Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][N:3]=1.[Li]C(C)(C)C.Cl([O-])(=O)(=O)=O.[CH2:20]1[C:27]2[CH2:26][CH2:25][CH2:24][N+:23]=2[CH2:22][CH2:21]1>CCOCC.CCCCC>[F:1][C:2]1[N:3]=[CH:4][C:5]([C:27]23[CH2:26][CH2:25][CH2:24][N:23]2[CH2:22][CH2:21][CH2:20]3)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(I)cnc1F
Reactant: C1CC2=[N+](C1)CCC2
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCCCC
Solvent: CCOCC
Product: Cc1cc(C23CCCN2CCC3)cnc1F
Temperature: -95 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
2-Fluoro-5-iodo-3-methylpyridine (200 mg, 0.84 mmol) was dissolved in Et2O and cooled to -95° C. A solution of 2.5M t-BuLi (1.7M in pentane, 1.1 mL, 1.80 mmol) in pentane was added dropwise. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (265 mg, 1.26 mmol) was added, and the reaction mixture was allowed to warm to -10° C. with stirring for 2 hours. The cold bath was removed, 2N HCl was added, and the phases were separated. The aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 99:1) to afford the title compound as an oil (123 mg, 67%) 1H NMR (CDCl3, 300 MHz) δ1.55-1.71 (m, 2H), 1.78-2.04 (m, 6H), 2.26 (s, 3H), 2.64-2.72 (m, 2H), 3.11-3.18 (m, 2H), 7.70 (m, 1H), 8.09 (m, 1H); MS (CI/NH3) m/z: 221 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1C.C1(CN2[C:35](=[O:36])C(CO)=CC(C3C=CC(OC)=C(F)C=3)=N2)CC1>>[CH:16]1([CH2:15][N:13]2[C:12](=[O:19])[C:11]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][C:7]([O:36][CH3:35])=[C:2]([F:1])[CH:3]=3)=[N:14]2)[CH2:17][CH2:18]1
Reactant: COc1ccc(-c2cc(CO)c(=O)n(CC3CC3)n2)cc1F
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Product: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F

Procedure:
Following the procedure of Example 1 (9), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl) -4-hydroxymethyl-2H-pyridazin-3-one was reacted to yield the title compound as slightly yellow needles (yield: 80.4%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].BrC[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:17][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: Clc1ccc(CCBr)cc1
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(Cl)cc3)CC1)O2
Yield: 92.7 %

Procedure:
(E)-3-{4-Oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (169 mg, 0.500 mmol, Intermediate 1, hydrochloride salt) was alkylated using 1-(2-bromo-ethyl)-4-chloro-benzene (0.15 ml, 1.5 mmol) as described in Example 56, Step A, giving (E)-3-{1′-[2-(4-chloro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (204 mg) as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:13][O:14][C:15]1[C:22]([CH3:23])=[C:21]([CH3:24])[C:20]([O:25][CH3:26])=[C:19]([CH3:27])[C:16]=1[CH2:17]Br>C(OCC)C.O>[CH3:26][O:25][C:20]1[C:21]([CH3:24])=[C:22]([CH3:23])[C:15]([O:14][CH3:13])=[C:16]([CH3:17])[C:19]=1[CH2:27][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: COc1c(C)c(C)c(OC)c(CBr)c1C
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1c(C)c(C)c(OC)c(Cc2cccnc2)c1C
Yield: 85.7 %

Procedure:
A solution of 15.5 g (98.1 mmol) of 3-bromopyridine in 200 ml of ethyl ether was cooled to -78° C., to which 61.3 ml (98.1 mmol) of n-butyllithium (1.6M hexane solution) was added dropwise. For 20 minutes after completion of the addition, the mixture was stirred at the same temperature, and then a solution of 26.8 g (98.1 mmol) of 2,5-dimethoxy-3,4,6-trimethylbenzyl bromide in 100 ml of ethyl ether was added dropwise. After stirring at -78° C. to room temperature for 1 hour, the reaction mixture was diluted with water and extracted with ethyl acetate. Then the extract was extracted reversely with 2N-hydrochloric acid, and the water layer was made weakly alkaline with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate), to give 22.8 g (85.8%) of 3-(2,5-dimethoxy- 3,4,6-trimethylbenzyl)pyridine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]1[N:34]=[C:33](B(O)O)[CH:32]=[CH:31][CH:30]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([CH3:28])[N:34]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: Cc1cccc(B(O)O)n1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: Cc1cccc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)n1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 6-methylpyridine-2-boronic acid following a procedure analogous to that described in Example 75 Step 1. LC-MS Method 2 tR=0.868 min, m/z=449.2; 1H NMR (CD3OD) 1.28 (m, 1H), 1.56 (d, 3H), 1.61 (m, 1H), 1.95 (m, 2H), 2.23 (m, 1H), 2.34 (m, 1H), 2.46 (m, 1H), 2.55 (s, 3H), 3.11 (m, 1H), 3.46 (m, 2H), 5.50 (m, 1H), 7.06 (m, 4H), 7.19 (d, 1H), 7.31 (m, 2H), 7.51 (d, 1H), 7.73 (m, 3H).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure BB and using phenylacetyl chloride (Aldrich) and L-alanine iso-Butyl Ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 45°-47° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>N1C=CC=CC=1>[CH3:33][N:34]([CH3:38])[C:35](=[O:36])[O:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:18](=[O:19])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)=[C:9]([CH:30]([CH3:32])[CH3:31])[N:8]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC(=O)N(C)C)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.2 %

Procedure:
General Procedure B. To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 18mg, 0.041mol) in pyridine (1 ml) was added dimethylcarbamyl chloride (40 μl, 0.41 mmol) and stirred at room temperature overnight. The reaction was quenched with water, extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a white solid (17 mg, 82%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12](C(OC(C)(C)C)=O)[CH:13]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:29]1[CH:30]=[CH:31][C:32]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)=[C:33]([CH:43]=1)[C:34]([NH:36][C:37]1[CH:42]=[CH:41][N:40]=[N:39][CH:38]=1)=[O:35]>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>[F:52][C:49]1[CH:48]=[CH:47][C:46]([CH2:45][O:44][C:32]2[CH:31]=[CH:30][C:29]([C:9]3[CH:13]=[N:12][NH:11][CH:10]=3)=[CH:43][C:33]=2[C:34]([NH:36][C:37]2[CH:42]=[CH:41][N:40]=[N:39][CH:38]=2)=[O:35])=[CH:51][CH:50]=1
Reactant: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
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
Product: O=C(Nc1ccnnc1)c1cc(-c2cn[nH]c2)ccc1OCc1ccc(F)cc1
Temperature: 120 °C

Procedure:
1,1-Dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (110 mg, 0.37 mmol), sodium carbonate (0.75 ml, 0.75 mmol) and tetrakis(triphenylphosphine)palladium(0) (25.9 mg, 0.02 mmol) were added to a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}-N-4-pyridazinylbenzamide (may be prepared as described in Example 77; 150 mg, 0.37 mmol) in 1,2-dimethoxyethane (5 ml). The reaction was heated at 120° C. for one hour. The solvent was removed in vacuo, triturated with 1:1 DMSO/methanol and washed with methanol (1 ml) and ethyl acetate (2 ml) to give a white solid. Recrystallisation with hot 1:1 DMSO/ethyl acetate yielded the title compound as a white solid. 48.6 mg.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:20]([O-])=O)[C:10]([F:19])=[C:11]([F:18])[C:12]=3[O:14][CH:15]([CH3:17])[CH3:16])[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.O>CC(O)=O.[Fe]>[NH2:20][C:9]1[C:10]([F:19])=[C:11]([F:18])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[C:13]2[C:8]=1[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(C)C)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(C)C)c(F)c(F)c(N)c2c1=O
Temperature: 90 °C
Reaction time: 5 h
Yield: 68.7 %

Procedure:
A suspension of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-isopropoxy-5-nitro-4-oxoquinoline-3-carboxylate (222 mg, 0.560 mmol) and iron powder (188 mg, 3.36 mmol) in AcOH (6 mL) was stirred at 90° C. for 5 h. After water was added, the reaction mixture was stirred for 30 min. The crude product was extracted with EtOAc, washed with saturated aq. NaHCO3 and brine, dried over MgSO4 and the solvent was removed in vacuo. The crude product was purified by column chromatography (Hexane:EtOAc 5:1→1:1) to yield ethyl 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-isopropoxy-4-oxoquinoline-3-carboxylate (141 mg, 69%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31]CC1C=CC(OC)=CC=1)[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:15]=[C:10]2[N:9]=[C:8]1[NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[OH:31][C:30]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)[CH:15]=[C:10]3[N:9]=[C:8]2[NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCOC(=O)Nc1nc2cc(-c3cnn(C)c3)cnc2n1Cc1ccc(OCc2ccc(OC)cc2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2cc(-c3cnn(C)c3)cnc2n1Cc1ccc(O)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a stirred solution of ethyl (3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (2.50 g, 4.61 mmol) in dichloromethane (100 mL) at 0° C. was added trifluoroacetic acid (4.47 g, 3.0 mL, 39.18 mmol). The resulting mixture was allowed to stir at 0° C. After 2 h, the mixture was treated with 2M potassium carbonate solution to adjust the pH to ˜9. The basic mixture was extracted with 1:1 methanol/dichloromethane solution (2×50 mL). The combined organic phases were washed with brine (2×50 mL), dried over sodium sulfate, filtered, and concentrated to provide 1.80 g (93%) of ethyl (3-(4-hydroxy-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a white solid.
Reaction SMILES: [F:1][C:2]1[C:26]([F:27])=[C:25]([F:28])[C:24]([F:29])=[C:23]([F:30])[C:3]=1[CH2:4][O:5][NH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@:8]1([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:13](=[S:16])[NH:14][CH3:15]>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[C:26]([F:27])=[C:25]([F:28])[C:24]([F:29])=[C:23]([F:30])[C:3]=1[CH2:4][O:5][NH:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@:8]1([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:13](=[S:16])[NH:14][CH3:15]
Reactant: CNC(=S)[C@]1(c2cccnc2)CCCCC1NOCc1c(F)c(F)c(F)c(F)c1F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNC(=S)[C@]1(c2cccnc2)CCCC[C@H]1NOCc1c(F)c(F)c(F)c(F)c1F

Procedure:
Prepared from (-)-(S)-2-(2,3,4,5, 6-pentafluorobenzyloxyamino)-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide (0.49 g) as described in Example 1. The crude product was subjected to flash chromatography on silica gel eluting with chloroform/methanol: 98.5/1.5 to give (1S,2R)-2-(2,3,4,5,6-pentafluoro-benzyloxyamino)-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, a yellow solid (0.34 g, 69%), m.p. 57°-60°. Found: C, 53.7; H, 4.37; N, 9.5%; C20H20F5N3OS requires C, 53.9; H, 4.53; N, 9.43%.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([OH:13])[CH:3]=1.[CH3:14][S:15]([C:18]1[CH:23]=[CH:22][C:21](F)=[C:20]([Cl:25])[CH:19]=1)(=[O:17])=[O:16]>>[Cl:25][C:20]1[CH:19]=[C:18]([S:15]([CH3:14])(=[O:17])=[O:16])[CH:23]=[CH:22][C:21]=1[O:13][C:4]1[CH:3]=[C:2]([F:1])[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)COc1ccc(F)cc1O
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Product: CS(=O)(=O)c1ccc(Oc2cc(F)ccc2OCC(=O)O)c(Cl)c1

Procedure:
The title compound was prepared by the method of example 1 step (ii) using the product from step (ii) and the product from example 7 step (ii).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3=[CH:17][S:18][C:19]([C:20]([OH:22])=O)=[C:15]3[N:14]=[C:13]2[C:23](=[O:34])[NH:24][CH:25]2[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]2)=[O:10])=[N:6][CH:7]=1.[CH2:35]1[CH2:41][O:40][CH2:39][CH2:38][NH:37][CH2:36]1.Cl>>[CH:31]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:23]([C:13]2[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[C:16]3[C:15](=[C:19]([C:20]([N:37]4[CH2:36][CH2:35][CH2:41][O:40][CH2:39][CH2:38]4)=[O:22])[S:18][CH:17]=3)[N:14]=2)=[O:34])[CH2:26][CH2:27]1)([CH3:32])[CH3:33]
Reactant: C1CNCCOC1
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)scc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Agent: Cl
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)N4CCCOCC4)scc3n2CC(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
3-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-6-([1,4]oxazepane-4-carbonyl)-3H-thieno[3,4-d]imidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 80 mg (0.158 mmol) 3-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid and 21.8 mg (0.158 mmol) homomorpholine-hydrochloride. The title compound was obtained as its formiate in form of a white amorphous solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][OH:8].[C:9]([O:13][C:14](=[O:24])[NH:15][C:16]([C:22]#[N:23])([CH3:21])[CH2:17][CH:18]1[CH2:20][CH2:19]1)([CH3:12])([CH3:11])[CH3:10]>O.C(O)C>[C:9]([O:13][C:14](=[O:24])[NH:15][C:16]([C:22](=[NH:23])[NH:7][OH:8])([CH3:21])[CH2:17][CH:18]1[CH2:19][CH2:20]1)([CH3:10])([CH3:12])[CH3:11]
Reactant: CC(C#N)(CC1CC1)NC(=O)OC(C)(C)C
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C)(CC1CC1)C(=N)NO
Temperature: 80 °C
Yield: 65 %

Procedure:
Sodium bicarbonate (247.52 mg, 2.94 mmol) was dissolved in water (2 mL) and hydroxylamine hydrochloride (204.747 mg, 2.94 mmol) was added. A solution of (1-cyano-2-cyclopropyl-1-methyl-ethyl)-carbamic acid tert-butyl ester (600 mg, 2.69 mmol) in ethanol (10 mL) was added thereto and the resulting reaction mixture was heated at 80° C. for 12 hours. After evaporation of solvents, the residue was dissolved with ethyl acetate (20 mL) and then filtered. The filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, 25 g, 3:7 ethyl acetate/n-hexane) to give the title compound (450 mg, 66%) as white solid; LC-MS (UV peak area, ESI) 100%, 258.4 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH:9]([CH:14]=[O:15])[CH2:8][CH2:7]2)=[O:5])[CH3:2].CC(C)=[O:18].OS(O)(=O)=O.O=[Cr](=O)=O>>[CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH:9]([C:14]([OH:18])=[O:15])[CH2:8][CH2:7]2)=[O:5])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)C12CCC(C=O)C(CC1)C2
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C12CCC(C1)C(C(=O)O)CC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To an ice-cold solution of 4-formyl-bicyclo[3.2.1]octane-1-carboxylic acid ethyl ester (3.85 mmol, 0.81 g) was added slowly Jones reagent (2.7 M, 1.43 mL). The reaction was stirred at ice temperature 20 min, then quenched by addition of iPrOH. diluted with H2O and extracted with Et2O (3×). The combined organic extracts were washed with H2O (2×), brine (1×), and dried (MgSO4). Filtration and evaporation provided the viscous oily bicyclo[3.2.1]octane-1,4-dicarboxylic acid 1-ethyl ester (0.76 g, 87%) as a mixture of axial and equatorial acids. 13C NMR (100 MHz, CDCl3): 14.16 (q), 19.86 (t), 21.07 (t), 25.98 (t), 29.20 (t), 31.52 (t), 31.87 (t), 32.27 (t), 33.39 (t), 37.80 (d), 38.07 (t), 38.10 (d), 42.06 (t), 44.80 (d), 45.78 (d), 49.38 (s), 49.60 (s), 60.31 (t), 60.36 (t), 177.08 (s), 180.01 (s).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:47])[CH2:30][CH2:31][N:32]([C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1)[C:33]([C:35]1[O:36][CH:37]=[CH:38][CH:39]=1)=[O:34]>>[CH3:28][N:29]([CH3:47])[CH2:30][CH2:31][N:32]([C:40]1[CH:41]=[CH:42][C:43]([NH:44]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:45][CH:46]=1)[C:33]([C:35]1[O:36][CH:37]=[CH:38][CH:39]=1)=[O:34]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(C)CCN(C(=O)c1ccco1)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)C(=O)c2ccco2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2-dimethylamino-ethyl)-N-(furan-2-carbonyl)-amino)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C32H30N4O5
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:9](=[O:11])[CH3:10])=[N:7][CH:8]=1.[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:12][CH2:10][C:9]([C:6]1[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=1)=[O:11]
Reactant: [Br-]
Reactant: COc1cnc(C(C)=O)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cnc(C(=O)CBr)cn1
Temperature: 25 °C
Yield: 9.1 %

Procedure:
To a chloroform (7.0 mL) solution of 1-(5-methoxypyrazin-2-yl)ethanone (0.35 g), tetrabutylammonium tribromide (1.2 g) was added, and the resultant was heated to reflux for 1 hour. After standing to cool to room temperature, the reaction solution was diluted with chloroform, and a 10% aqueous sodium thiosulfate solution was added to the dilution, followed by extraction with chloroform. An organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=95/5→80/20) to obtain the title compound (26 mg) as a white solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([S:7]([NH:10]O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.CO.[CH2:14](Br)[C:15]#[CH:16].C[O-].[Na+]>CCOCC>[CH2:16]([NH:10][S:7]([C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)(=[O:9])=[O:8])[C:15]#[CH:14]
Reactant: C#CCBr
Reactant: O=S(=O)(NO)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: C#CCNS(=O)(=O)c1ccccc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To 8.6 g. piloty acid dissolved in 50 ml. methanol, propargyl bromine (6.6 g.) was added. 10.8 g. sodium methoxide (25%) was added slowly dropwise. An exothermic reaction resulted, the temperature was maintained at 30° C. The reaction mixture was stirred for approximately 1 hour at room temperature. The solvent was removed in vacuo. There was obtained a yellow solid. This material was treated with ether and the solid filtered off and dried. There was obtained 3.1 g. of the title compound, a low melting solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH:13]([C:16]([CH3:18])=O)([CH3:15])[CH3:14]>>[CH3:18][C:16]1[C:13]([CH3:15])([CH3:14])[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: Nc1ccccc1
Reactant: CC(=O)C(C)C
Agent: O=S(=O)(O)O
Product: CC1=Nc2ccccc2C1(C)C
Yield: 90 %

Procedure:
This diazonium salt solution was reacted, likewise continuously, with 2.55 mol of sodium sulphite/sodium bisulphite mixture per mole of aniline to form a phenylhydrazodisulphonate solution. A portion of this mixture, corresponding to 1.91 mol of aniline, was added dropwise at 80° C. to 200 ml of a 48% strength sulphuric acid (1.35 mol). After a reaction time of 2 h at 80° C., 225 ml (2.1 mol) of methyl isopropyl ketone were metered in in the course of 30 min. After a reaction time of 3 hours at 95° to 100° C., the mixture was cooled. The batch was neutralised and the organic phase was separated off and distilled. 273.8 g of 98.2% pure 2,3,3-trimethylindolenine were obtained. Yield: 88.4% of the theoretical yield, based on aniline.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.Br[CH:11]([CH3:15])[C:12](=O)[CH3:13]>O1CCCC1>[Br:9][C:5]1[CH:6]=[C:7]([Br:8])[C:2]2[N:3]([C:11]([CH3:15])=[C:12]([CH3:13])[N:1]=2)[CH:4]=1
Reactant: CC(=O)C(C)Br
Reactant: Nc1ncc(Br)cc1Br
Solvent: C1CCOC1
Product: Cc1nc2c(Br)cc(Br)cn2c1C

Procedure:
A mixture of 31.8 g of 2-amino-3,5-dibromopyridine, 22 g of 3-bromo-2-butanone and 350 ml of tetrahydrofuran is heated at reflux for 9 days, and the precipitate formed is filtered off and dried in vacuo. It is then suspended in 1 l of water and adjusted to pH 8 using 6 molar aqueous sodium hydroxide solution. The precipitate formed here is filtered off and washed with water. 28 g of the title compound of melting point over 90° C. (sintering) are obtained.