Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[NH:12]1[CH2:15][CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C1COCC1>[NH2:1][C:2]1[C:3]([C:9]([N:12]2[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(N)c(C(=O)O)n1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1ccc(N)c(C(=O)N2CCC2)n1
Temperature: 70 °C
Yield: 65.5 %

Procedure:
To a stirred mixture of 3-amino-6-methylpicolinic acid (525 mg, 2.17 mmol) and azetidine (124 mg, 146 μl, 2.17 mmol) at r.t. in THF (15 ml) under an argon atmosphere were added HATU (1.65 g, 4.35 mmol) and 4-methylmorpholine (719 μl, 6.52 mmol). The mixture was heated to 70° C. overnight, then cooled to r.t. and concentrated. The crude product was purified by silica gel chromatography using a n-heptane/EtOAc gradient to give the title compound (272 mg, 65%) as off-white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[NH:43][N:42]=[N:41][N:40]=3)=[CH:29][CH:28]=2)[C:8]2[CH:9]([C:21]([O:23][CH3:24])=[O:22])[N:10]([C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:51](Cl)([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[N:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[N:43]([C:51]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:64]4[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=4)[C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=4)[N:42]=[N:41][N:40]=3)=[CH:31][CH:32]=2)[C:8]2[CH:9]([C:21]([O:23][CH3:24])=[O:22])[N:10]([C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)N(C(=O)CC(=O)OCC)CC2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OC)N(C(=O)CC(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a mixture of methyl 2-n-butyl-5-ethoxycarbonylacetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (2.0 g), triethylamine (0.69 g) and chloroform (20 ml) is added trityl chloride (1.43 g), and the mixture is stirred at room temperature for 30 minutes. The reaction solution is washed, dried, and evaporated under reduced pressure. The resulting residue is purified by silica gel column chromatography (solvent; ethyl acetate/n-hexane) to give methyl 2-n-butyl-5-ethoxycarbonylacetyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.29 g) as needles. m.p. 124°-126° C. (decomposed)
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Cl[C:16]1[N:21]=[N:20][C:19]([Cl:22])=[C:18]2[CH:23]=[N:24][CH:25]=[CH:26][C:17]=12.CCN(C(C)C)C(C)C.CN1C(=O)CCC1>O>[Cl:22][C:19]1[C:18]2[CH:23]=[N:24][CH:25]=[CH:26][C:17]=2[C:16]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][C@H:2]2[CH3:1])=[N:21][N:20]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Clc1nnc(Cl)c2cnccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nnc(Cl)c2cnccc12
Temperature: 100 °C
Yield: 2 %

Procedure:
To (R)-tert-butyl 3-methylpiperazine-1-carboxylate (3.30 g, 16.5 mmol) and 1,4-dichloropyrido[4,3-d]pyridazine 3 (3.00 g, 15.0 mmol), suspended in Hünig's base (9.14 ml, 52.5 mmol) was added NMP (6 ml). The reaction was stirred at 100° C. The reaction contents were poured into water (120 mL) and extracted with dichloromethane (3×50 mL). Silica gel chromatography (gradient elution 20 to 80% EtOAc in hexanes) afforded 110 mg of (R)-tert-butyl 4-(4-chloropyrido[4,3-d]pyridazin-1-yl)-3-methylpiperazine-1-carboxylate 26 eluting after the 1-substitution product. 1H NMR (500 MHz, CDCl3) δ ppm 9.66 (s, 1H) 9.06 (d, J=6.1 Hz, 1H) 7.77 (d, J=5.5 Hz, 1H) 3.28-4.23 (m, 7H) 1.51 (s, 9H) 1.28 (d, J=6.7 Hz, 3H).
Reaction SMILES: [C:1]12([S:11][CH2:12][CH2:13][NH2:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C[O-].[Na+].Br[CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20]([OH:22])=[O:21]>C(O)(C)(C)C>[C:23]([CH:19]([C:20]([OH:22])=[O:21])[NH:14][CH2:13][CH2:12][S:11][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)([CH3:26])([CH3:25])[CH3:24]
Reactant: NCCSC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)C(Br)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)C(NCCSC12CC3CC(CC(C3)C1)C2)C(=O)O

Procedure:
A mixture of 42.3 parts of 2-(1-adamantylthio)ethylamine, 10.8 parts of sodium methoxide, 39.0 parts of 2-bromo-2-tert-butyl acetic acid and 315 parts of tert-butanol is refluxed, under a nitrogen atmosphere, for 5 hours. The product is recovered in the manner described in Example 5 to yield 2-tert-butyl-N-[2-(1 -adamantylthio)ethyl-]glycine, melting at about 220°-230°.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[N:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[N:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1ccc(B(O)O)cn1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)nc3)cccc2c1N
Yield: 70.8 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.49 mmol) and (6-methoxypyridin-3-yl)boronic acid (153 mg, 1.00 mmol) were reacted to afford the title compound (117 mg, 72% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ8.55 (bs, 1H), 8.43 (d, J=1.65 Hz, 1H), 8.05 (dd, J=8.5, 1.9 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.71-7.81 (m, 2H), 6.89 (d, J=8.5 Hz, 1H), 4.01 (s, 3H), 3.46 (apparent q, J=6.6 Hz, 2H), 1.67 (apparent sextet, J=7.2 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H). MS APCI, m/z=338 (M+H) HPLC 1.73 min.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[CH3:28][CH:29]([C:33]([NH:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])=[O:34])[C:30](O)=[O:31]>>[CH2:13]([O:12][CH2:11][CH2:10][N:7]1[C:8](=[O:9])[C@@H:2]([NH:1][C:30](=[O:31])[CH:29]([CH3:28])[C:33]([NH:35][CH2:36][C:37]([F:42])([F:43])[C:38]([F:39])([F:40])[F:41])=[O:34])[C:3]2[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=2[C:5]2[CH:23]=[CH:22][CH:21]=[CH:20][C:6]1=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Product: CC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid, the title compound was prepared in the same manner as described for example 1c). White solid (89% yield). MS: m/e=490(M+H+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][NH2:13])[C:5]=2[O:4][CH2:3][CH2:2]1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1cccc2c1OCCO2
Product: CC(=O)NCCc1cccc2c1OCCO2

Procedure:
In close analogy to the procedure described above, 2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]([CH:16]2[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)CS(C)(=O)=O)[CH:6]=[CH:7][C:8]=1[Cl:9].[CH3:27][OH:28]>>[ClH:2].[CH:27]1([O:28][CH:10]([C:5]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=2)[CH:16]2[CH2:17][NH:18][CH2:19]2)[CH2:7][CH2:8][CH2:3][CH2:4]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CC(C(CS(C)(=O)=O)c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Product: Clc1ccc(C(OC2CCCC2)C2CNC2)cc1Cl
Temperature: 60 °C
Yield: 97 %

Procedure:
1 N HCl (3.0 mL) was added to 10 mL of tertiary butyl 3-(1-(3,4-dichlorophenyl)-2-(methylsulfonyl)ethyl)azetidine-1-carboxylate (0.15 g, 0.36 mmol) dissolved in the methanol solution and heated to reflux at 60° C. for one day. Thereafter, the solvent of the reaction mixture was removed by reduced pressure evaporation to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:14].O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][O:8][CH3:14])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In THF (100 ml) was dissolved 4-bromophenethyl alcohol (10 g). To the mixture was added under ice-cooling 65% sodium hydride (1.7 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added dropwise under ice-cooling iodomethane (3.7 ml), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=6/1) to give 1-bromo-4-(2-methoxyethyl)benzene (8.3 g). In THF (100 ml) was dissolved 1-bromo-4-(2-methoxyethyl)benzene (8.2 g). To the mixture was added dropwise at −78° C. 1.6M n-butyllithium/hexane (26.0 ml), and the mixture was stirred for 1 hour. To the mixture was added dropwise a solution of trimethyl borate (11.8 g) in THF (12 ml), and the mixture was stirred for 30 minutes and warmed to room temperature. To the mixture was added 10% sulfuric acid (40 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was washed with hexane/isopropylether to give 4-(2-methoxyethyl)phenyl borate (3.7 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][N:13]=[CH:14]3)=[CH:9][C:8]=2[OH:17])[CH:2]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:17][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:7]=1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH:14]=[N:13][CH:12]=[CH:11]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cc2ccncc2cc1-c1cccnc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccncc4cc3-c3cccnc3)c2cc1OC
Temperature: 140 °C
Reaction time: 4 h
Yield: 54.3 %

Procedure:
7-Pyridin-3-yl-isoquinolin-6-ol (7 mg), 4-chloro-6,7-dimethoxyquinoline (21 mg), and 4-dimethylaminopyridine (12 mg) were suspended in o-dichlorobenzene (1.5 ml), and the suspension was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (7 mg, yield 55%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([Cl:10])[CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[C:4]([Cl:10])[CH:3]=1
Reactant: OCc1ccc(Br)cc1Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1ccc(Br)cc1Cl

Procedure:
To a solution of (4-bromo-2-chlorophenyl)methanol (2.8 g, 12.8 mmol) that was obtained in Example 24 (24e) in dichloromethane (50 ml) was added pyridinium dichromate (7.2 g, 19.2 mmol) with stirring, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, ether (250 ml) was added to the reaction mixture under stirring, and the resulting mixture was filtered with Celite. The filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:20) as the eluent to afford the title compound (2.0 g, yield: 70%) as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[S:11]([NH:14][C:15]1[CH:16]=[CH:17][C:18]2[CH2:22][O:21][B:20]([OH:23])[C:19]=2[CH:24]=1)(=[O:13])=[O:12]>C(O)(=O)C.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([S:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[CH2:22][O:21][B:20]([OH:23])[C:19]=3[CH:24]=2)(=[O:12])=[O:13])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(Cl)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(Cl)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
Iron powder (0.19 g, 3.30 mmol) was added to a solution of 2-chloro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-nitro-benzenesulfonamide (0.25 g, 0.67 mmol) in acetic acid (10 mL). The reaction mixture was stirred at 80° C. (bath temp) for 2 h. The mixture was then cooled to rt, and the acetic acid was removed under reduced pressure. The residue was diluted with ethyl acetate (50 mL), the undissolved particulates were removed by filtration through a pad of Celite. The filtrate was washed with water, brine and dried over Na2SO4, decanted and concentrated in vacuo. Purification was accomplished by flash silica gel column chromatography (3% methanol in dichloromethane) followed by dissolving in acidic water (with dilute HCl) and lyophilized provided 48.0 mg (21%) of the title compound as light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.10 (s, 1H), 7.63 (d, J=8.9 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.19 (dd, J=8.2, 1.9 Hz, 1H), 6.59 (d, J=2.2 Hz, 1H), 6.46 (dd, J=8.6, 2.2 Hz, 1H), 4.85 (s, 2H); MS (ESI) m/z=339 (M+1, positive); HPLC purity: 97.48% (MaxPlot 200-400 nm), 97.96% (220 nm).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6](=O)[CH2:7][C:8]3([O:14]2)[CH2:13][CH2:12][CH2:11][O:10][CH2:9]3)=[CH:4][C:3]=1[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].C[Si]([N:30]=[C:31]=[N:32][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:21]([C:20]1[CH:19]=[C:18]([C:3]2[CH:4]=[C:5]3[C:15](=[CH:16][C:2]=2[CH3:1])[O:14][C:8]2([CH2:13][CH2:12][CH2:11][O:10][CH2:9]2)[CH2:7][C:6]3=[N:32][C:31]#[N:30])[CH:25]=[CH:24][CH:23]=1)#[N:22]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: Cc1cc2c(cc1-c1cccc(C#N)c1)C(=O)CC1(CCCOC1)O2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2c(cc1-c1cccc(C#N)c1)C(=NC#N)CC1(CCCOC1)O2
Reaction time: 1 h
Yield: 132.3 %

Procedure:
To a solution of 3-(7-methyl-4-oxo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-6-yl)benzonitrile (72 mg, 0.22 mmol) in anhydrous DCM (15 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 0.44 mL, 0.44 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (0.114 mL, 0.506 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was quenched with ice-water (10 g), and stirred for 30 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted 3 times with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give 104 mg the crude desired product as light yellow solid, which was used for next step without further purification. MS ESI +ve m/z 358 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10](=[CH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=3[C:33]([F:36])([F:35])[F:34])[N:19]=[CH:18]4)[C:11](=[O:13])[N:12]=2)[CH2:4][CH2:3]1.[OH-:37].[Na+]>Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[S:9][C:10](=[CH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]([NH2:30])=[O:37])=[CH:27][C:26]=3[C:33]([F:36])([F:35])[F:34])[N:19]=[CH:18]4)[C:11](=[O:13])[N:12]=2)[CH2:6][CH2:7]1
Reactant: [OH-]
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C#N)cc4C(F)(F)F)c3)S2)CC1
Agent: Cl
Agent: [Na+]
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(N)=O)cc4C(F)(F)F)c3)S2)CC1
Temperature: 45 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
4-{5-[2-(4-Methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-indazol-1-ylmethyl}-3-trifluoromethyl-benzonitrile (Example 10) (15.2 mg, 0.03 mmol) was dissolved in 1 mL of concentrated HCl and the mixture was stirred at 45° C. for 5 h. It was neutralized with aqueous 2N NaOH and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield the desired product (10.8 mg, 68% yield).
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:33])[N:14]([N:23]=[C:24]3[CH2:29][CH2:28][CH:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:34]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:33])[N:14]([NH:23][CH:24]3[CH2:25][CH2:26][CH:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: CC(C)C1CCC(=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)C1CCC(Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 246A (0.095 g, 0.20 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.015 mL, 0.42 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.30 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with dichloromethane to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.86 (m, 6 H) 1.43 (m, 7 H) 1.87 (m, 1 H) 2.94 (m, 1 H) 3.14 (m, 1 H) 5.71 (m, 1 H) 7.04 (t, J=7.54 Hz, 1 H) 7.28 (t, J=8.46 Hz, 2 H) 7.50 (m, 2 H) 7.70 (m, 2 H) 8.06 (m, 1 H) 16.30 (s, 1 H). MS (ESI−) m/z 479 (M−H)−.
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:6]=[N+:7]([CH2:11][CH2:12][CH2:13][C:14](=[O:24])[NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])[NH2:3].S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[C:2]([C:5]1[CH2:10][CH:9]=[CH:8][N:7]([CH2:11][CH2:12][CH2:13][C:14](=[O:24])[NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1)(=[O:4])[NH2:3]
Reactant: NC(=O)c1ccc[n+](CCCC(=O)NCCc2ccccc2)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Br-]
Agent: [Na+]
Product: NC(=O)C1=CN(CCCC(=O)NCCc2ccccc2)C=CC1
Yield: 70.2 %

Procedure:
The product of Example 125 (3.92 g, 0.01 mol) was reduced with sodium dithionite (6.96 g, 0.04 mol) according to the procedure of Example 126. A yield of 2.2 g (65%) of the title compound was obtained as an orange-yellow amorphous powder, m.p. 55°-60° C. UV max (methanol) 358 nm; IR (CHCl3) 3325 (NH), 1682 (CO), 1645 (CO) cm-1. Anal. calc. for C18H23N3O2.3/4H2O: C,66.07; H,7.49; N,12.85. Found C,66.05; H,7.56; N,12.84. The structure of the product was further confirmed by PMR to be: ##STR1519##
Reaction SMILES: [F:1][C:2]([F:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][OH:6].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]OCC(F)(F)CCC1C=CC=CC=1>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:6][CH2:5][CH2:4][CH2:3][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([F:13])[F:1]
Reactant: OCCCC(F)(F)c1ccccc1
Reactant: FC(F)(CCc1ccccc1)COCCCCCCBr
Product: FC(F)(CCCOCCCCCCBr)c1ccccc1

Procedure:
Obtained from Intermediate 22 (0.6 g, 3.22 mmol) by the procedure described in Intermediate 3. The title compound was obtained (1.98 g, 63% purity) as oil.
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:19][OH:20].O[Li].O.O>C(O)C>[C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=[N:19][OH:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: ON=C(c1ccccc1)c1cc2ccncc2[nH]1
Yield: 43.1 %

Procedure:
To a mixture of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 35) (161 mg, 0.72 mmol) and hydroxylamine hydrochloride (100 mg, 1.45 mmol) in ethanol (3.6 mL) were added LiOH.H2O (120 mg, 2.16 mmol) and water (1.0 mL). The reaction mixture was heated under reflux until TLC analysis indicated consumption of the ketone. The mixture was concentrated to dryness. The residue was treated with water, and the residual solid was collected by filtration to give predominately one isomer of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone oxime (75.8 mg, 0.31 mmol, 44%) as a yellow solid. The aqueous filtrate was extracted with methylene chloride (3×). The combined extracts were washed with saturated NaCl, dried over Na2SO4, filtered, and concentrated to give ca. 1:1 mixture of isomers of the oxime (72 mg, 0.30 mmol, 42%) as a yellow solid:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.C=CC=C.[C:12]1(=O)O[C:15](=O)[C@H:14]2[CH2:18]C=C[CH2:21][C@@H:13]12.[OH-].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2]>C1C=CC=CC=1.O1CCOCC1.[N+](C)([O-])=O>[CH3:12][C:13]1[CH2:21][CH:2]2[CH:3]([CH2:15][C:14]=1[CH3:18])[C:4](=[O:5])[O:6][C:1]2=[O:7]
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Reactant: O=C1C=CC(=O)O1
Agent: C=CC=C
Agent: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Solvent: C[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: CC1=C(C)CC2C(=O)OC(=O)C2C1

Procedure:
As shown above in 2.1.2 to 2.4.2 maleic acid anhydride is reacted with a suitable conjugated diene compound to give the wanted Diels-Alder reaction product. For example maleic acid anhydride reacted with butadiene in benzene or dioxane at ambient temperature is quantatively transferred to cis-1,2,3,6-tetrahydrophthalic acid anhydride (K. Alder et al, Liebigs Annalen der Chemie, 460, 98 (1928) and 514, 1 (1934)). In the reaction of maleic acid anhydride with 2,3-dimethyl-1,3-dibutadiene in nitromethane and addition of 5 mol % of a rhuthenium catalyst on a hydroxyl apatite support, 5,6-dimethyl-3a,4,7,7a-tetrahydro-isobenzofurane-1,3-dione is formed (K. Mori et al. JACS 125, 11460 (2003)). 4,10-dioxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione is formed by reacting maleic acid anhydride with furane in diethylether. First the kinetically faster endo-product is formed which during 8 h at ambient temperature completely rearranges to the thermodynamically stable exo-product (R. B. Woodward and H. Baer, JACS 70 1161 (1948)). Maleic acid anhydride and 1,3-cyclohexadiene in benzene with heating at ambient temperature quantitatively react to 4-oxatricyclo[5.2.2.02,6]undec-8-ene-3,5-dione.