=NC#N)Oc2ccccc2)C1=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCO
Product: CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=NC#N)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)C1=O
Yield: 4.6 %

Procedure:
A solution of phenyl N′-cyano-N-[(3R,6S)-6-(2,3-difluorophenyl)-1-ethyl-2-oxoazepan-3-yl]imidocarbamate (166 mg, 0.402 mmol) and 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (116 mg, 0.402 mmol), in 1-pentanol (10 mL) was treated with N,N-diisopropylethylamine (52 mg, 0.402 mmol). This mixture was heated to reflux for 24 h. Concentration and purification by silica gel chromatography (0%→10% methanol/dichloromethane) followed by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (10 mg). MS 537.5 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[N:2]1.Cl.[CH2:12](O)[CH3:13]>C(O)C>[NH:1]1[CH:5]=[N:4][C:3]([CH2:6][CH2:7][C:8]([O:10][CH2:12][CH3:13])=[O:9])=[N:2]1
Reactant: CCO
Reactant: O=C(O)CCc1nc[nH]n1
Agent: Cl
Product: CCOC(=O)CCc1nc[nH]n1
Temperature: 90 °C
Reaction time: 15 h
Yield: 33 %

Procedure:
A suspension of 3-(1H-1,2,4-triazol-3-yl)propanoic acid obtained in Reference Example 22 (11.6 g, 3.54 mmol) and 2N hydrogen chloride/ethanol (100 mL) in ethanol (100 mL) was stirred at 90° C. for 15 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate and water. The aqueous layer was neutralized with saturated aqueous sodium carbonate solution, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated to give the title compound as a yellow powder (4.36 g, 33%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=C)[N:16]=3)=[C:9]([F:30])[CH:8]=1.[O:31]=[O+][O-]>C(Cl)Cl.CO>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:31])[N:16]=3)=[C:9]([F:30])[CH:8]=1
Reactant: O=[O+][O-]
Reactant: C=C(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylvinyl)thiazolo[5,4-b]pyridine (2.66 g, 6.4 mmol) in 3:1 CH2Cl2/MeOH (128 mL) at −78° C. was treated with ozone for 15 min. The solution was then sparged with O2, dimethyl sulfide (18 mL) was added, and the bath was allowed to expire. The resulting solution was stirred at 25° C. for 3 d and then concentrated in vacuo. This residue was taken up in CH2Cl2 (400 mL) and sequentially washed with water and brine, then concentrated in vacuo to provide (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)thiazolo[5,4-b]pyridine-5-yl)(phenyl)methanone as a yellow solid. MS (ESI) m/z: Calculated: 420.1; Observed: 421.1 (M++1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:32]=[CH:31][C:12]([O:13][C:14]3[N:22](COCC[Si](C)(C)C)[C:17]4=[N:18][CH:19]=[CH:20][CH:21]=[C:16]4[N:15]=3)=[CH:11][CH:10]=2)O1.Br[C:35]1[C:39]2=[N:40][CH:41]=[CH:42][CH:43]=[C:38]2[N:37]([CH2:44][CH3:45])[N:36]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:44]([N:37]1[C:38]2[C:39](=[N:40][CH:41]=[CH:42][CH:43]=2)[C:35]([C:9]2[CH:10]=[CH:11][C:12]([O:13][C:14]3[NH:22][C:17]4=[N:18][CH:19]=[CH:20][CH:21]=[C:16]4[N:15]=3)=[CH:31][CH:32]=2)=[N:36]1)[CH3:45]
Reactant: CCn1nc(Br)c2ncccc21
Reactant: CC1(C)OB(c2ccc(Oc3nc4cccnc4n3COCC[Si](C)(C)C)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCn1nc(-c2ccc(Oc3nc4cccnc4[nH]3)cc2)c2ncccc21
Yield: 118 %

Procedure:
A mixture of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridine (100 mg), 3-bromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine (140 mg), Pd(PPh3)4 (7 mg), Na2CO3 (79 mg), DME (5 mL), and water (1 mL) was refluxed overnight under Ar atmosphere. The mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) and recrystallized from AcOEt/hexane to give the title compound (90 mg).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:29][NH2:30])[N:18]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:14]=2[C:13]2[CH:12]=[CH:11][C:10]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:9][C:8]=2[N:7]=1>CN(C=O)C>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:29][NH:30][C:3]([NH:2][CH3:1])=[O:4])[N:18]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26])[C:14]=2[C:13]2[CH:12]=[CH:11][C:10]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:9][C:8]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)NCCn1c(CN)nc2c(N)nc3cc(OCc4ccccc4)ccc3c21
Reactant: CN=C=O
Solvent: CN(C)C=O
Product: CNC(=O)NCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.2 %

Procedure:
Methyl isocyanate (322.9 mg, 5.66 mmol, 1.1 eq) was added to a solution of tert-butyl 2-(4-amino-2-aminomethyl-7-benzyloxy-1H-imidazo[4,5-c]quinolin-1-yl)ethylcarbamate (2.38 g, 5.14 mmol, 1 eq) in DMF and stirred at ambient temperature for 2 days. The crude reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (on silica gel, 0-6% methanol in dichloromethane) and concentrated under reduced pressure to yield 2.73 g of tert-butyl 2-{4-amino-7-benzyloxy-2-[(3-methylureido)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}ethylcarbamate.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[O:10][C:11]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=4[N:13]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)[C:37]=1[C:38](O)=[O:39].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[Cl:18][C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:9]([N:8]3[C@@H:1]4[C@@H:6]([CH2:5][CH2:4][N:3]([C:38]([C:37]5[C:41]([N:45]6[N:49]=[CH:48][CH:47]=[N:46]6)=[CH:42][CH:43]=[CH:44][C:36]=5[F:35])=[O:39])[CH2:2]4)[CH2:7]3)=[N:13][C:12]=2[CH:14]=1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: Clc1ccc2oc(N3C[C@@H]4CCNC[C@@H]43)nc2c1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: O=C(c1c(F)cccc1-n1nccn1)N1CC[C@H]2CN(c3nc4cc(Cl)ccc4o3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting 2-((1R,6S)-3,8-diazabicyclo[4.2.0]octan-8-yl)-5-chlorobenzo[d]oxazole (Intermediate 32) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 15) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C22H18ClFN6O2, 452.88; m/z found 453.0 [M+H]+. 1H NMR (CD3OD): 8.04-7.74 (m, 2H), 7.67-7.24 (m, 4H), 7.15-6.64 (m, 2H), 5.04-4.23 (m, 3H), 4.20-3.35 (m, 4H), 3.20 (br s, 1H), 2.37-1.88 (m, 2H).
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([Si:10]([CH3:22])([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH3:19])=[CH:14][CH:13]=1)([CH3:9])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:6]([Si:10]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:1])=[CH2:19])=[CH:14][CH:13]=1)([CH3:22])[CH3:21])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(C)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
Methyl(triphenylphosphonium) bromide (17.1 g, 48.0 mmol) was suspended in THF (96 mL) and cooled to 0° C. n-Butyllithium (2.5 M in hexane, 19.2 mL, 48.0 mmol) was added dropwise to the mixture. The red solution was stirred at rt for 0.5 h. 1-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-ethanone (10.0 g, 40.0 mmol) was added. The solution turned bright yellow and a white precipitate formed. The mixture was stirred for 1 h at rt and then the solution was quenched with saturated NaHCO3. The aqueous phase was extracted with diethyl ether and the combined organic layers were washed with saturated NaHCO3. The organic layers were dried over sodium sulfate, filtered and concentrated. The resultant mixture was eluted through a plug of silica gel (hexanes) and the filtrate was concentrated to provide tert-butyl-(4-isopropenyl-phenoxy)-dimethyl-silane (8.36 g, 84%) as a colorless oil. ESI MS (m/z 249, M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([CH3:37])=[C:21]([C:22]4[CH:23]=[C:24]([CH2:28][NH:29]C(=O)OC(C)(C)C)[CH:25]=[CH:26][CH:27]=4)[C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][CH2:28][C:24]1[CH:23]=[C:22]([C:21]2[C:13]3[C:14](=[N:15][C:16]([CH3:18])=[CH:17][C:12]=3[NH:11][S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:9])=[O:10])[S:19][C:20]=2[CH3:37])[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(CNC(=O)OC(C)(C)C)c3)c(C)sc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(CN)c3)c(C)sc2n1
Reaction time: 1 h
Yield: 8.5 %

Procedure:
To a solution of 1,1-dimethylethyl {[3-(4-{[(3-chlorophenyl)sulfonyl]amino}-2,6-dimethylthieno[2,3-b]pyridin-3-yl)phenyl]methyl}carbamate (Example 70) (40 mg, 0.072 mmol) in DCM (2 mL) was added TFA (0.276 mL, 3.58 mmol) and the mixture stirred for 1 h. The mixture was then loaded onto an SCX cartridge and flushed with MeOH (3×5 mL) followed by 2M NH3 in MeOH (3×5 mL). The desired fractions were combined and concentrated and further purified by normal phase chromatography, eluting with a gradient of 0-20% 2M NH3 in MeOH in DCM, to give the title compound (2.8 mg). LCMS (A) m/z: 458 [M+1]+, Rt 0.96 min (basic).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=2)[CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[C:41]=1[C:47]1[C:56]2[N:55]=[CH:54][CH:53]=[N:52][C:51]=2[C:50]([C:57](O)=[O:58])=[CH:49][CH:48]=1>C(Cl)Cl.CO>[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:57]([C:50]3[C:51]4[N:52]=[CH:53][CH:54]=[N:55][C:56]=4[C:47]([C:41]4[C:42]([CH3:46])=[CH:43][CH:44]=[CH:45][C:40]=4[CH3:39])=[CH:48][CH:49]=3)=[O:58])=[N:14][CH:15]=2)[CH2:5][CH2:4]1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)c2nccnc12
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc(C)c1-c1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)cn2)c2nccnc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 2 days at rt, using 2 equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Example 31), TBTU (2 equiv) and 8-(2,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid (Example 71). Title compound: ESI-MS: 467.1 [M+H]+; tR=3.55 min (System 1); TLC: Rf=0.15 (DCM/MeOH, 9:1).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C:33]3[CH:50]=[CH:49][CH:48]=[CH:47][C:34]=3[CH2:35][N:36]3C(=O)C4C(=CC=CC=4)C3=O)[N:14]3[C:19]4[CH:20]=[CH:21][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:18]=4[N:17]=[CH:16][C:15]=23)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].NN.[OH-].[Na+]>CCO.CCOC(C)=O>[NH2:36][CH2:35][C:34]1[CH:47]=[CH:48][CH:49]=[CH:50][C:33]=1[C:13]1[N:14]2[C:19]3[CH:20]=[CH:21][NH:22][C:18]=3[N:17]=[CH:16][C:15]2=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[CH:6][CH:7]=2)[N:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(-c4ccc(C(C)(C)O)cc4)nc(-c4ccccc4CN4C(=O)c5ccccc5C4=O)n23)cc1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(O)c1ccc(-c2nc(-c3ccccc3CN)n3c2cnc2[nH]ccc23)cc1
Temperature: 85 °C
Yield: 24.5 %

Procedure:
The 2-(2-(3-(4-(2-hydroxypropan-2-yl)phenyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)benzyl)isoindoline-1,3-dione (0.154 g, 0.226 mmol) in EtOH (4 mL) was treated with hydrazine (0.147 mL, 4.68 mmol) then heated to about 85° C. for about 15 min. The mixture was diluted with EtOAc (20 mL). The insoluble material was removed by filtration and washed with EtOAc (5 mL). The filtrate was concentrated under reduced pressure then the material was dissolved in 1,4-dioxane (4 mL) and treated with aqueous NaOH (50 wt %, 0.260 g, 3.25 mmol). The mixture was heated in a microwave at about 120° C. for about 20 min. The mixture was concentrated under reduced pressure then dissolved in AcOH (1 mL) and DMF (3 mL). The material was purified by preparative reverse phase HPLC (Table 2, Method i). The fractions with desired material were collected and lyophilized. The material was purified using a 5 g Si-Carbonate column (Silicycle™) and eluting wiht MeOH. The material was treated with EtOAc (˜10 mL) then concentrated under reduced pressure. This was repeated several times until a yellow solid was obtained. The material was triturated with EtOAc (3 mL) and heptane (15 mL) and the solid was collected by filtration and dried to constant weight under vacuum at about 70° C. to give 2-(4-(1-(2-(aminomethyl)phenyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (0.022 g, 25%): LC/MS (Table 2, Method a) Rt=1.62 min; MS m/z 398 (M+H)+. Syk IC50=B.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH:2]=[CH2:3].[H-].[Na+].[CH3:23]I>CN(C=O)C.O>[CH2:1]([C:4]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH3:23])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCc1c(OCc2ccccc2)ccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1c(OCc2ccccc2)ccc2c1ccn2C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
4-Allyl-5-(benzyloxy)-1H-indole (368.7 mg, 1.40 mmol) (Example 58) was dissolved in anhydrous DMF (12 mL) under an inert atmosphere, and the reaction mixture was cooled in an ice-water bath. Sodium hydride (60% in mineral oil) (181 mg, 1.68 mmol) was added, and the reaction mixture was stirred for an additional 30 min. Methyl iodide (278 mg, 1.96 mmol) was added and stirring at rt was continued for 30 min. The reaction mixture was heated to 40° C. for 12 h, cooled to rt, and water (10 drops) was added. The reaction mixture was concentrated under reduced pressure, after which water was added, and the aqueous phase was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v)=1:15) gave 259 mg (67%) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 3.72 (m, 5H), 4.98 (d, 1H), 5.07 (d, 1H), 5.12 (s, 2H), 6.06 (m, 1H), 6.47 (s, 1H), 7.00 (d, 1H), 7.03 (s, 1H), 7.12 (d, 1H), 7.31 (m, 1H), 7.39 (m, 2H), 7.48 (m, 2H).
Reaction SMILES: C([O:8]C1C=CC(C(=O)C)=CC=1CO)C1C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([C:42](=[O:44])[CH3:43])[CH:31]=[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:35]([O:34][C:32]1[CH:31]=[C:30]([C:42]([CH:43]=[O:8])=[O:44])[CH:29]=[C:28]([O:27][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:33]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(CO)c1
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Product: O=CC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
The title compound was prepared as a hydrate by the process of Description 54, replacing 1-(4-benzyloxy-3-hydroxymethylphenyl)ethanone. by 1-(3,5-dibenzyloxyphenyl)ethanone. γ(CDCl3) 6.40 (2H, s) 5.00 (4H, s), 2.40-3.50 (14H, m).
Reaction SMILES: [I-].[C:2]1([CH2:8][C:9]([NH:11][CH:12]2[C:55](=[O:56])[N:14]3[C:15]([C:39]([O:41][CH:42]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:40])=[C:16]([CH2:19][P+](C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:57]1([CH:60]=O)[CH2:59][CH2:58]1.O.[OH-].[Na+]>C(Cl)Cl>[C:2]1([CH2:8][C:9]([NH:11][CH:12]2[C:55](=[O:56])[N:14]3[C:15]([C:39]([O:41][CH:42]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)=[O:40])=[C:16](/[CH:19]=[CH:60]\[CH:57]4[CH2:58][CH2:59]4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: O=CC1CC1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\C3CC3)CS[C@H]12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
15.9 g (17.9 mmol ) of benzhydryl 7-phenylacetamido-3-(triphenylphosphonio)methyl-3-cephem-4-carboxylate iodide (Example 7) are taken in 100 ml of methylene chloride and 17.56 g (250.6 mmol) of cyclopropanecarboxaldehyde in a 250 ml three-necked flask. The mixture is cooled to 0° C. and 100 ml of water are added. 16.3 ml of 1N NaOH are then added dropwise in the course of 4 hours, the pH being kept constant at 8.6. The reaction solution is diluted with methylene chloride and the organic phase is separated off, washed once with water and then dried over sodium sulphate. After the drying agent has been removed, a further 13 ml (233 mmol) of cyclopropanecarboxaldehyde are added to the methylene chloride solution and the mixture is stirred overnight. The reaction solution is then concentrated to dryness, the residue is again dissolved in a little methylene chloride and the mixture is introduced onto a column filled with 500 ml of silica gel (0.04-0.063 mm). 400 ml fractions are collected and all the fractions are investigated for the cis-isomer compound by means of analytical HPLC.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10]O)=[N:7][CH:8]=1)#[N:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH2:10])=[N:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(CCO)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1ccc(C#N)cn1
Yield: 36.3 %

Procedure:
A mixture of 0.163 g (1.1 mmol) 5-cyano-2-(2-hydroxyethyl)pyridine and 0.029 g (0.15 mmol) p-toluenesulfonic acid hydrate in 10 mL toluene was heated to reflux for five hours in a flask equipped with a Dean-Stark trap. The cooled mixture was neutralized with 5 mL saturated sodium bicarbonate solution and extracted with ether (3×15 mL). The extract was washed with 3 mL brine, dried over sodium sulfate, and filtered. The filtrate was concentrated to give an oil which was purified by flash chromatography on silica gel elating with 1:3 ethyl acetate:hexane to give 0.052 g (36%) 5-cyano-2-vinylpyridine, mp 29°-30° C.