Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([S:11][CH2:12][CH2:13][NH:14][C@H:15]([C:17]([OH:19])=[O:18])[CH3:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(O)(=O)C.[N:24]([O-])=[O:25].[Na+]>O>[C:1]12([S:11][CH2:12][CH2:13][N:14]([N:24]=[O:25])[C@H:15]([C:17]([OH:19])=[O:18])[CH3:16])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=N[O-]
Reactant: C[C@H](NCCSC12CC3CC(CC(C3)C1)C2)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](C(=O)O)N(CCSC12CC3CC(CC(C3)C1)C2)N=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 22.7 parts of N-[2-(1- adamantylthio)ethyl]alanine in 216 parts of acetic acid is cooled to 15°, then treated with a solution of 6.2 parts of sodium nitrite in 20 parts of water, added dropwise over a 15 minute period. Stirring is continued at low temperature for an additional 15 minutes, then at room temperature for another 15 minutes. The resultant clear yellow solution is added to 1000 parts of ice-water and stirring is continued. The resultant mixture is extracted with methylene chloride. The organic phase is separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to yield, as a gumlike material, N-[2-(1-adamantylthio)ethyl]-N-nitrosoalanine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:20])[C:14]=1[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[Cl:27]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([CH2:12][C:13]1[CH:18]=[C:17]([Cl:27])[C:16]([NH2:19])=[C:15]([CH3:20])[C:14]=1[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C[C@H](Cc1ccc(N)c(C)c1COC(C)=O)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C[C@H](Cc1cc(Cl)c(N)c(C)c1COC(C)=O)C(=O)OCC
Temperature: 60 °C
Yield: 59 %

Procedure:
2-(S)-(2-Acetoxymethyl-4-amino-3-methyl-benzyl)-succinic acid diethyl ester (3.0 g, 8.2 mmol) was dissolved in acetonitrile (40 mL). Mixture was warmed to 60° C. N-Chlorosuccinimide (1.29 g, 9.7 mmol) was added to the warm solution. Reaction mixture was heated at reflux for 10 minutes. Mixture was cooled to room temperature then diluted with ethyl acetate (20 mL). Mixture was washed successively with saturated aqueous sodium bicarbonate (40 mL), and brine (20 mL). Organic was dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography (ethyl acetate-hexanes) afforded the desired product in 59% yield as an amber oil. 1H NMR (300 MHz, CDCl3): δ=6.98 (s, 1H), 5.15 (d, J=3.3, 2H), 4.09 (m, 4H), 2.99 (m, 2H), 2.69 (m, 2H), 2.39 (dd, J1=4.8, J2=16.5, 1H), 2.17 (s, 3H), 2.06 (s, 3H), 1.20 (m, 6H). MS m/e (M−C2H4O2+H)+=340.0.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[C:20]([C:32]4[CH:33]=[C:34]([NH:38]C(=O)C5C(F)=CC=CC=5F)[CH:35]=[CH:36][CH:37]=4)=[N:21][N:22]4[CH:27]=[C:26](C(F)(F)F)[CH:25]=[CH:24][C:23]=34)[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1.ClCCO[C:54]1[CH:55]=C(NC2N=C(C3C(C4C=C(NC(=O)C(F)(F)F)C=CC=4)=NN4C=CC=CC=34)C=CN=2)C=C[CH:59]=1.CNCC=C>>[NH2:38][C:34]1[CH:33]=[C:32]([C:20]2[C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH2:55][CH:54]=[CH2:59])[CH:7]=4)[N:18]=3)=[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]3[N:21]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCl)c3)n2)c1)C(F)(F)F
Reactant: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4cc(C(F)(F)F)ccc34)n2)c1
Agent: C=CCNC
Product: C=CCN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1

Procedure:
The title compound was obtained by treating N-(3-{3-[2-({3-[(2-chloroethyl)oxy]phenyl}amino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)-2,2,2-trifluoroacetamide with N-methyl-2-propen-1-amine in a manner similar to Example 136 to give the product, ES-LCMS m/z 492 (M+H).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[O:11]=[C:12]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:15]([C:24]([O:26][CH3:27])=[O:25])[CH2:14][CH2:13]1.CI.[CH3:30]C(O)=O>C1COCC1>[CH3:30][C@H:13]1[C:12](=[O:11])[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:15]([C:24]([O:26][CH3:27])=[O:25])[CH2:14]1
Reactant: CC(=O)O
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)[C@@H]1C[C@@H](C)C(=O)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
This compound is prepared as described by Gu et al, Tetrahedron Lett., 2003, 44, 3203-3205. Lithium hexamethyldisilazide in THF (1.0 M; 8.47 mL, 8.47 mmol) was added dropwise over 30 min. to a solution of 1-tert-butyl 2-methyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate (2.0 g, 8.2 mmol) in THF (20 mL) at −78° C. The resulting mixture was stirred at −78° C. for 1 h. Methyl iodide (1.30 mL, 20.9 mmol) was then added dropwise over 10 min. After stirring at −78° C. for 2 h, the reaction mixture was allowed to warm to room temperature and stirred for 14 h. The reaction was then quenched by the addition of AcOH (1.00 mL, 17.6 mmol), and the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL), washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to give the sub-title compound (0.47 g, 22%). LCMS calc. for C12H19NNaO5 (M+Na)+: m/z=280.1. found 280.1. 1H NMR (CDCl3, 400 MHz) δ 4.57 (1H, dd, J=1.6 and 9.6 Hz), 3.77 (3H, s), 2.68 (1H, m), 2.27 (1H, m), 1.93 (1H, m), 1.49 (9H, s), 1.21 (3H, d, J=6.8 Hz) ppm.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](=[O:33])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2NC(OC(C)(C)C)=O)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH2:7][Cl:8].[Li+].[OH-:36].Cl>CO.O>[C:4]([O:36][C:17]([NH:18][N:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:17](/[CH:16]=[CH:15]/[C:12]1[CH:13]=[CH:14][C:9]([CH:4]([CH2:5][CH2:6][CH2:7][Cl:8])[C:3]([OH:2])=[O:34])=[CH:10][CH:11]=1)=[O:33])=[O:33])([CH3:9])([CH3:5])[CH3:3]
Reactant: COC(=O)C(CCCCl)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NN(C(=O)/C=C/c1ccc(C(CCCCl)C(=O)O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (E)-2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-5-chloro-pentanoic acid methyl ester (48.7 mg, 10 mmol) in MeOH/H2O (4:1) (2 mL), LiOH (24 mg, 100 mmol) was added. After the solution was stirred at room temperature for 5 h, the solution was neutralized with 2N HCl to pH 5-6. The mixture was evaporated to dryness under reduced pressure, then EtOAc (10 mL) was added. The organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated to obtain of a yellow solid product without further purification. MS: calc'd 473 (MH+), exp 473 (MH+). 1H NMR (400 MHz, DMSO-d6) 12.50 (s, 1H), 9.73 (s, 1H), 8.50 (s, 1H), 6.89-7.64 (m, 10H), 3.61 (m, 3H), 1.55-2.10 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:22](=[O:40])[N:23]([C@@H:27]3[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]3)[CH:24]([CH3:26])[CH3:25])[C:19]([CH3:21])=[CH:20][C:15]=2[O:14][C:13]([CH3:44])([C:41](O)=[O:42])[C:12]1=[O:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C>O1CCCC1>[CH2:1]([N:8]([CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:22]([N:23]([CH:24]([CH3:25])[CH3:26])[C@@H:27]3[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:28]3)=[O:40])[C:19]([CH3:21])=[CH:20][C:15]=2[O:14][C:13]([CH2:41][OH:42])([CH3:44])[C:12]1=[O:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCN(Cc1ccccc1)Cc1ccccc1)C(=O)C(C)(C(=O)O)O2
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCN(Cc1ccccc1)Cc1ccccc1)C(=O)C(C)(CO)O2
Reaction time: 1 h
Yield: 84.4 %

Procedure:
Under nitrogen atmosphere, the mixture was cooled with ice-bath, and to a solution of the obtained 4-[2-(dibenzylamino)ethyl]-2,7-dimethyl-6-{[(3R)-1-{[(2-methyl-2-propanyl)oxy]carbonyl}-3-piperidinyl](2-propanyl)carbamoyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (27.2 g) in tetrahydrofuran (75 ml) were added triethylamine (5.8 g) and chloroformic acid isobutyl ester (6.2 g), and the mixture was stirred for one hour. The precipitated salt was filtered, and the filtrate was added dropwise into a suspension of sodium borohydride (2.9 g) in tetrahydrofuran-ethanol (50 ml-50 ml) under ice-cooling. The mixture was stirred for one hour, and thereto was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 2-methyl-2-propanyl (3R)-3-[({4-[2-(dibenzylamino)ethyl]-2-(hydroxymethyl)-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(2-propanyl)amino]-1-piperidinecarboxylate (22.5 g).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([CH3:12])=[N:11][C:5]=2[C:4](=[O:13])[NH:3]1.C1C=C(Cl)C=[C:16]([C:21]([O:23]O)=[O:22])C=1.C(OC(=O)C)(=O)C>C(O)(=O)C>[C:21]([O:23][CH2:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2](=[O:1])[NH:3][C:4](=[O:13])[C:5]=2[N:11]=1)(=[O:22])[CH3:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc2[nH]c(=O)[nH]c(=O)c2n1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCc1ccc2[nH]c(=O)[nH]c(=O)c2n1
Yield: 66 %

Procedure:
1.77 g of 1 (10 mmol) in 50 ml of glacial acetic acid containing 6.5 g of MCPBA (57-85%) was refluxed for 3 hours. Acetic anhydride (40 ml) was added to the hot reaction mixture and the refluxing was continued for another half an hour. The clear brown solution was evaporated to dryness and the solid was stirred with ether (100 ml) and filtered. The solid was crystallized from ethanol to give 1.55 g (66%) of 2.
Reaction SMILES: [Cl:1][C:2]([Cl:54])([Cl:53])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:52])[C@@H:14]([NH:21][C:22](=[O:51])[C@@H:23]([NH:27][C:28](=[O:50])[C:29]([CH3:49])([CH3:48])/[CH:30]=[CH:31]/[C:32]2[CH:41]=[C:40]3[C:35]([CH:36]=[CH:37][C:38]([C@H:42]([O:44][C:45](=[O:47])[CH3:46])[CH3:43])=[N:39]3)=[CH:34][CH:33]=2)[CH:24]([CH3:26])[CH3:25])[CH2:15]N2C=CC=N2)[NH:8]1)=[O:6].ClC(Cl)(Cl)[CH2:57][O:58]C([C@@H]1CCCN(C(=O)[C@@H](NC(=O)[C@@H](NC(OC(C)(C)C)=O)C(C)C)COC)N1)=O>>[Cl:1][C:2]([Cl:54])([Cl:53])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:52])[C@@H:14]([NH:21][C:22](=[O:51])[C@@H:23]([NH:27][C:28](=[O:50])[C:29]([CH3:49])([CH3:48])/[CH:30]=[CH:31]/[C:32]2[CH:41]=[C:40]3[C:35]([CH:36]=[CH:37][C:38]([C@H:42]([O:44][C:45](=[O:47])[CH3:46])[CH3:43])=[N:39]3)=[CH:34][CH:33]=2)[CH:24]([CH3:26])[CH3:25])[CH2:15][O:58][CH3:57])[NH:8]1)=[O:6]
Reactant: COC[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Reactant: CC(=O)O[C@H](C)c1ccc2ccc(/C=C/C(C)(C)C(=O)N[C@H](C(=O)N[C@@H](Cn3cccn3)C(=O)N3CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N3)C(C)C)cc2n1
Product: COC[C@H](NC(=O)[C@@H](NC(=O)C(C)(C)/C=C/c1ccc2ccc([C@@H](C)OC(C)=O)nc2c1)C(C)C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1

Procedure:
Compound 117c was prepared in the same manner as (S)-1-[(S)-2-((S)-2-{(E)-4-[2-((R)-1-acetoxy-ethyl)-quinolin-7-yl]-2,2-dimethyl-but-3-enoylamino}-3-methyl-butyrylamino)-3-pyrazol-1-yl-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester using (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-methoxy-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (700 mg, 1.25 mmol) instead of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-pyrazol-1-yl-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester to afford the title compound as an off white foam (460 mg, 48%) and as a 1:1 mixture of two diastereoisomers. LCMS (m/z) 770.2 [M+H], Tr=3.06 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][Cl:14].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:14][CH2:13][CH2:12][CH2:11][CH2:10][N:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[N:6][C:5]1=[O:8]
Reactant: Cc1cnc(=O)[nH]c1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cnc(=O)n(CCCCCl)c1
Temperature: 0 °C

Procedure:
10.5 g (95.0 mmol) of 5-methylpyrimidin-2(1H)-one from Example 6.1, 16.3 g (95.0 mmol) of 1-bromo-4-chlorobutane and 39.4 g (285.0 mmol) of K2CO3 in 200 ml of dimethyl sulfoxide were stirred at room temperature for 12 hours. The reaction mixture was added to ice-water, and the aqueous mixture was extracted twice with diethyl ether. The aqueous phase was extracted twice with methylene chloride. The methylene chloride phase was dried over Na2SO4 and filtered to remove the desiccant, and the solvent was evaporated to dryness in vacuo. The resulting solid residue was stirred with diethyl ether, and the precipitate was filtered off with suction, washed with diethyl ether and dried. Yield: 5.0 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[S:14]1[C:22]2[CH2:21][CH2:20][NH:19][CH2:18][C:17]=2[CH:16]=[CH:15]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[S:14][CH:15]=[CH:16][C:17]=4[CH2:18]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: c1cc2c(s1)CCNC2
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2sccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: BrC1C=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.BrC1C=C(C=CC=1)N.Br[C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[O:21][CH2:22][C:23]([O:25]CC)=[O:24].S1C=CC(C2C=C(CC(O)=S)C=CC=2)=C1.S1C=CC(C2C=C(NCC(O)=O)C=CC=2)=C1>>[S:8]1[CH:7]=[CH:6][C:5]([C:18]2[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=2)[O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:4]1
Reactant: Sc1cccc(Br)c1
Reactant: CCOC(=O)COc1cccc(Br)c1
Agent: O=C(O)CNc1cccc(-c2ccsc2)c1
Agent: OC(=S)Cc1cccc(-c2ccsc2)c1
Solvent: Nc1cccc(Br)c1
Product: O=C(O)COc1cccc(-c2ccsc2)c1

Procedure:
When the same reactions as in Referential Example 12 are carried out using 3-bromothiophenol or 3-bromoaniline instead of the starting 3-bromophenol, 3-(3-thienyl)phenylthioacetic acid and 3-(3-thienyl)phenylaminoacetic acid are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][CH2:10]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][O:3]1.CN(C)C=O.[Br-:28].[Li+]>O>[Br:28][CH2:10][CH2:9][CH2:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:22])([CH3:1])[O:6]1
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)OCCCCC2COC(C)(C)O2)cc1
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCCCBr)O1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a stirred solution of 220 g. of 2,2-dimethyl-4-(4-p-toluenesulfonyloxybutyl)-1,3-dioxolane in 800 ml. of dimethylformamide at 0° C. is added 115 g. of anhydrous lithium bromide in portions during 5 minutes. The resulting mixture is stirred at ambient temperature for 22 hours, diluted with water, and extracted with ehter. The extract is washed with sodium bicarbonate solution, water, and brine; dried over magnesium sulfate; and concentrated. The residue is distilled to give a colorless liquid, b.p. 71°-74° C. (0.2 mm.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:6]3=[C:7]([C:11]4[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=4)[CH:14]=O)[NH:8][C:9]([CH:10]=1)=[C:5]23.C1([C:30]2[NH:31]C3C=CC=C4C(=O)NCCC=2C=34)C=CC=CC=1.C(C1C=C(B(O)O)C=CC=1)=O.CN>>[F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:6]3=[C:7]([C:11]4[CH:18]=[CH:17][CH:16]=[C:13]([CH2:14][NH:31][CH3:30])[CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23
Reactant: O=Cc1cccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)c1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Agent: CN
Agent: O=Cc1cccc(B(O)O)c1
Product: CNCc1cccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)c1

Procedure:
3-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzaldehyde (247 mg, 0.80 mmol; prepared in a manner similar to that described for compound 12 from 2-bromo-8-fluoro-1,3,4,5-etrahydro-azepino[5,4,3-cd]indol-6-one and 3-formylphenylboronic acid) was reacted with methylamine (4.91 mmol) as described for Compound PPP to yield 8-fluoro-2-(3-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 193 mg (74%) as an off-white solid: m.p. 270-272° C. (dec); 1H NMR (300 MHz, d6-DMSO) 2.34 (s, 3H), 3.05 (m, 2H), 3.39 (m, 2H), 3.78 (s, 2H), 7.42 (m, 5H), 7.61 (br s, 1H), 8.26 (br t, 1H), 11.70 (br s, 1H). HRMS (MALDI, MH+) Calcd for C19H18N3OF: 324.1512. Found: 324.1498. Anal. (C19H18N3OF.1.5 H2O.0.35 CHCl3) C, H, N.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[Cl:7][C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH:14]([CH2:18][NH:19][C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:21])[CH2:13]1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:7][C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH:14]([CH2:18][NH:19][C:20]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:27][CH2:28]2)=[O:21])[CH2:13]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)NC1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(NC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)CC1
Temperature: 23 °C
Reaction time: 5 h

Procedure:
Methane sulphonyl chloride (0.009 ml) was added to a solution of Intermediate 16 (0.04 g) and N,N-diisopropylethylamine (0.048 ml) in dichloromethane (3 ml). The solution was stirred for 5 h at 23° C. The solvent was removed in vacuo and the residue was purified by solid phase extraction (Isolute SCX sulphonic acid column) eluting with methanol followed by 10% 0.880 ammonia solution in methanol, to give the title compound as a pale yellow gum (0.034 g).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[C:18]([CH3:31])[C:19]2[N:20]([C:22]([C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH3:30])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH3:31][C:18]1[C:19]2[N:20]([C:22]([C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH3:30])=[N:23][N:24]=2)[CH:21]=[C:16]([O:12][C@H:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C@@H:2]([NH2:1])[CH2:3][CH2:4]2)[CH:17]=1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: Cc1cc(F)cn2c([C@@H]3CCCN3C)nnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(O[C@@H]2CC[C@H](N)c3ccccc32)cn2c([C@@H]3CCCN3C)nnc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.8 %

Procedure:
A mixture of Intermediate A (44 mg, 0.267 mmol) and sodium hydride (60% in mineral oil, 29 mg, 0.729 mmol) in anhydrous DMF (1 mL) was stirred at RT for 20 min under argon atmosphere. To the reaction mixture was added a solution of Intermediate 105d (57 mg, 0.243 mmol) in anhydrous DMF (2 mL) and stirring at 60° C. was continued for 2.5 h. After cooling to RT, the reaction mixture was diluted with EtOAc and poured into ice-water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by SCX cartridge by washing the cartridge with 10% MeOH in DCM and eluting the product with 10% (2M NH3 in MeOH) in DCM and then by FCC on silica, using 10% MeOH in DCM followed by 10% [2M NH3 in MeOH] in DCM, to give the title compound (53 mg, 58%). LCMS (Method 1): Rt 0.38, 1.54 min, m/z 378 [MH+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:23][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: COc1cccc(O)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: COc1cccc(Oc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 3-methoxyphenol (27 μl, 0.243 mmol) similar to Example 13 and isolated as a white oil (24 mg, 34%). 1H NMR (CDCl3): 8.79-8.76 (m, 1H), 8.26-8.23 (m, 1H), 7.75-7.69 (m, 1H), 7.33-7.28 (m, 2H), 6.82-6.72 (m, 3H), 6.58 (s, 1H), 3.77 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: I[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:6]=1.[CH3:25][C:26]1([CH3:33])[C:30]([CH3:32])([CH3:31])[O:29][BH:28][O:27]1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:5]2[CH:6]=[C:2]([B:28]3[O:29][C:30]([CH3:32])([CH3:31])[C:26]([CH3:33])([CH3:25])[O:27]3)[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)=[N:4]2)=[CH:9][CH:10]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: COc1ccc(Cn2cc(I)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Yield: 79.9 %

Procedure:
1 g (2.3 mmol) of 4-iodo-1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazole (prepared as described in Example 27) was dissolved in 20 ml of dry toluene and 3.18 ml of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (23 mmol), 20 mg (0.08 mmol) of palladium(II) chloride diacetonitrile complex, 80 mg (0.005 mmol) of S-Phos (2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl) and 774 μl (5.7 mmol) of triethylamine were added successively. The reaction mixture was submitted to microwave irradiation in a sealed vial at 90° C. for 30 minutes. The mixture was then filtered through a celite pad and the filtrate evaporated in vacuo. The residue was taken up with dichloromethane and washed with water and the organic layer dried over sodium sulphate and evaporated again. The crude was finally purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3 1%), affording 800 mg (80%) of the title compound, crystallized from diethylether.