Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH:26]([NH:29]N)([CH3:28])[CH3:27].CCN(CC)CC>C(O)C.Cl>[CH3:27][CH:26]([N:29]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1)[CH3:28]
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: CC(C)NN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)n1nccc1-c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 61.8 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (500 mg, 1.5 mmol) in ethanol (10 mL) were added isopropylhydrazine hydrochloride (246 mg, 2.2 mmol) and Et3N (0.41 mL, 3.0 mmol). The mixture was stirred at 100° C. for 5 h. The mixture was diluted with 1N HCl aqueous solution, extracted with AcOEt, washed with brine, dried over Na2SO4, concentrated in vacuo, purified by column chromatography on silica gel (hexane/AcOEt=10/90 to 0/100) and recrystallized with AcOEt/i-Pr2O to yield the title compound as a pale yellow solid (323 mg, 63%).
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:4]=1)=O.[C:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])#[N:25].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1>[NH2:23][S:20]([C:17]1[CH:16]=[CH:15][C:14]([N:5]2[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:7][C:3]([CH:1]=[C:26]([C:24]#[N:25])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:4]2)=[CH:19][CH:18]=1)(=[O:21])=[O:22]
Reactant: NS(=O)(=O)c1ccc(-n2nc(C=O)cc2-c2ccccc2)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=Cc1cc(-c2ccccc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Yield: 65.8 %

Procedure:
To a solution of the aldehyde from Step 1 (1.2 g, 3.6 mmol) in benzene (18 mL) was added ethyl cyanoacetate (0.38 mL, 3.6 mmol), ammonium acetate (50 mg, 0.7 mmol) and glacial acetic acid (0.17 mL, 2.8 mmol). The solution was heated at reflux for 18 hours, cooled, and partitioned between water and ethyl acetate. The organic solution was washed with a saturated aqueous sodium bicarbonate solution, water and brine. The organic solution was dried and concentrated. The residue was chromatographed on silica (40% hexane in ethyl acetate) to give the desired product (1.0 g, 66%): Anal. calc'd for C21H18N4O4S: C, 59.82; H, 4.30; N, 13.22. Found: C, 59.70; H, 4.29; N, 13.26.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[N:12]([CH2:37][O:38][C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: ClCOc1ccc(Cl)cc1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CN3CCOCC3)cc2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cn(COc2ccc(Cl)cc2)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 100 °C
Yield: 71 %

Procedure:
A suspension of N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (0.21 gm) from Preparation No. 40 and cesium carbonate (0.33 gm) in DMF (2 mL) is treated with α,4-dichloroanisole (0.13 gm). The mixture is tightly capped and heated to 100° C. for 3 hrs. The reaction mixture is allowed to cool to room temperature, diluted with dichloromethane (50 mL) and washed with water. The aqueous phase is extracted with two additional portions of dichloromethane. The combined organic phase is washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 1% to 4% methanol in dichloromethane and then by recrystallization with acetonitrile to afford 0.20 gm of the title compound as a white solid.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[S:20]1[C:24]([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)=[CH:23][N:22]=[CH:21]1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:24]3[S:20][CH:21]=[N:22][CH:23]=3)[CH:26]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2cncs2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2cncs2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 3-(thiazol-5-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.78 min.; [M+H]+: 409.08 g/mol.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:31](O)[CH2:32][CH2:33][OH:34].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:8]2([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[O:34][CH2:33][CH2:32][CH2:31][O:9]2)[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: OCCCO
Reactant: COc1ccc(C(=O)c2cccc(C)n2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C2(c3cccc(C)n3)OCCCO2)cc1OC
Reaction time: 17 h

Procedure:
About 77.1 g. of (3,4-dimethoxyphenyl) (6-methyl-2-pyridyl) ketone, 74.1 g. of p-toluenesulfonic acid and 22.8 ml of 1,3-propanediol in 600 ml of toluene were heated under reflux with stirring for 17 hours. The water evolved during the reaction was neutralized with 500 ml of saturated sodium bicarbonate. Two phases formed and the phases were separated. The organic layer was washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. Removal of the desiccant and solvent gave a solid residue which, on recrystallization from a mixture of acetone and petroleum ether (b.p. 60°-80°C.), yielded 2-(3,4-dimethoxyphenyl)-2-(6-methyl-2-pyridyl)-1,3-dioxane, m.p. 124°-126°C.
Reaction SMILES: [C:1]1([CH3:50])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH2:11][CH2:12][N:13]([S:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)(=[O:42])=[O:41])[CH2:14][CH2:15][N:16]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:17][CH2:18][NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:53][N:54]([CH2:58][CH2:59]Cl)[CH2:55][CH2:56]Cl>CN(C=O)C>[CH3:53][N:54]1[CH2:58][CH2:59][N:19]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:18][CH2:17][N:16]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:31])=[O:32])[CH2:15][CH2:14][N:13]([S:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)(=[O:41])=[O:42])[CH2:12][CH2:11][N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:50])=[CH:2][CH:3]=2)(=[O:8])=[O:9])[CH2:56][CH2:55]1
Reactant: Cc1ccc(S(=O)(=O)NCCN(CCN(CCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CN(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCN(C)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a stirred solution of 1,4,7,10-tetra(p-toluenesulfonyl)-1,4,7,10-tetraazadecane prepared as in Example 15B (66.5 g, 0.0872 mole) in anhydrous DMF (1 l) was added sodium hydride (5.22 g--80% in mineral oil, 0.174 mole) in portions under a dry nitrogen blanket. The resulting mixture was stirred for 30 minutes under a dry argon atmosphere. The solution was then heated to 100° C. and a solution of N-methylbis(2-chloroethyl)amine freshly prepared as in Example 15A (13.6 g, 0.0872 mole) in anhydrous DMF (200 ml) was added dropwise over a 1.5 h period, maintaining the temperature at 100° C. After stirring an additional 45 minutes at 100° C., the solution was concentrated in vacuo to a volume of 750 ml. H2O was slowly added at room temperature to crystallize the product. The resulting brown solid was filtered, washed thoroughly with H2O and dried in vacuo over P2O5 to give 62.9 g (85% yield) of the crude product as a brown solid. The product was purified by crystallization from DMF-H2O to give a yellow solid: mp 170°-1° C.; 1H NMR (CDCl3) δ2.15 (s, 3 H), 2.43 (s, 6 H), 2.44 (s, 6 H), 2.51 (t, J=5.5 Hz, 4 H), 3.15 (t, J=5.5 Hz, 4 H), 3.29 (m, S H), 3.36 (s, 4 H), 7.32 (m, 8 H), 7.69 (m, 8 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[CH3:27])[NH2:23].C(O)(C)C>CN(C=O)C>[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[CH3:27])[NH:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: Cc1ccc(N)cc1O
Reactant: COCCOc1cc2nncc(Cl)c2cc1OC
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: COCCOc1cc2nncc(Nc3ccc(C)c(O)c3)c2cc1OC

Procedure:
A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (0.4 g, 1.5 mmol) and 3-hydroxy-4-methylaniline (0.2 g, 1.6 mmol) in DMF (5 ml) was heated at 150° C. for 20 minutes. After cooling, isopropanol (15 ml) was added and the resulting solid filtered off, washed with isopropanol and dried under vacuum to give 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline as the hydrochloride salt (yellow solid, 537 mg 91%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]#[CH:26])[CH2:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N)CCC>[C:11]1([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]#[C:26][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[NH:7][CH:6]=[CH:5]4)[CH2:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C#CCCN1CC=C(c2ccccc2)CC1
Solvent: CCCCN
Product: C(#Cc1ccc2[nH]ccc2c1)CCN1CC=C(c2ccccc2)CC1

Procedure:
A solution of 5-bromoindole (0.5 g, 0.0025 mol) and the acetylene prepared in Example 9, Step (a) in 15 mL of N-butylamine is degassed by bubbling in dry nitrogen for 15 minutes, and 0.06 g, (5.0×10-5 mol) of tetrakis (triphenylphosphine)palladium(0) is added. The flask is flushed with nitrogen and the mixture is headed at reflux for 18 hours. The solvent is removed under reduced pressure, and the residue is partitioned between 50 mL of dichloromethane and 50 mL of saturated aqueous sodium bicarbonate. The aqueous layer is extracted with 25 mL of dichloromethane and the combined organic layers are washed with 25 mL of water and dried (sodium sulfate), and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 1% methanol/99% dichloromethane) to give the title compound containing 0.3 mol of water; mp 173°-174° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH2:25][CH:24]([CH2:26][O:27][C:28]3[CH:32]=[CH:31][O:30][N:29]=3)[O:23][N:22]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:20])[CH2:15][O:16]C(=O)C)[CH2:10][CH2:9]1.N>CO.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH2:25][CH:24]([CH2:26][O:27][C:28]3[CH:32]=[CH:31][O:30][N:29]=3)[O:23][N:22]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:20])[CH2:15][OH:16])[CH2:10][CH2:9]1
Reactant: CC(=O)OCC(=O)N1CCN(c2ccc(C3=NOC(COc4ccon4)C3)cc2F)CC1
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CO)N1CCN(c2ccc(C3=NOC(COc4ccon4)C3)cc2F)CC1
Temperature: 25 °C
Reaction time: 40 h
Yield: 90.7 %

Procedure:
(5RS)-3-(3-Fluoro-4(4-(2-acetoxyacetyl)piperazin-1-yl)phenyl)-5-isoxazol-3-yloxymethyl-4,5-dihydroisoxazole (112 mg, 0.25 mM) was suspended in a saturated solution of ammonia in methanol (8 ml), diluted with tetrahydrofuran (5 ml). The mixture was stirred at ambient temperature for 40 hours. The residue after evaporation was chromatographed on a 5 g silica Mega Bond Elut® column, eluting with a gradient from 0–5% methanol in dichloromethane. Relevant fractions were combined to give the desired product (92 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][C:13](=O)[CH3:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)=O.C([NH2:21])=O.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][CH:13]([NH2:21])[CH3:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: CC(=O)CC1(c2ccc(Cl)cc2)CCC1
Agent: Cl
Solvent: O
Solvent: O=CO
Product: CC(N)CC1(c2ccc(Cl)cc2)CCC1
Temperature: 180 °C

Procedure:
A mixture of 1-[1-(4-chlorophenyl)cyclobutyl]propan-2-one prepared as described in Example 3 (15 g) and 98% formic acid (4 ml) was added dropwise to formamide (12 ml) at 160° C. The temperature was raised to 180° C. and maintained at this temperature for ten hours. The mixture was cooled, diluted with water and extracted with dichloromethane. The extract was washed, dried and evaporated to yield a yellow oil which was hydrolysed with concentrated hydrochloric acid under reflux. The resulting aqueous solution after dilution with water was washed with ether, aqueous NaOH was added and the aqueous solution extracted with ether. The extracts were washed, dried and evaporated to yield a residue which on distillation gave 2-[1-(4-chlorophenyl)cyclobutyl]-1-methylethylamine (b.p. 105°-107°/0.7 mm Hg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[CH:18]=O)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1.N1CCCC1>CO>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1/[CH:18]=[C:26]1\[C:27](=[O:31])[NH:28][C:29]2[C:25]\1=[CH:24][CH:23]=[C:22]([Cl:21])[CH:30]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(Cl)cc1C=O
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)NCCOc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Yield: 131.9 %

Procedure:
In a manner similar to the method described in Example 227b, [2-(4-chloro-2-formyl-phenoxy)-ethyl]-carbamic acid tert-butyl ester (8 g, 27 mmol) was reacted with 6-Chlorooxindole (4.5 g, 27 mmol) and pyrrolidine (2.1 g, 30 mmol) in methanol to give title compound as a yellow solid (16 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].Cl>ClCCl>[CH3:17][S:18]([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([NH:1][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:3][CH:4]=1)(=[O:20])=[O:19]
Reactant: Nc1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Reaction time: 2 h
Yield: 29.4 %

Procedure:
4-Aminophenethyl alcohol (2.74 g) was dissolved in dichloromethane (10 ml) and pyridine (5 ml) and then methanesulphonyl chloride (2×2.52 g) was added in 2 portions one hour apart, with stirring at 0°. After a further 2 hours, the mixture was acidified (to pH about 2) with 2N aqueous hydrochloric acid. The title compound (4.85 g) was filtered from the two-phase mixture. The organic layer plus a further dichloromethane extract of the aqueous layer yielded a further 0.95 g product after drying (sodium sulphate) and evaporation. The combined solids were washed with ether and recrystallized from ethyl acetate, yield of the title compound 4.13 g, m.p. 135°-7°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13]CC)=O)=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH:16]1([C:19]2[C:27]3[C:26]([NH2:28])=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)[N:20]=2)[CH2:18][CH2:17]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:28][C:26]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:27]=3[C:19]([CH:16]3[CH2:18][CH2:17]3)=[N:20][N:21]4[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)=[O:13])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c(N)cccc32)n1
Reactant: CCOC(=O)c1cnc2cc(Cl)ccn12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(Cl)ccn45)cccc32)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A mixture of ethyl 7-chloroimidazo[1,2-a]pyridine-3-carboxylate (10.0 g, 44.5 mmol) and 3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (12.4 g, 44.5 mmol) in THF (100 mL) was cooled to 0° C. using an ice/water bath. A solution of 1.0M lithium bis(trimethylsilyl)amide (102 mL, 102 mmol) was added slowly over 40 minutes keeping the internal temperature below 5° C. The mixture was stirred at 0° C. for 30 minutes, diluted with IPA (100 mL), and then concentrated under reduced pressure. The residue was diluted with IPA (100 mL) and concentrated under reduced pressure. The residue was dissolved in IPA (100 mL) and treated with a 10% aqueous ammonium chloride solution (200 mL) to give a slurry which was filtered and dried to give 7-chloro-N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide as a light brown solid (18.4 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C(O)(=O)C.S(=O)(=O)(O)O>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Yield: 103.9 %

Procedure:
A mixture of 94 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 600 ml of glacial acetic acid, 450 ml of water and 70 ml of concentrated sulphuric acid is heated to reflux for 1.5 hours. The hot suspension is then poured onto ice, and the precipitate is filtered off with suction, thoroughly washed with water, and dried in vacuo at 100° C. In this manner, 88.9 g of pure 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid II (X1 =X2 =F) of melting point 228°-230° C. (decomposition) are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH:8]([C:11]([O:13]CC)=O)[C:6](=[O:7])[N:5]([CH3:16])[C:3]1=[S:4].[CH3:17][C:18]1[C:19]([O:24][C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)=[N:20][CH:21]=[CH:22][N:23]=1>C(O)C>[CH3:16][N:5]1[C:6](=[O:7])[CH:8]([C:11](=[O:13])[NH:29][C:28]2[CH:27]=[CH:26][C:25]([O:24][C:19]3[C:18]([CH3:17])=[N:23][CH:22]=[CH:21][N:20]=3)=[CH:31][CH:30]=2)[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[S:4]
Reactant: CCOC(=O)C1C(=O)N(C)C(=S)N(C)C1=O
Reactant: Cc1nccnc1Oc1ccc(N)cc1
Solvent: CCO
Product: Cc1nccnc1Oc1ccc(NC(=O)C2C(=O)N(C)C(=S)N(C)C2=O)cc1
Reaction time: 20 h

Procedure:
2.5 g (10 mmol) of 1,3-dimethyl-5-ethoxycarbonyl-2-thiobarbituric acid, 2.0 g (10 mmol) of 4-(3-methylpyrazin-2-yloxy)aniline and 30 ml of ethanol are mixed and, with stirring, are kept at 60° C. for 20 hours. The mixture is then allowed to cool and the crystalline precipitate formed is isolated by filtration, washed with ethanol and dried in vacuo at 80° C.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:14]/[C:15](/[CH2:19][CH2:20][CH:21]=[C:22](C)[CH3:23])=[CH:16]\CO.O(C)[Na]>C1CCCCC1.CCOCC>[O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6]/[CH:7]=[C:22](\[CH3:23])/[CH2:21][CH2:20][CH:19]=[C:15]([CH3:16])[CH3:14])=[O:4]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CCOC(=O)C(=O)c1ccccc1
Agent: CO[Na]
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CC(C)=CCC/C(C)=C/COC(=O)C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of ethyl 2-oxo-2-phenylacetate (17.6 g, 99 mmol), (E)-3,7-dimethyl-2,6-octadienol (18.5 g, 120 mmol) and NaOCH3 (30% in methanol, 1.5 ml) in cyclohexane (170 ml) was heated under reflux for 72 h. After cooling to room temperature the reaction mixture was taken up in ether, washed with water (pH≈7), dried (Na2SO4), filtered and concentrated. Column chromatography (SiO2, heptane/ether 8:2) afforded 14.5 g (52%) of a slightly yellow oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][C@@H:8]2[CH2:12][CH2:13][CH2:14][C@H:7]12)C.[NH3:16]>CO>[O:11]=[C:10]1[N:6]([CH2:5][C:4]([NH2:16])=[O:3])[C@H:7]2[CH2:14][CH2:13][CH2:12][C@H:8]2[CH2:9]1
Reactant: CCOC(=O)CN1C(=O)C[C@@H]2CCC[C@@H]21
Reactant: N
Solvent: CO
Product: NC(=O)CN1C(=O)C[C@@H]2CCC[C@@H]21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A example of this step is a solution of cis-hexahydro-2-oxo-cyclopenta[b]pyrrole-1(2H)-acetic acid ethyl ester (3.25 g, 0.0154 mole) in methanol (200 ml) is saturated with anhydrous ammonia and stirred at ambient temperature 24 hours. The solution is concentrated at reduced pressure to yield a solid. Recrystallization from acetonitrile yields pure cis-hexahydro-2-oxo-cyclopenta[b]pyrrole-1(2H)acetamide with a mp 142.5°-143.5° C. ##STR4##
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.C(N(CC)CC)C.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].Cl>O1CCCC1.CN(C)C1C=CN=CC=1>[O:7]([CH:5]1[CH2:6][C:2](=[O:1])[CH:3]=[CH:4]1)[Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: O=C1C=CC(O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A solution of 4-hydroxy-2-cyclopentenone (191 g, 1.95 mol, prepared in example 1) and triethylamine (430 mL, 3.09 mol) in anhydrous tetrahydrofuran (1 L) is treated with 4-dimethylaminopyridine (4.90 g, 40.0 mmol). The solution is cooled to 0° C. and treated portionwise, over 10 minutes, with tert-butyldimethylsilyl chloride (278 g, 1.84 mol) maintaining the temperature at or below 10° C. The reaction is then allowed to stir overnight at room temperature. It is then poured into aqueous HCl (0.5N, 1 L). The phases are separated and the aqueous phase is extracted with heptane (2×1 L). The organic phase and organic extracts are combined, washed with aqueous HCl (0.5N, 2×500 mL), then 5% sodium bicarbonate (500 mL), then brine (500 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum (40° C., 20 mmHg) to provide the title compound (325 g). This is purified by Kugelrohr distillation (70°-80° C., 1 mmHg) to provide the title compound (282 g, 72% yield) as a light yellow oil, Rf =0.55, 20% ethyl acetate/hexane, GC retention time is 14.97 minutes; 1H NMR (CDCl3) δ 7.48 (dd, J=5.7, 2.4 Hz, 1 H), 6.20 (d, J=5.7 Hz, 1 H), 4.95-4.99 (m, 1 H), 2.72 (dd, J=18.2, 6.0 Hz, 1 H), 2.25 (dd, J=18.2, 2.3 Hz, 1 H), 0.88 (s, 9 H), 0.11 (s, 6 H); 13 C NMR (CDCl3) δ 206.4, 163.8, 134.4, 70.8, 44.9, 25.7, 25.6, 18.0; IR (neat) νmax 2957, 2931, 2887, 2858, 1725 cm-1 ; MS (EI) m/e (% relative intensity) 212 (M+, 5), 155 (M+ -57, 100).