Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH3:15])[NH:8][CH2:7][CH2:6]2.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](O)=[O:27])([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]1[CH3:15])=[O:27])([O-:18])=[O:17]
Reactant: COc1cc2c(cc1OC)C(C)NCC2
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Product: COc1cc2c(cc1OC)C(C)N(C(=O)Cc1ccccc1[N+](=O)[O-])CC2
Yield: 72.1 %

Procedure:
Using the procedures described in Example 3 hereinabove, 9.4 g of 1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline is reacted with 8.0 g 2-nitrophenylacetic acid to give 11.8 g N-(2-nitrophenylacetyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline. This amide is reduced with borane in THF to produce 13.2 g of N-(2-nitrophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline hydrochloride. Reduction of the nitro function by catalytic hydrogenation over palladium provides, after recrystallization from ethanol/ether and drying under vacuum, 9.6 g N-(2-aminophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline dihydrochloride, m.p. 229°-230°.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[CH2:12])=[N:3]1.[N+](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N-]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]2[CH2:12][CH:15]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:3]1
Reactant: C=Cc1nn(C)c2ccccc12
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1c1nn(C)c2ccccc12

Procedure:
A solution of compound 2 (1.1 g, 7 mmol) in toluene (5 mL) was treated with ethyl diazoacetate (1.2 g, 10 mmol) and stirred at reflux overnight under N2. The mixture was concentrated and the residue was purified by gradient elution on silica gel (PE: EA=5:1) to afford the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Br:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[C:15]([NH2:20])=[CH:14][CH:13]=1>CCCCCC>[Br:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][CH:1]=[O:3])=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: COc1nc(Br)ccc1N
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Product: COc1nc(Br)ccc1NC=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To formic acid (12 mL) was added acetic anhydride (12 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min. 6-Bromo-2-methoxypyridin-3-amine (8.8 g) was gradually added to the reaction mixture at 0° C. over 10 min, and the mixture was stirred at 0° C. for 30 min. IPE (50 mL) and hexane (50 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The obtained solid was collected by filtration to give the title compound (8.1 g).
Reaction SMILES: [CH2:1]([N:4]([C:11]1[N:19]=[CH:18][N:17]=[C:16]2[C:12]=1[NH:13][CH:14]=[N:15]2)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[O:26]1[CH:28]([CH3:29])[CH2:27]1>CS(C)=O>[CH2:1]([N:4]([C:11]1[N:19]=[CH:18][N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][N:15]2[CH2:27][CH:28]([OH:26])[CH3:29])[CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCN(c1ncnc2nc[nH]c12)C1CCCCC1
Reactant: CC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCN(c1ncnc2c1ncn2CC(C)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 12.8 g. (50 mmole) 6-[N-allyl-N-cyclohexylamino)-purine (compound of Example 8 j) in 150 ml. dimethyl sulphoxide are added at 40° C. 7.6 g. potassium carbonate. The reaction mixture is stirred for 10 minutes, cooled to ambient temperature, 5.8 g. 1,2-epoxypropane are added dropwise thereto, the reaction mixture is stirred for 5 days at ambient temperature and evaporated and the residue chromatographed on silica gel (elution agent: dichloromethane/methanol 97:3 v/v). After trituration with diethyl ether, there are isolated 5.7 g. of the title compound )36% of theory); m.p. 108°-110° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([O:7][CH:8]([CH3:10])C)=[N:4][CH:3]=1.[C:11]1([CH3:29])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]2[N:19]([CH:26]=[CH:27][N:28]=2)[CH:20]=[C:21](B(O)O)[CH:22]=1>>[CH2:8]([O:7][C:5]1[S:6][C:2]([C:21]2[CH:22]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH3:29])[C:18]3[N:19]([CH:26]=[CH:27][N:28]=3)[CH:20]=2)=[CH:3][N:4]=1)[CH3:10]
Reactant: CC(C)Oc1ncc(Br)s1
Reactant: Cc1ccccc1-c1cc(B(O)O)cn2ccnc12
Product: CCOc1ncc(-c2cc(-c3ccccc3C)c3nccn3c2)s1

Procedure:
Example 190 was prepared using the procedure describe for Example 34, step 4 from 5-bromo-2-(isopropyloxy)thiazole and 8-o-tolylimidazo[1,2-a]pyridin-6-ylboronic acid. LCMS (Conditions C): Tr 2.63 min.; (M+H)+: 336.31
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH:10]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccccc3)CC2)c1
Reactant: Oc1ccc(Cl)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(Cl)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-chlorophenol and N-{3-[1-(5-hydroxy-5-phenylpentyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.72-6.72 (m, 13H), 5.12-5.04 (m, 1H), 3.66-3.52 (m, br, 2H), 3.01-2.83 (br, 2H), 2.68-2.62 (m, br, 2H), 2.62-2.48 (m, br, 4H), 2.04-1.82 (m, br, 6H), 1.62-1.40 (m, br, 2H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 519.1 (M+H)+.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[Cl:37][C:38]1[CH:39]=[C:40]([C:45](=O)[CH3:46])[CH:41]=[CH:42][C:43]=1[Cl:44].[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:45]([C:40]2[CH:41]=[CH:42][C:43]([Cl:44])=[C:38]([Cl:37])[CH:39]=2)[CH:46]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc(Cl)c(Cl)c4)ccc3c1)n2C1CCCCC1
Yield: 10 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(3,4-dichloro-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (12 mg, 10% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH3:18]>>[CH2:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH2:17][CH3:18]
Reactant: O=C1CCNCC1
Reactant: CCCOCCCCCCCl
Product: CCCOCCCCCCN1CCC(=O)CC1

Procedure:
1-(6-Propoxyhexyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-6-propoxyhexane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [CH2:1]([C@@:3]1([CH2:13][CH2:14][C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)O)[CH2:12][CH2:11][CH2:10][CH2:9][C:4]21OCC[O:5]2)[CH3:2].O>C(O)(=O)C>[C:17]1([C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:14][CH2:13][C@:3]2([CH2:1][CH3:2])[CH2:12][CH2:11][CH2:10][CH2:9][C:4]2=[O:5])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC[C@@]1(CCC(O)(c2ccccc2)c2ccccc2)CCCCC12OCCO2
Solvent: O
Solvent: CC(=O)O
Product: CC[C@@]1(CC=C(c2ccccc2)c2ccccc2)CCCCC1=O

Procedure:
A solution of (S)-6-ethyl-α,α-diphenyl-1,4-dioxaspiro[4.5]decane-6-propanol (175 g) in 1 L of acetic acid containing 50 mL of water was refluxed for 3.5 hours. Most of the acetic acid was removed on a rotary evaporator, and the oily residue was poured into 300 mL of water. It was extracted with ether (2×300 mL) and the extracts were combined. They were washed with 1M sodium hydroxide (2×150 mL, first wash neutral, second wash basic) and brine (300 mL). Concentration afforded 140 g of cloudy brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[C:11]1[C:12]2[N:13]([C:17](/[C:22](/[CH2:26][CH2:27][CH3:28])=[CH:23]\[CH2:24][CH3:25])=[C:18]([CH2:20][CH3:21])[N:19]=2)[CH:14]=[CH:15][N:16]=1>C(O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[C:11]1[C:12]2[N:13]([C:17]([CH:22]([CH2:23][CH2:24][CH3:25])[CH2:26][CH2:27][CH3:28])=[C:18]([CH2:20][CH3:21])[N:19]=2)[CH:14]=[CH:15][N:16]=1
Reactant: CC/C=C(/CCC)c1c(CC)nc2c(-c3c(C)cc(C)cc3OC)nccn12
Agent: [Pd]
Solvent: CCO
Product: CCCC(CCC)c1c(CC)nc2c(-c3c(C)cc(C)cc3OC)nccn12
Temperature: 45 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
2-[2-Ethyl-3-[(Z)-1-propyl-1-butenyl]imidazo[1,2-a]pyrazin-8-yl]-3,5-dimethylphenyl methyl ether (41 mg, 0.12 mmol) was dissolved in ethanol (1.5 mL), then 10% palladium-carbon (50% hydrous product; 120 mg) was added thereto, and the mixture was heated under stirring at 45° C. for 4 hours at a normal pressure under hydrogen atmosphere. The mixture was further stirred at room temperature for 15 hours. The reaction mixture was filtered and washed with ethyl acetate, and then the filtrates were combined and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1) to give the title compound (25 mg) as white crystals.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=3[Cl:17])[CH2:23][CH2:24]2)[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc(Cl)c2c(c1)CCN2
Reactant: CC[C@@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CC[C@@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials. mp 128-130° C.; 1H NMR (300 MHz, CDCl3): δ 6.93 (s, 1 H), 6.71 (s, 2 H), 4.34-4.24 (m, 2H), 4.11-3.99 (m, 1 H), 3.75 (s, 3 H), 3.08 (t, J=7.9 Hz, 2 H), 1.93-1.73 (m, 2 H), 1.06-0.99 (m, 1 H), 0.92 (t, J=7.3 Hz, 3 H), 0.79-0.72 (m, 1 H), 0.54-0.43 (m, 2 H), 0.34-0.24 (m, 1 H); HRMS (ESI) calcd for C19H22N3O2Cl2 (M+H)+: 394.1089; found m/z 394.1088.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[N:26]([CH2:29][CH3:30])=[C:27]=[O:28].O>C1COCC1>[Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:25]=[N:24][N:23]([C:27]([NH:26][CH2:29][CH3:30])=[O:28])[CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCN=C=O
Reactant: COc1ncc(Cl)c2c1c(-c1cn[nH]c1)nn2-c1c(F)cccc1F
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)n1cc(-c2nn(-c3c(F)cccc3F)c3c(Cl)cnc(OC)c23)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-chloro-1-(2,6-difluorophenyl)-4-methoxy-3-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (40 mg) obtained in Step A of Example 177 in THF (3 mL) was added isocyanatoethane (0.018 mL), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (45 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[N:13][C:12]([NH:15][NH2:16])=[C:11]([CH:17]2[CH2:19][CH2:18]2)[CH:10]=1.[N:20]#[C:21]Br>>[Cl:8][C:9]1[CH:10]=[C:11]([CH:17]2[CH2:19][CH2:18]2)[C:12]2[N:13]([C:21]([NH2:20])=[N:16][N:15]=2)[N:14]=1
Reactant: NNc1nnc(Cl)cc1C1CC1
Reactant: N#CBr
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc2c(C3CC3)cc(Cl)nn12
Temperature: 55 °C
Reaction time: 6 h

Procedure:
(6-Chloro-4-cyclopropylpyridazin-3-yl)hydrazine trifluoroacetic acid salt (W3.010; 400 mg) was converted and worked up analogously to W2.009. However, one further equivalent of cyanogen bromide was added and the mixture was additionally stirred at 55° C. for 6 h. 252 mg of the title compound were obtained.
Reaction SMILES: [C:1]([NH:20][C@H:21]([CH2:24][CH3:25])[CH:22]=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([Mg]Br)[CH3:27].O>CCOCC>[C:1]([NH:20][C@@H:21]([CH2:24][CH3:25])[CH:22]([OH:23])[CH2:26][CH3:27])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCC(O)[C@H](CC)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (R)-2-(trityl-amino)-butyraldehyde (1.5 g, 1 eq, 4.53 mmol) in Et2O (150 mL) under an argon atmosphere at −78° C., was added ethylmagnesium bromide (3 M in Et2O, 1.51 mL, 1 eq, 4.53 mmol) dropwise. The solution was stirred at −78° C. for 2 h, then allowed to warm to room temperature over 16 h. The mixture was recooled to 0° C., H2O (150 mL) added, and the organic phase separated. The aqueous phase was extracted with more Et2O (2×50 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane:ether (90:10) to afford the title compound as a light yellow oil. Yield: 1.19 g (73%). (65% de 3R,4S: 35% de 3S,4S). 1H-NMR (d6-DMSO, 250 MHz): δ 0.46+0.69 (t & m, 6H, J=7.34 Hz, —NHCH(CH2CH3)CH(CH2CH3)OH), 1.13-1.29 (m, 4H, —NHCH(CH2CH3)CH(CH2CH3)OH), 2.17 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 2.55 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.20-3.39 (m, 1H, —NHCH(CH2CH3)CHCH2CH3)OH), 4.29 & 4.39 (2×d, 1H, J=4.74 & 5.53 Hz, —NHCH(CH2CH3)CH(CH2CH3)OH), 7.15-7.52 (m, 15H, 3×Ph).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([CH3:22])=[C:12]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:23](I)[CH3:24]>CN(C)C=O.[H-].[Na+]>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([CH3:22])=[C:12]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH:13]=2)[N:8]([CH2:23][CH3:24])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCCC(=O)c1cc2c(=O)c(C(=O)OCC)c[nH]c2cc1C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(=O)c1cc2c(=O)c(C(=O)OCC)cn(CC)c2cc1C
Reaction time: 1 h

Procedure:
30 g of 6-butyryl-7-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester are dissolved in 1000 ml of dimethylformamide and, in the course of one hour, 4.8 g of a 50% strength sodium hydride dispersion in mineral oil are added in portions. Stirring is carried out for 1 hour at room temperature and then 31.2 g of ethyl iodide are added, and the mixture is then stirred at room temperature for 1 hour, concentrated under reduced pressure, cooled with ice-water and filtered with suction. The product obtained by filtering with suction is dissolved in ethyl acetate, washed with water, dried over sodium sulphate, concentrated and cooled in an ice bath. The precipitated crystallisate is filtered with suction and recrystallised from ethyl acetate. 1-Ethyl-6-butyryl-7-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester having a melting point of 145°-146° is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH2:14])[CH3:2].N1C=CC=CC=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>ClCCl>[CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)(=[O:30])=[O:29])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C=Cc1ccc(Cl)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C=Cc1ccc(Cl)cc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
To 3-(2-amino-4-chloro-phenyl)-acrylic acid ethyl ester (18.0g, 79.8 mmol) in dichloromethane (144 ml) was added pyridine (9.04 ml, 112 mmol) and p-toluenesulfonyl chloride (16.0g, 83.9 mmol). The reaction was stirred at room temperature for 18 hours and poured into 1N hydrochloric acid (150 ml). The layers were separated and the organic layer was dried over magnesium sulfate, filtered, and concentrated. The resulting solid was slurried in hexanes and filtered to afford 3-[4-chloro-2-(toluene-4-sulfonylamino)-phenyl]-acrylic acid ethyl ester (28.3g, 93%). mp=124-127° C. 1H NMR (300 MHz, CDCl3) d 1.35 (t, 3, J=7.2), 2.40 (s, 3), 4.27 (q, 2, J=7.2), 6.12 (dd, 1, J=15.9, 0.9), 7.20-7.39 (m, 4), 7.39 (d, 1, J=8.6), 7.48-7.53 (m, 2), 7.62 (d, 2, J=8.3). 13C NMR (75 MHz, CDCl3) d 15.50, 22.79, 62.24, 122.48, 127.98, 128.49, 129.34, 129.50, 131.05, 136.82, 137.00, 137.73, 138.93, 145.55, 167.59. IR 3214, 1694, 1631, 1318, 1167 cm−1. Analysis calculated for C18H18ClNO4S: C, 56.91; H, 4.78; N, 3.69. Found: C, 57.10; H, 5.08; N, 3.70.
Reaction SMILES: P(Br)(Br)([Br:3])=O.O[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][N:8]=1>CN(C=O)C>[Br:3][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][N:8]=1
Reactant: Cc1cnc(O)c([N+](=O)[O-])c1
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Product: Cc1cnc(Br)c([N+](=O)[O-])c1
Temperature: 5 °C
Yield: 85.8 %

Procedure:
POBr3 (222.8 g, 0.78 mol) was added in portions to 2-hydroxy-5-methyl-3-nitropyridine (100 g, 0.65 mol) in DMF (500 mL) with stirring at 0-10° C. then the reaction mixture was stirred at 80° C. under nitrogen for 12 h. Reaction mixture was cooled and poured into crushed ice (1 Kg), obtained solid was filtered, washed thoroughly with ice-cold water (2×500 mL), dried in a desiccator under high vacuum for one day to obtain 2-bromo-5-methyl-3-nitropyridine as yellow solid (121 g) in 86% yield. (M+H) Expected: 217. found 216.9.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:3]=[CH:2]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=1[S:33](Cl)(=[O:35])=[O:34]>O1CCCC1>[S:1]1[CH:5]=[C:4]([N:6]([S:33]([C:26]2[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:25]=2[F:24])(=[O:35])=[O:34])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)Nc1cscn1
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of tert-butyl 1,3-thiazol-4-ylcarbamate (Preparation 72, 28.94 g, 144.55 mmol) in anhydrous tetrahydrofuran (600 ml), cooled to −70° C., under nitrogen was added lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (1 M in tetrahydrofuran, 144.55 ml, 144.55 mmol) dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hour before cooling −70° C. 2,4,5-trifluro benzenesulfonyl chloride (40 g, 173.46 mmol) in tetrahydrofuran (80 ml) was added dropwise and then the reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. Organic layer was washed with water and saturated aqueous sodium chloride solution before concentrating in vacuo. The crude residue was purified by column chromatography eluting with ethyl acetate:hexane (gradient 1:19 to 3:17, by volume) to afford the title compound as white solid, 37 g, 64% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=2)[CH:9]=[C:10]([C:12](OC(C)C)=[O:13])[CH:11]=1.[CH2:28]([CH2:30][NH2:31])[OH:29].N12CCCN=C1CCCCC2>CO>[CH3:21][C:19]1[N:20]=[C:7]2[C:6]([NH:5][CH2:4][C:3]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:2]=3[CH3:1])=[CH:11][C:10]([C:12]([NH:31][CH2:30][CH2:28][OH:29])=[O:13])=[CH:9][N:8]2[C:18]=1[CH3:22]
Reactant: Cc1cccc(C)c1CNc1cc(C(=O)OC(C)C)cn2c(C)c(C)nc12
Reactant: NCCO
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccc(C)c1CNc1cc(C(=O)NCCO)cn2c(C)c(C)nc12
Temperature: 5 °C
Yield: 81.9 %

Procedure:
Isopropyl 8-[(2,6-dimethylbenzyl)amino]-2.3-dimethylimidazo[1,2-a]pyridine-6-carboxylate (obtained as described in WO2/20523) (5 g, 14 mmol), ethanolamine (2.0 g 33 mmol) and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) 1.5 g, 10 mmol) were dissolved in methanol (25 ml). The mixture was refluxed over night. The reaction mixture was cooled to 5° C. The solid product was filtered off and washed with methanol (15 ml). 4.2 g (84%) of the title compound was obtained as a white solid. The structure of the compound was confirmed with 1H-NMR spectrum.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:16]([F:19])([F:18])[F:17])[C:10]([O:13][CH2:14][CH3:15])=[N:11][CH:12]=1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>CCOCC>[CH2:14]([O:13][C:10]1[C:9]([C:16]([F:19])([F:18])[F:17])=[CH:8][C:7]([B:20]([OH:25])[OH:21])=[CH:12][N:11]=1)[CH3:15]
Reactant: CCOc1ncc(Br)cc1C(F)(F)F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOc1ncc(B(O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
Alternatively, n-butyl lithium (1.6 M solution in hexane, 0.9 mL, 1.43 mmol) was slowly added to a solution of 5-bromo-2-ethoxy-3-trifluoromethyl-pyridine (352 mg, 1.3 mmol) in 2.6 mL anhydrous Et2O at −78° C. under nitrogen. The mixture was kept at −78° C. for 1 hr, and then to this mixture was added triisopropyl borate (489 mg, 2.6 mmol). The mixture was allowed to warm to ambient temperature overnight. The reaction was quenched by water and the pH was adjusted to 5 by carefully addition of 1N aqueous HCl. Two layers were separated and the aqueous layer was extracted with ethyl acetate three times. The extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 2-ethoxy-3-trifluoromethylpyridine-5-boronic acid as a brown oil (240 mg, 67% yield). The product was used for the next step without purification.